Swen Malte John, Jeanne Duus Johansen, Thomas Rustemeyer, Peter PDF

Swen Malte John
Jeanne Duus Johansen

Thomas Rustemeyer
Peter Elsner
Howard I. Maibach
Editors
Kanerva’s
Occupational
Dermatology
Third Edition
Kanerva’s Occupational Dermatology
Swen Malte John
Thomas Rustemeyer
Peter Elsner • Howard I. Maibach
Editors
Kanerva’s Occupational
Dermatology
Third Edition
With 349 Figures and 447 Tables

Editors
Swen Malte John Jeanne Duus Johansen
Department of Dermatology National Allergy Research Centre
Environmental Medicine and Department of Dermatology and
Health Theory Allergy, Herlev-Gentofte University
University of Osnabrück Hospital, Hellerup
Osnabrück, Germany Hellerup, Denmark
Thomas Rustemeyer Peter Elsner

Department of Dermatology Department of Dermatology
and Allergology University Hospital Jena
VU University Medical Center Jena, Germany
Amsterdam, The Netherlands
Howard I. Maibach
Department of Dermatology
University of California
San Francisco, CA, USA
ISBN 978-3-319-68615-8 ISBN 978-3-319-68617-2 (eBook)

ISBN 978-3-319-68616-5 (print and electronic bundle)
https://doi.org/10.1007/978-3-319-68617-2
1st and 2nd edition: © Springer-Verlag Berlin Heidelberg 2000, 2012
3rd edition: © Springer Nature Switzerland AG 2020
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Preface to the Third Edition
The knowledge on the huge spectrum of occupational skin diseases and their
causation has greatly increased since the second edition; much of this knowl-
edge, including major aspects of prevention, has now become progressively
more evidence-based. Therefore, the book had to be significantly expanded.
For this reason also, the number of contributing multidisciplinary experts in
the field has been increased and the editors appreciate their valuable contribu-
tions. Accordingly, the book intends to be the up-to-date global encyclopedia
of occupational dermatology, providing its interdisciplinary readers all avail-
able practical, as well as way-leading scientific background information, in the
field.
Of course, comments from our readers are invited and welcome; the new
format of the book as a Springer Major Reference Work (MRW) will even
make it possible for our authors to include evolving knowledge and take
readers’ comments into account.
The publication of the third edition coincides with several favorable devel-
opments on the global political stage, relevant to work-related skin diseases.
Within the context of the UN Sustainable Development Goals (SDG) 2030, the
World Health Organization (WHO) and the International Labour Organization
(ILO), in March 2019, have signed an agreement, for the first time ever, to
focus on the effects of work on health, which these UN institutions have
identified as neglected domains. Dermatoses, being the most prevalent work-
related diseases in many countries, have inevitably come into the focus of this
new effort (1). On top of that, with the WHO International Statistical Classi-
fication of Diseases and Related Health Problems ICD 11, adopted by the
World Health Assembly (WHA) on 25 May 2019 it is now possible through
extension codes to explicitly code for occupational causation of skin diseases,
ranging from contact dermatitis to keratinocytic skin cancers. Also, a wide
range of allergens is now available, and the localization of dermatoses can be
precisely depicted; in fact, the spectrum of options for coding dermatoses has
never been so extensive. As a result, the options to reveal the true magnitude of
the prevalence of work-related skin diseases in all 194 WHO Member States
have been remarkably improved.
Now, with the UN institutions making new inroads in this area, it is now our
responsibility, e.g., as dermatologists, occupational physicians, industrial
hygienists, chemists, and health educationalists, to provide a substantial
v
vi Preface to the Third Edition
contribution to fight negligence regarding occupational dermatoses. In most

countries, the greatest challenge is still the lack of prevalence data due to
substantial underreporting of cases. The editors are convinced that this book
can help improve awareness as well as catalyze sustainable efforts for preven-
tion and skillful patient management on a global scale.
October 2019 Swen Malte John

Thomas Rustemeyer
Peter Elsner
Howard I. Maibach
The Editors
References
Paulo MS et al (2019) WHO/ILO work-related burden of disease and injury:

protocol for systematic reviews of occupational exposure to solar ultravi-
olet radiation and of the effect of occupational exposure to solar ultraviolet
radiation on melanoma and non-melanoma skin cancer’. Environ Int.
https://doi.org/10.1016/j.envint.2018.09.039
Preface to the Second Edition
The knowledge of occupational Dermatology has expanded – vibrantly – in

the decade since the first edition.
The field is far more multidisciplinary – including numerous industrial
hygienists, occupational physicians, dermatologists, allergologists, chemists
of many types, modellers, and many other health care professionals including
nurse practitioners and physician assistants. Prevention more and more may
become a stronghold for dermatology: by their specific knowledge and com-
petence – in cooperation with other disciplines – dermatologists can save their
patients’ health and jobs, and thus also save expenses for tax-payers and
insurance systems. Undoubtedly however, awareness to occupational skin
diseases, their pathogenesis, and prevention by those at risk has, as yet, to be
improved in all countries. Furthermore, preventive intervention needs to be
accompanied by global regulatory efforts to limit exposure to hazardous sub-
stances, including evidence-based standards for adequate manufacturing and
use of gloves, protective creams, and after-work skin care.
Although we look forward to the science and techniques of delivery of
health care and prevention to the day when occupational dermatology is no
longer necessary, we have much work to do before this can be seriously
envisioned. Nevertheless the increased support and work in the last decade
should lead all to be optimistic that this will occur – within the century.
The field is far more evidence-based than before – perhaps leading the
dermatologic sciences in the rapid progress in this technique and philosophy.
We hope this textbook will provide you with all practical as well as back-
ground information needed. It may become a resilient support in your daily
care for patients.
We are saddened by the loss of Professor Jan Wahlberg and the illness of
Professor Lasse Kanerva. Both played a major role in the First Edition and the
development of the field Sui Generis. Fortunately their work, their colleagues
and students have continued many of their intellectual and practical
endeavours.
The current editors (from the First Edition – Peter Elsner and Howard
Maibach) and the new arrivals (Thomas Rustemeyer and Swen Malte John)
welcome your criticisms and suggestions.
For the legal implications of occupational skin diseases in the various
countries and social insurance systems please refer to: International legal
vii
viii Preface to the Second Edition
aspects of workers’ compensation for occupational contact dermatitis.

In: Duus Johansen J, Frosch PJ, Lepoittevin JP (eds.) Contact Dermatitis.
Springer Berlin, Heidelberg, (2011), 5th edition, 1029–1051.
Thomas Rustemeyer
Peter Elsner
Swen Malte John
Howard I. Maibach
The Editors
Preface to the First Edition
The Field of occupational dermatology has been well served by textbooks. The
twentieth giants in this field have produced books that are universally
accepted. These include Schwartz, Tullipan, and Birmingham, as well as
Fousseau and Adams.
What then is the need in terms of the next generation of textbooks in this
rapidly evolving and complex clinical research area? The varied complexity
and inordinate detail of information makes it difficult for any one individual to
cover this huge expanse of knowledge. The present volume stresses individual
excellence and scholarship covering the various areas. It is not meant to be a
static book. If the readership finds it as interesting as the editors and authors
have, this should evolve over generations. The information in the various
chapters includes nineteenth century approaches, such as morphology and
histology, but is amply supplemented by late twentieth and early twenty-first
century clinical bioassays.
Although the field is served by general dermatologists, occupational phy-
sicians, and occupational dermatologists, other health workers are also fre-
quently involved. For this reason, we have deliberately included a number of
redundancies in an attempt to make it easier for the reader. Whenever possible,
we have emphasized evidence-based dermatology, and the authors were cho-
sen on the basis of both their scientific approach and clinical good sense.
Hopefully, a second edition will benefit by increased controlled experimen-
tation currently under way, so that there will be even more hard data included.
The editors welcome your comments for the proposed second edition.
The Editors
ix
Contents
Volume 1
Part I General Aspects of Occupational Dermatology . . . . . . . . 1
1 Immunology and Barrier Function of the Skin . . . . . . . . . . . 3

Thomas Rustemeyer and Manigé Fartasch
2 Percutaneous Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Austin Jiang, Howard I. Maibach, Aaron Wiener, and
Rasika Reddy
3 Quality of Life (QoL) in Relation to Occupational Skin

Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Tove Agner
4 Pharmacoeconomics of Occupational Diseases . . . . . . . . . . . 27

Matthias Augustin
5 Occupational Dermatology: Ethical Aspects . . . . . . . . . . . . . 37

Nikolaus Knoepffler and Martin O’Malley
6 History of Occupational Dermatology . . . . . . . . . . . . . . . . . . 51

Jean-Marie Lachapelle
7 Classification of Occupations ......................... 61

Wolfgang Uter
8 Surveillance in Occupational Contact Dermatitis . . . . . . . . . 69

Wolfgang Uter
9 Occupational Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Thomas L. Diepgen and Hans Drexler
10 Other Occupational Skin Diseases . . . . . . . . . . . . . . . . . . . . . 97

Elke Weisshaar and Thomas L. Diepgen
11 Websites, Online Databases, and Sources of Information . . . 105

Marc Rocholl, Swen Malte John, and Annika Wilke
xi
xii Contents
Part II Occupational Skin Diseases: Clinical . . . . . . . . . . . . . . . . . . 117
12 Contact Dermatitis due to Irritation . . . . . . . . . . . . . . . . . . . 119

Dimitar Antonov, Sibylle Schliemann, and Peter Elsner
13 Chemical Skin Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Audris Chiang, Magnus Bruze, Sigfrid Fregert, and
Birgitta Gruvberger
14 Mechanisms of Allergic Contact Dermatitis . . . . . . . . . . . . . 151
Thomas Rustemeyer, Ingrid M. W. van Hoogstraten,
B. Mary E. von Blomberg, and Rik J. Scheper
15 Phototoxic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Margarida Gonçalo
16 Photoallergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . 211
James Ferguson and Alastair C. Kerr
17 Airborne Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . 229
18 Acute and Recurrent Vesicular Hand Dermatitis . . . . . . . . . 241
Jacob P. Thyssen and Torkil Menné
19 Hyperkeratotic Dermatitis of the Palms . . . . . . . . . . . . . . . . . 257
20 Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Kristine Breuer and Thomas Werfel
21 Frictional Trauma/Mechanic Skin Diseases . . . . . . . . . . . . . . 279
Niels H. Bennike and Klaus E. Andersen
22 Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Christophe J. Le Coz
23 Biologic Causes of Occupational Dermatoses . . . . . . . . . . . . 303
24 Occupation-Induced Skin Cancer . . . . . . . . . . . . . . . . . . . . . . 321
M. L. Lam, A. N. Patel, and John S. C. English
25 Occupational Nail Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Robert Baran and An Goossens
26 Hair Disorders Induced by External Factors . . . . . . . . . . . . . 345
Becky S. Li, Marcel C. Pasch, and Howard I. Maibach
27 Pigment Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Maryam Yazdani
28 Noneczematous Occupational Contact Reactions . . . . . . . . . 385
Anthony Teik Jin Goon and Chee Leok Goh
Contents xiii
29 Occupational Connective Tissue Disorders . . . . . . . . . . . . . . 393

Uwe-Frithjof Haustein and Bettina Lietzberg
30 Systemic Diseases by Absorption Through the Skin . . . . . . . 427
Hans Drexler and Sonja Kilo
31 Occupational and Environmental Acne . . . . . . . . . . . . . . . . . 435
Penpun Wattanakrai and James S. Taylor
32 Psoriasis and Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Christoph Skudlik and Swen Malte John
33 Physical Causes: Heat, Cold, and Other Atmospheric
Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Wolfgang Uter and Lasse Kanerva
34 Chronic Venous Insufficiency and Occupation . . . . . . . . . . . 481
Edith M. de Boer
Volume 2
Part III Causative Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
35 Antiseptics and Disinfectants . . . . . . . . . . . . . . . . . . . . . . . . . 493

36 Isothiazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Jakob Ferløv Schwensen and Jeanne Duus Johansen
37 Formaldehyde and Formaldehyde-Releasers . . . . . . . . . . . . . 521
Anton C. de Groot and Mari-Ann Flyvholm
38 Fiberglass, Dusts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Daniel J. Hogan, Megan Morrison, and Anand Desai
39 Drug Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Andreas J. Bircher
40 Fragrances and Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . 579
Anton C. de Groot
41 Colophony: Rosin in Unmodified and Modified
Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Ann-Therese Karlberg and Lina Hagvall
42 Industrial Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
David A. Basketter and Monika Raulf
43 Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Anneli Julander and Carola Lidén
44 Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
John Havens Cary, Howard I. Maibach, Desmond Burrows,
and Jurij J. Hostynek
xiv Contents
45 Cobalt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
Anneli Julander, Jolinde Kettelarij, and Carola Lidén
46 Gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Marléne Isaksson
47 Some Other Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
48 Cement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
David Bregnbak and Christian Avnstorp
49 Occupational Skin Products . . . . . . . . . . . . . . . . . . . . . . . . . . 713
50 Adverse Effects of Skin Protective Products, Including
Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
Sibylle Schliemann
51 Acrylic Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
Kristiina Aalto-Korte
52 Epoxy Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
Claire Higgins, Jennifer Cahill, Riita Jolanki, and
Rosemary Nixon
53 Contact Allergy to Phenol-Formaldehyde Resins . . . . . . . . . 789
Erik Zimerson and Magnus Bruze
54 Polyurethane Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
Kristiina Aalto-Korte, Malin Engfeldt, Tuula Estlander, and
Riita Jolanki
55 Polyester Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Rosemary Nixon
56 Other Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821
George-Sorin Ţiplica, Letiţia Bucur, Gheorghe Bucur, and
Carmen Maria Sălăvăstru
57 Plastic Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Katri Suuronen and Maria Pesonen
58 Inks and Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
59 Occupational Skin Infections . . . . . . . . . . . . . . . . . . . . . . . . . 861
Burkhard Kreft and Cord Sunderkötter
60 Leather and Shoes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
Johannes Geier and Holger Lessmann
Contents xv
61 Adhesives and Glues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891

Judit Lukács, Jana Präßler, Matthias Gebhardt, and
Peter Elsner
62 Electronic Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
E. J. Roberts, V. Smith, and John S. C. English
63 Paints, Lacquers, and Varnishes in Occupational
Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
Rebecca M. Law and Howard I. Maibach
64 Coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
Carmen Maria Sălăvăstru, Letiţia Bucur, Gheorghe Bucur, and
George-Sorin Ţiplica
65 Organic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953
Sibylle Schliemann, Anders Boman, and J. E. Wahlberg
66 Cutting Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Michael F. Koller and Iain S. Foulds
67 Rubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
Marie-Noëlle Crepy and Donald V. Belsito
68 Occupational Allergy to Natural Rubber Latex (NRL) . . . . 1015
Henning Allmers
69 Pesticide-Related Dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . 1029
Michael O’Malley, Mai A. Ngo, and Howard I. Maibach
70 Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1059
Christopher Roland Lovell
71 Spices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
Stefanie E. Pentinga
72 Vegetables and Fruit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
Andrea Bauer, Wolfgang Uter, and Christiane Szliska
73 Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Päivikki Susitaival
74 Woods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
Yonah Levy and B. M. Hausen
75 Wet Work and Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1117
Dimitar Antonov, Sibylle Schliemann, Peter Elsner, and
Swen Malte John
76 Detergents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Lilla Landeck, Lynn A. Baden, and Swen Malte John
xvi Contents
77 UV Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145
Peter Knuschke
78 Ionizing Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
Seema Garg and David J. Gawkrodger
79 Mechanical Causes of Occupational Skin Disease . . . . . . . . . 1189
Richard Brans
80 Smoking (Including Non-smoking) . . . . . . . . . . . . . . . . . . . . . 1199
Richard Brans
81 Self-Inflicted Skin Lesions (SISL) . . . . . . . . . . . . . . . . . . . . . . 1209
Wolfgang Harth
82 Immediate and Delayed Hypersensitivity
Reactions Occurring in the Kitchen: Hazards Related
to Being a Chef or Kitchen Staff . . . . . . . . . . . . . . . . . . . . . . . 1223
Maria Antonia Pastor-Nieto and Ana M. Giménez-Arnau
Volume 3
Part IV Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261
83 Workplace Survey: Guiding Principles from

Occupational Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . 1263
Diandra Budd, Irena Kudla, and D. Linn Holness
84 Questionnaire Methods in Occupational Skin
Disease Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1273
85 Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279
86 Patch Testing with Patient’s Own Materials Handled
at Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1289
Andrea Krautheim, Holger Lessmann, and Johannes Geier
87 Pitfalls in the Diagnosis of Occupational Contact
Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1307
An Goossens
88 Prick and Intracutaneous Testing and IgE
Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1317
Vera Mahler
89 In Vitro Delayed-Type Sensitivity Testing . . . . . . . . . . . . . . . 1347
Detlef Becker
90 Physiochemical Methods for Detection of Occupational
Contact Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353
Malin Engfeldt, Birgitta Gruvberger, and Magnus Bruze
Contents xvii
91 Skin Biopsy and Dermatopathology . . . . . . . . . . . . . . . . . . . . 1371

Mirjana Ziemer
92 Skin Bioengineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387
Enzo Berardesca and Cameli Norma
Part V Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397
93 Evidence-Based Management of Hand Eczema . . . . . . . . . . . 1399

Marie Louise A. Schuttelaar, Jart A. F. Oosterhaven,
Wietske A. Christoffers, Geertruida L. E. Romeijn, and
Angelique N. Voorberg
94 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417
Sonja C. Molin and Thomas Ruzicka
95 Topical and Systemic Corticosteroids . . . . . . . . . . . . . . . . . . . 1433
Magdalena Kraft, Stephanie Soost, and Margitta Worm
96 Treatment of Chronic Hand Eczema: Other
Immunomodulating Therapies . . . . . . . . . . . . . . . . . . . . . . . . 1445
Rodrigo da Mota and Bernhard Homey
97 Emollients: Effects, Evidence, and Side Effects . . . . . . . . . . . 1451
Tove Agner and Jakob Mutanu Jungersted
98 Iontophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1461
Erhard Hölzle
99 Other Topical Therapies (Dyes, Tanning Agents,
Tars, CO2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475
Claudia Schröder-Kraft
100 Treatment of Occupational Skin Cancer . . . . . . . . . . . . . . . . 1483
Rudolf Herbst
101 Occupational MRSA Infection: Risk Factor, Disposition,
Prevention, and Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1493
Richard Brans, O. Kaup, and N. Y. Schürer
Part VI Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505
102 Prognosis of Occupational Contact Dermatitis . . . . . . . . . . . 1507

103 Prognosis of Irritant Contact Dermatitis . . . . . . . . . . . . . . . . 1517
Peter Elsner and Kaija Lammintausta
104 Prognosis of Allergic Contact Dermatitis . . . . . . . . . . . . . . . . 1527
John S. C. English
105 Atopy as a Factor in the Prognosis of Hand Dermatitis . . . . 1533
Birgitta Meding
xviii Contents
Part VII Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1541
106 Prediction of Skin Irritation by Noninvasive

Bioengineering Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543
Ron A. Tupker
107 Identification of Skin Irritants and Allergens
by In Vivo and In Vitro Methods . . . . . . . . . . . . . . . . . . . . . . 1561
Rasika Reddy, Howard I. Maibach, Viswanath Reddy Belum,
Geetanjali Sethi, and Philip Hewitt
108 Identification of Skin Allergens by In Vivo Assay . . . . . . . . . 1579
David A. Basketter
109 Identification of Contact Allergens by In Vitro Cell
Culture-Based Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1589
Susan Gibbs, Stefan F. Martin, Emanuela Corsini, and
Hermann-Josef Thierse
110 Genetic Identification of Individuals with Increased
Risk of Developing Occupational Skin Diseases . . . . . . . . . . 1609
Sanja Kezic
111 Prevention and Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . 1617
112 Prevention in Health-Care Professionals . . . . . . . . . . . . . . . . 1631
Lilla Landeck, Britta Wulfhorst, and Swen Malte John
113 Prevention in Food Workers . . . . . . . . . . . . . . . . . . . . . . . . . . 1645
Andrea Bauer
114 Prevention in Metalworkers . . . . . . . . . . . . . . . . . . . . . . . . . . 1655
Christian Apfelbacher, Jochen Schmitt, and
Thomas L. Diepgen
115 Protective Gloves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
Marie-Noëlle Crepy, Anders Boman, and
François Zimmermann
116 Prevention of Occupational Skin Cancer . . . . . . . . . . . . . . . . 1685
Andrea Bauer, Kerry E. Adam, Peter H. Soyer, and
Keith William James Adam
Volume 4
Part VIII Job Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1699
117 Aircraft Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1701

Marléne Isaksson
118 Air Hammer Operators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1707
David J. Gawkrodger and Mili Shah
Contents xix
119 Aromatherapists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1715

Niels H. Bennike and Jeanne Duus Johansen
120 Bakers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1719
Niels K. Veien
121 Barbers’ Dermatoses (Barber’s Hair Sinus) . . . . . . . . . . . . . 1725
Agustin Alomar, Luis Conde-Salazar, and Felipe Heras
122 Bartenders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1729
Marie Louise A. Schuttelaar and Jart A. F. Oosterhaven
123 Bath Attendants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1733
Richard Brans
124 Batik Manufacturing Workers . . . . . . . . . . . . . . . . . . . . . . . . 1743
Retno W. Soebaryo and Windy Keumala Budianti
125 Battery Makers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1753
M. H. Beck and J. D. L. Williams
126 Beekeepers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1757
Randolf Brehler
127 Boatbuilders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1763
Kristiina Aalto-Korte and Katri Suuronen
128 Brake-Lining Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1767
M. H. Beck and J. D. L. Williams
129 Butchers and Slaughterhouse Workers . . . . . . . . . . . . . . . . . 1771
Niels K. Veien
130 Contact Dermatitis in Cabinetmakers . . . . . . . . . . . . . . . . . . 1775
Lauren Fried and David E. Cohen
131 Candle Makers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1789
Richard Brans
132 Cleaners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1793
Andrea Bauer
133 Confectionery and Candymakers . . . . . . . . . . . . . . . . . . . . . . 1799
Ayda Alhammadi, Firas A. Al-Niaimi, and Calum C. Lyon
134 Carpenters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1809
Michael Haeberle
135 Automotive Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819
Horst Christoph Broding and Manigé Fartasch
136 Cement Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1829
137 Ceramic and Pottery Workers . . . . . . . . . . . . . . . . . . . . . . . . 1835
H. Smith, John S. C. English, and J. Hobson
xx Contents
138 Cheese Makers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1839

Peter Elsner and Frank O. Nestle
139 Chemists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1843
Andrew Ezersky, Howard I. Maibach, and Riita Jolanki
140 Child Daycare Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1851
Marjolein Wintzen
141 Cigarette and Cigar Makers and Tobacco Workers . . . . . . . 1855
Christophe J. Le Coz, Caterina Foti, Domenico Bonamonte,
Gianni Angelini, and Paolo Romita
142 Construction Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1861
143 Cosmetologists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1867
John Havens Cary and Howard I. Maibach
144 Occupational Contact Dermatitis in Dental Personnel . . . . . 1879
Thomas Rustemeyer and Peter J. Frosch
145 Detergent Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1891
Markku Vanhanen and Axel Schlieter
146 Divers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1897
Menno T. W. Gaastra
147 Electronics Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1909
David Koh and Claire Quah
148 Electroplaters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1917
Antti Lauerma, Lasse Kanerva, and Mirja Kiilunen
149 Embalmers (Including Funeral Service Workers) . . . . . . . . . 1921
D. Linn Holness and Diandra Budd
150 Engravers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925
Adriene Lee
151 Farmers and Farmworkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929
Radoslaw Spiewak
152 Floor Layers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1947
Luis Conde-Salazar, Felipe Heras, and Agustin Alomar
153 Florists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1951
154 Forestry Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1957
Michael Haeberle
155 Foundry Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1987
Mariko Sugiura and Keiji Sugiura
Contents xxi
156 Fur Farming and the Fur Industry . . . . . . . . . . . . . . . . . . . . 1991

Jukka Uitti
157 Furniture Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1997
Michael Haeberle
158 Gardeners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2007
159 Glass Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2017
Faheem Latheef and Mark S. Wilkinson
160 Greenhouse Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2023
Roy Gerth van Wijk, Liu Liu, and Nicolette W. de Jong
161 Skin Decontamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2037
Austin Jiang and Howard I. Maibach
162 Grinders and Brazers of Hard Metal and Stellite . . . . . . . . . 2041
Katri Suuronen and Markku Linnainmaa
163 Hairdressers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2047
Harma Stenveld
164 Healthcare Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2061
Rasika Reddy, Howard I. Maibach, and Donald V. Belsito
165 Highway Construction Workers . . . . . . . . . . . . . . . . . . . . . . . 2073
Hanspeter Rast
166 Houseworkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2075
F. H. W. Jungbauer
167 Insulation Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2079
R. Riala
168 Jewelers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083
Juan Vilaplana
169 Laboratory Technicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2093
Marwa Hakimi, Riita Jolanki, and Howard I. Maibach
170 Leather Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103
171 Locksmiths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2107
Adriene Lee
172 Machinists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2111
Diana Miguel, Sibylle Schliemann, Undine Frank, and
Peter Elsner
173 Masseurs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2117
Marléne Isaksson
xxii Contents
174 Metal Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2123

Ana Luiza Lima and Peter Elsner
175 Military Personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2127
Akiva Trattner, Aneta Lazarov, and Arieh Ingber
176 Mining (Tunneling) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2137
Hanspeter Rast
177 Mountain Guides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2141
Matthias Moehrle
178 Musicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2147
Nicolas Kluger and Derk P. Bruynzeel
179 Oil Rig Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2153
Markus F. C. Steiner and Anthony D. Ormerod
180 Operating Room Staff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2169
D. Linn Holness and Diandra Budd
181 Painters, Lacquerers, and Varnishers in Occupational
Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2173
182 Pulp and Paper Workers, and Paper Dermatitis . . . . . . . . . . 2183
Michael Haeberle
183 Pharmaceutical and Cosmetic Industries . . . . . . . . . . . . . . . . 2203
An Goossens, Julie Geebelen, Kim Vander Hulst, and
Liesbeth Gilissen
184 Photographers and Other Photo-Lab Workers . . . . . . . . . . . 2221
Carola Lidén
185 Poultry Processors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2229
Margarida Gonçalo
186 Pitch Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2233
James S. Taylor, Chuan Ma, and Thomas F. Downham II
187 Plumbers and Pipe Fitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2247
Uwe Hillen
188 Printers and Lithographers . . . . . . . . . . . . . . . . . . . . . . . . . . 2251
Catriona I. Wootton and John S. C. English
189 Skin Disorders in Athletes: Professional and
Recreational Sports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2259
R. Blake Steele, James S. Taylor, and Savina Aneja
190 Railroad Shop Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2283
Hanspeter Rast
191 Roofers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2285
Hoang N. Ho-Pham and Howard I. Maibach
Contents xxiii
192 Shoe Manufacturers and Repairers . . . . . . . . . . . . . . . . . . . . 2295

193 Silk-Screen Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2299
A. Goossens
194 Stonemasons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305
Anne Schmidt
195 Sugar Artists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2309
Peter Elsner
196 Swimming Pool Worker Dermatoses . . . . . . . . . . . . . . . . . . . 2311
Nina R. Blank and David E. Cohen
197 Tattoo Artists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2321
Margarida Gonçalo
198 Textile Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2325
Ângelo Azenha
199 Veterinarians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2343
200 Welding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2351
Monica Hindsén and Magnus Bruze
Part IX Chemistry and Concentrations of Patch Test

Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2355
201 Dictionary of Contact Allergens: Chemical Structures,

Sources, and References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2357
Jean-Pierre Lepoittevin and Christophe J. Le Coz
202 Patch Test Concentrations and Vehicles for Testing
Contact Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2473
Anton C. de Groot
203 Risk Assessment for Occupational Skin Exposure . . . . . . . . 2527
John W. Cherrie
204 Multiple Chemical Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . 2539
Hans Drexler and Annette Greiner
205 Advantages and Disadvantages of Gloves . . . . . . . . . . . . . . . 2547
Becky S. Li, Tuula Estlander, Riita Jolanki, and
Howard I. Maibach
206 Chemically Induced Hair Loss/Alopecia . . . . . . . . . . . . . . . . 2563
Becky S. Li, Howard I. Maibach, and Ian Yamaguchi
207 Polyvinyl Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2575
Carmen Maria Sălăvăstru, Letiţia Bucur, George-Sorin Ţiplica,
and Gheorghe Bucur
xxiv Contents
208 Sulfuric Acid Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2587

Austin Jiang, Howard I. Maibach, Geetanjali Sethi, and
Viswanath Reddy Belum
209 Contact Urticaria Syndrome: Occupational Aspects . . . . . . . 2595

Becky S. Li, Iris S. Ale, and Howard I. Maibach
210 Nonimmunologic Contact Urticaria . . . . . . . . . . . . . . . . . . . . 2629

John Havens Cary, Howard I. Maibach, Ian Yamaguchi, and
A. Lahti
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2637
Editors
Swen Malte John Department of Dermatology, Environmental Medicine and

Health Theory, University of Osnabrück, Osnabrück, Germany
Jeanne Duus Johansen National Allergy Research Centre, Department of
Dermatology and Allergy, Herlev-Gentofte University Hospital, Hellerup,
Denmark
Thomas Rustemeyer Department of Dermatology and Allergology, VU
University Medical Center, Amsterdam, The Netherlands
Peter Elsner Department of Dermatology, University Hospital Jena, Jena,
Germany
Howard I. Maibach Department of Dermatology, University of California,
xxv
Contributors
Kristiina Aalto-Korte Occupational Medicine, Finnish Institute of Occupa-

tional Health, Helsinki, Finland
Kerry E. Adam Faculty of Health Sciences, School of Health and Rehabil-

itation Sciences, The University of Queensland, Brisbane, Australia
Keith William James Adam Medibank Health Solutions, Brisbane, QLD,

Australia
Faculty of Health Sciences, The University of Queensland, Brisbane, QLD,
Australia
Tove Agner Department of Dermatology, Faculty of Health Science,

Bispebjerg Hospital, University of Copenhagen, Copenhagen NV, Denmark
Iris S. Ale Department of Dermatology and Allergology, Republic University

of Uruguay, Montevideo, PC, Uruguay
Ayda Alhammadi Department of Dermatology, Hamad Medical Corpora-

tion, Doha, Qatar
Henning Allmers Department of Dermatology, Environmental Medicine and

Health Sciences, University of Osnabrueck, Osnabrueck, Germany
Department of Occupational Medicine, University of Osnabrueck,
Osnabrueck, Germany
Firas A. Al-Niaimi Department of Dermatology, Cumberland Infirmary,

London, UK
Agustin Alomar Servicio de Dermatología, Hospital de la Santa Creu i Sant

Pau, Barcelona, Spain
Dermatología, Hospital University Quirón Dexeus, Barcelona, Spain
Klaus E. Andersen Department of Dermatology and Allergy Centre, Odense

University Hospital, University of Southern Denmark, Odense, Denmark
Savina Aneja Department of Dermatology, Desk A-61, Dermatology-Plastic

Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
Private Practice, Orlando, FL, USA
xxvii
xxviii Contributors
Gianni Angelini Department of Biomedical Science and Human Oncology,

Dermatological Clinic, University of Bari, Bari, Italy
Dimitar Antonov Department of Dermatology, University Hospital Jena,
Jena, Germany
Christian Apfelbacher Medizinische Soziologie, Institut für Epidemiologie
und Präventivmedizin, Fakultät Medizin, Universität Regensburg, Regens-
burg, Germany
Matthias Augustin Institute for Health Services Research in Dermatology
and Nursing (IVDP), University Medical Center Hamburg-Eppendorf (UKE),
Hamburg, Germany
Christian Avnstorp Dermatology Clinic, Rødovre, Denmark
Ângelo Azenha Department of Dermatology, Hospital Privado da Trofa,
Trofa, Portugal
Lynn A. Baden Centre Dermatology and Aesthetic Medicine, Newton, MA,
USA
Robert Baran Nail Disease Center, Cannes, France
David A. Basketter DABMEB Consultancy Ltd., Sharnbrook, Bedfordshire,
UK
Andrea Bauer Department of Dermatology, University Allergy Center, Uni-
versity Hospital Carl Gustav Carus, Technical University of Dresden, Dresden,
Germany
M. H. Beck Royal Bolton Hospital, Bolton, UK
Department of Occupational and Environmental Health, Contact Dermatitis
Investigation Unit, University of Manchester Dermatology, Hope Hospital,
Salford, Lancashire, Manchester, UK
Detlef Becker Department of Dermatology, University Medical Center,
Mainz, Germany
Donald V. Belsito Department of Dermatology, Columbia University
College of Physicians and Surgeons, New York, NY, USA
Viswanath Reddy Belum Wexner Medical Center at The Ohio State
University, Columbus, OH, USA
Niels H. Bennike National Allergy Research Centre, Department of
Denmark
Enzo Berardesca San Gallicano Dermatological Institute, Rome, Italy
Andreas J. Bircher Allergy Unit, Department of Dermatology, University
Hospital, Basel, Switzerland
R. Blake Steele Department of Dermatology, Desk A-61, Dermatology-
Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
Contributors xxix
Nina R. Blank Weill Cornell Medical College, Weill Cornell Medicine, New
York, NY, USA
Anders Boman Department of Occupational and Environmental, Karolinska
Institutet, Institute of Environmental Medicine, Occupational and Environ-
mental Dermatology, Stockholm, Sweden
Domenico Bonamonte Department of Biomedical Science and Human
Oncology, Dermatological Clinic, University of Bari, Bari, Italy
Richard Brans Department of Dermatology, Environmental Medicine and
Institute for Interdisciplinary Dermatologic Prevention and Rehabilitation
(iDerm), University of Osnabrück, Osnabrück, Germany
David Bregnbak Department of Dermatology and Allergy, Herlev-Gentofte
University Hospital, Hellerup, Denmark
Randolf Brehler Department of Dermatology, University Hospital Münster,
Münster, Germany
Kristine Breuer Private Practice, Reinbek, Germany
Horst Christoph Broding Occupational Medicine and Corporate Health
Management, Faculty of Health - School of Medicine, Witten/Herdecke Uni-
versity, Witten, NRW, Germany
Derk P. Bruynzeel VU University Medical Centre, Amsterdam, The
Netherlands
Magnus Bruze Department of Dermatology, University of California Med-
ical School, San Francisco, CA, USA
Department of Occupational and Environmental Dermatology, Skåne Univer-
sity Hospital Malmö, Lund University, Malmö, Sweden
Letiţia Bucur Department of Occupational Health, Belsana Grup LLC,
Bucharest, Romania
Gheorghe Bucur Bucharest, Romania
Diandra Budd Dalla Lana School of Public Health and Department of
Medicine, University of Toronto, Toronto, ON, Canada
Division of Occupational Medicine, St. Michael’s Hospital, Toronto, ON,
Canada
Centre for Urban Health Solutions, Li Ka Shing Knowledge Institute, St.
Michael’s Hospital, Toronto, ON, Canada
Windy Keumala Budianti Faculty of Medicine, Department of Dermatol-
ogy and Venereology, Universitas Indonesia, Jakarta, Indonesia
Desmond Burrows Department of Dermatology, University of California,
Gheorghe Bucur: deceased.

xxx Contributors
Jennifer Cahill Occupational Dermatology Research and Education Centre,

Skin and Cancer Foundation, Melbourne, VIC, Australia
John Havens Cary Louisiana State University School of Medicine, New
Orleans, LA, USA
Department of Dermatology, University of California Medical School, San
Francisco, CA, USA
John W. Cherrie Institute of Occupational Medicine, Edinburgh, UK
Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt
University, Edinburgh, UK
Audris Chiang Department of Dermatology, University of California Med-
Wietske A. Christoffers Department of Dermatology, University Medical
Center Groningen, University of Groningen, Groningen, The Netherlands
David E. Cohen The Ronald O. Perelman Department of Dermatology, New
York University School of Medicine, NYU Langone Medical Center, New
York, NY, USA
Luis Conde-Salazar Servicio de Dermatología Laboral, Escuela Nacional de
Medicina del Trabajo, Madrid, Spain
Emanuela Corsini Department of Pharmacological Sciences, Università
degli Studi di Milano, Milan, Italy
Marie-Noëlle Crepy Occupational and Environmental Diseases Department
Unit, Hotel-Dieu Hospital, Paris, France
Dermatology Department Unit, Cochin Hospital, Paris, France
Rodrigo da Mota Department of Dermatology, University Hospital
Duesseldorf, Duesseldorf, Germany
Edith M. de Boer Department of Dermatology, VU Medisch Centrum,
Anton C. de Groot Acdegroot Publishing, Wapserveen, The Netherlands
Nicolette W. de Jong Section of Allergology, Department of Internal Med-
icine, Erasmus MC, Rotterdam, The Netherlands
Anand Desai University of Central Florida College of Medicine, Orlando,
FL, USA
Thomas L. Diepgen Department of Social Medicine, Occupational and
Environmental Dermatology, University Heidelberg, Heidelberg, Germany
Thomas F. Downham II Department of Dermatology, Henry Ford Health
System, Taylor, MI, USA
Hans Drexler Institute and Outpatient Clinic for Occupational, Social and
Environmental Medicine, Friedrich-Alexander-University, Erlangen-
Nürnberg, Erlangen, Germany
Contributors xxxi
Peter Elsner Department of Dermatology, University Hospital Jena, Jena,

Germany
Malin Engfeldt Department of Occupational and Environmental Dermatol-
ogy, Skåne University Hospital (SUS), Lund University, Malmö, Sweden
John S. C. English Department of Dermatology, Nottingham Circle Treat-
ment Centre, Nottingham University Hospital, Nottingham, UK
Tuula Estlander Terveystalo Healthcare Oyj, Helsinki, Finland
Andrew Ezersky University of Southern California, Los Angeles, CA, USA
Manigé Fartasch Department for Clinical and Experimental Occupational
Dermatology, Institute for Prevention and Occupational Medicine of the
German Social Accident Insurance/Institute of the Ruhr-University, Bochum,
Germany
James Ferguson Photobiology Unit, Ninewells Hospital and Medical
School, Dundee, UK
Mari-Ann Flyvholm National Research Centre for the Working Environ-
ment, Copenhagen, Denmark
Caterina Foti Department of Biomedical Science and Human Oncology,
Iain S. Foulds Institute of Occupational and Environmental Medicine, Uni-
versity of Birmingham, Birmingham, UK
Undine Frank Department of Dermatology, University Hospital Jena, Jena,
Germany
Sigfrid Fregert Malmö, Sweden
Lauren Fried The Ronald O. Perelman Department of Dermatology and
Allergic, Occupational and Environmental Dermatology, NYU Langone Med-
ical Center, New York, NY, USA
Peter J. Frosch Klinikum Dortmund, Department of Dermatology, Univer-
sity of Witten/Herdecke, Dortmund, Germany
Menno T. W. Gaastra Outpatients Clinic for Dermatology and Phlebology,
Centrum Oosterwal, Alkmaar, Noordwest Ziekenhuisgroep, Huid Medisch
Centrum, Amsterdam, The Netherlands
Seema Garg Department of Dermatology, Royal Hallamshire Hospital, Shef-
field, UK
David J. Gawkrodger Department of Oncology and Human Metabolism,
University of Sheffield Medical School, Sheffield, UK
Sigfrid Fregert: deceased.

xxxii Contributors
Matthias Gebhardt Dermatology Practice, Zwickau, Germany

Julie Geebelen KU Leuven, Leuven, Belgium
Johannes Geier Information Network of Departments of Dermatology
(IVDK), University Medical Center Goettingen, Goettingen, Germany
Susan Gibbs Department of Dermatology, VU University Medical Centre,
Liesbeth Gilissen Department of Dermatology, University Hospital KU
Leuven, Leuven, Belgium
Ana M. Giménez-Arnau Department of Dermatology, Hospital del Mar-
Institut Mar d’Investigacions Mèdiques, Universitat Autònoma de Barcelona,
Barcelona, Spain
Chee Leok Goh National Skin Centre, Singapore, Singapore
Margarida Gonçalo Clinic of Dermatology, Unit of Skin Allergy, University
Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Anthony Teik Jin Goon National Skin Centre, Singapore, Singapore
An Goossens Contact Allergy Unit, Department of Dermatology, University
Hospital K.U. Leuven, Leuven, Belgium
Annette Greiner Institute and Outpatient Clinic for Occupational, Social
and Environmental Medicine, Friedrich-Alexander-University, Erlangen-
Birgitta Gruvberger Department of Occupational and Environmental Der-
matology, Skåne University Hospital Malmö, Lund University, Malmö,
Sweden
Michael Haeberle Dermatological Practice, Kuenzelsau, Germany
Lina Hagvall Department of Dermatology, Sahlgrenska Academy, Univer-
sity of Gothenburg, Gothenburg, Sweden
Marwa Hakimi Alameda Health System – Highland Hospital, Oakland, CA,
USA
Wolfgang Harth Klinik für Dermatologie und Allergologie, Vivantes
Klinikum Spandau, Berlin, Germany, Germany
B. M. Hausen Amsterdam, The Netherlands
Uwe-Frithjof Haustein Department of Dermatology, Venerology and
Allergology, University of Leipzig, Leipzig, Germany
Felipe Heras Servicio de Dermatología Laboral, Escuela Nacional de
Medicina del Trabajo, Madrid, Spain
Servicio de Dermatología, Fundación Jiménez Díaz, Madrid, Spain
B. M. Hausen: deceased.
Contributors xxxiii
Rudolf Herbst Dermatologie und Allergologie, Helios Hauttumorzentrum

Erfurt, Helios Klinikum Erfurt, Erfurt, Thüringen, Germany
Philip Hewitt Molecular and Cellular Toxicology (MS-DDT-EMT), Early,
Genetic and Molecular Toxicology, Toxicology, Merck Serono R&D, Merck
KGaA, Darmstadt, Germany
Claire Higgins Occupational Dermatology Research and Education Centre,
Skin and Cancer Foundation, Melbourne, VIC, Australia
Uwe Hillen Klinik für Dermatologie und Venerologie, Vivantes Klinikum
Neukölln, Berlin, Germany
Monica Hindsén Department of Occupational and Environmental Derma-
tology, Lund University, Skåne University Hospital, Malmö, Sweden
J. Hobson Occupational Physician, Hobson Health, Stoke-on-Trent, UK
Daniel J. Hogan Internal Medicine (Dermatology) NOVA Southeastern Uni-
versity College of Osteopathic Medicine, Davie, FL, USA
D. Linn Holness Division of Occupational Medicine, St Michael’s Hospital,
Toronto, ON, Canada
Dalla Lana School of Public Health and Department of Medicine, University
of Toronto, Toronto, ON, Canada
Erhard Hölzle Department of Dermatology and Allergology, University
Hospital, Klinikum Oldenburg, Oldenburg, Germany
Bernhard Homey Department of Dermatology, University Hospital
Duesseldorf, Duesseldorf, Germany
Ingrid M. W. van Hoogstraten Department Pathology, VU University Med-
ical Center, Amsterdam, The Netherlands
Hoang N. Ho-Pham Houston, TX, USA
Jurij J. Hostynek Department of Dermatology, University of California, San
Francisco, CA, USA
Kim Vander Hulst Private Dermatologist, Aarschot, Belgium
Arieh Ingber Department of Dermatology, Hadassah University Hospital,
Jerusalem, Israel
Marléne Isaksson Department of Occupational and Environmental Derma-
tology, Department of Clinical Sciences Malmö Lund University, Skåne
University Hospital, Malmö, Sweden
Austin Jiang University of Cincinnati College of Medicine, Cincinnati, OH,
USA
Jeanne Duus Johansen National Allergy Research Centre, Department of
Denmark
xxxiv Contributors
Swen Malte John Department of Dermatology, Environmental Medicine and

Riita Jolanki Section of Dermatology/Control of Hypersensitivity Diseases,
Finnish Institute of Occupational Health (FIOH), Helsinki, Finland
Anneli Julander Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden
F. H. W. Jungbauer Klinisch Arbeidsgeneeskundige, stralingsarts,
bedrijfsartsopleider, VeAC Verzuim en ArboCare, Werkt!, Marum, The
Netherlands
Jakob Mutanu Jungersted Department of Dermatology, Bispebjerg Hospi-
tal, University of Copenhagen, Copenhagen, NV, Denmark
Lasse Kanerva Section of Dermatology, Finnish Institute of Occupational
Health, Helsinki, Finland
Ann-Therese Karlberg Dermatochemistry and Skin Allergy, Department of
Chemistry and Molecular Biology, University of Gothenburg, Gothenburg,
Sweden
O. Kaup Department of Dermatology, Environmental Medicine and Health
Theory, University of Osnabrück, Osnabrück, Germany
Alastair C. Kerr Department of Dermatology, Queen Elizabeth University
Hospital, Glasgow, UK
Jolinde Kettelarij Institute of Environmental Medicine, Karolinska
Institutet, Stockholm, Sweden
Sanja Kezic Coronel Institute of Occupational Health, Amsterdam Public
Health Research Institute, Academic Medical Center, University of Amster-
dam, Amsterdam, The Netherlands
Mirja Kiilunen Biomonitoring Laboratory, Finnish Institute of Occupational
Sonja Kilo Institute and Outpatient Clinic for Occupational, Social and
Environmental Medicine, Friedrich-Alexander-University, Erlangen-
Nicolas Kluger Department of Dermatology, Allergology and Venereology,
Helsinki University Central Hospital, Helsinki, Finland
Nikolaus Knoepffler Department of Applied Ethics, Friedrich-Schiller-
University, Jena, Germany
Peter Knuschke Department of Dermatology, Carl Gustav Carus Faculty of
Medicine, Technische Universität Dresden, Dresden, Germany
David Koh PAPRSB Institute of Health Sciences, Universiti Brunei
Darussalam, Brunei Darussalam, Brunei
Saw Swee Hock School of Public Health, National University of Singapore,
Singapore, Singapore
Contributors xxxv
Michael F. Koller Division of Occupational Medicine, Suva, Lucerne,

Switzerland
Magdalena Kraft Department of Dermatology, Venerology and Allergy,
Charité – Universitätsmedizin Berlin, Berlin, Germany
Division of Allergy and Immunology, Department of Dermatology,
Venerology and Allergy, Charité – Universitätsmedizin Berlin, Berlin,
Germany
Andrea Krautheim Information Network of Departments of Dermatology
(IVDK), Georg-August-University, Goettingen, Germany
Burkhard Kreft Universitätsklinik und Poliklinik für Dermatologie und
Venerologie, Universitätsklinikum Halle (Saale), Halle (Saale), Germany
Irena Kudla Occupational Health Clinic, St. Michael’s Hospital, Toronto,
ON, Canada
Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
Jean-Marie Lachapelle Department of Dermatology, Catholic University of
Louvain, Brussels, Belgium
A. Lahti Department of Dermatology, University of California Medical
School, San Francisco, CA, USA
M. L. Lam Department of Dermatology, Nottingham NHS Treatment Cen-
tre, Nottingham, UK
Kaija Lammintausta Department of Dermatology, Turku University Hos-
pital, Turku, Finland
Lilla Landeck Department of Dermatology, Ernst von Bergmann General
Hospital, Potsdam, Germany
Faheem Latheef The Leeds Centre for Dermatology, Leeds Teaching Hos-
pitals Trust, Chapel Allerton Hospital, Leeds, UK
Antti Lauerma Centre for Inflammatory Diseases, Helsinki University Cen-
tral Hospital and University of Helsinki, Helsinki, Finland
Skin and Allergy Hospital, Helsinki, Finland
Rebecca M. Law School of Pharmacy and Faculty of Medicine, Memorial
University of Newfoundland, St. John’s, NL, Canada
Department of Dermatology, University of California San Francisco, San
Francisco, CA, USA
Aneta Lazarov Tel Aviv University, Tel Aviv, Israel
Private Clinic, Herzeliya, Israel
Adriene Lee Department of Dermatology, Monash Medical Centre, Mel-
bourne, VIC, Australia
Department of Dermatology, St Vincents Hospital Melbourne, Melbourne,
VIC, Australia
xxxvi Contributors
Occupational Dermatology Research and Education Centre, Skin and Cancer

Foundation Victoria, Melbourne, VIC, Australia
Christophe J. Le Coz Cabinet de Dermatologie, Strasbourg, France
Laboratoire de Dermatochimie, Strasbourg, France
Jean-Pierre Lepoittevin Laboratoire de Dermatochimie, University of Stras-
bourg, Strasbourg, France
Holger Lessmann Information Network of Departments of Dermatology
(IVDK), Department of Dermatology, University of Goettingen, Goettingen,
Germany
Information Network of Departments of Dermatology (IVDK), University
Medical Center Goettingen, Goettingen, Germany
Yonah Levy UCSF, San Francisco, CA, USA
Becky S. Li Howard University College of Medicine, Washington, DC, USA
Carola Lidén Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden
Bettina Lietzberg Department of Dermatology, Venerology and
Allergology, University of Leipzig, Leipzig, Germany
Ana Luiza Lima Department of Dermatology, University Hospital Jena,
Jena, Germany
Markku Linnainmaa Material and Particle Research, Finnish Institute of
Occupational Health, Tampere, Finland
Liu Liu Section of Allergology, Department of Internal Medicine, Erasmus
MC, Rotterdam, The Netherlands
Christopher Roland Lovell Department of Dermatology Unit, Royal United
Hospital, Bath, UK
Judit Lukács Department of Dermatology, University Hospital Jena, Jena,
Germany
Calum C. Lyon Department of Dermatology, York Hospitals NHS Founda-
tion Trust, York Hospital, York, UK
Chuan Ma Department of Dermatology, Peking University Third Hospital,
Beijing, China
Vera Mahler Division of Allergology, Paul-Ehrlich-Institut, Langen,
Germany
Medical Faculty, Friedrich-Alexander-University Erlangen-Nuremberg,
Erlangen, Germany
Howard I. Maibach Department of Dermatology, University of California,
Stefan F. Martin Allergy Research Group, Department of Dermatology,
Faculty of Medicine, University of Freiburg, Freiburg, Germany
Contributors xxxvii
Birgitta Meding Institute of Environmental Medicine, Karolinska Institutet,

Stockholm, Sweden
Torkil Menné Department of Dermatology and Allergy, Herlev-Gentofte

Diana Miguel Department of Dermatology, University Hospital Jena, Jena,

Germany
Matthias Moehrle Praxisklinik Tuebingen – Haut und Venen, Tuebingen,

Germany
Department of Dermatology, Universitaets–Hautklinik, Tuebingen, Germany
Sonja C. Molin Division of Dermatology, Queen’s University, Kingston,

Canada
Megan Morrison Stones River Dermatology, Murfreesboro, TN, USA
Frank O. Nestle St. John’s Institute of Dermatology, King’s College London

and NIHR Biomedical Research Centre, Guy’s and St. Thomas’ Hospitals,
London, UK
Mai A. Ngo Department of Pesticide Regulation, California Environmental

Protection Agency, Sacramento, CA, USA
Rosemary Nixon Occupational Dermatology Research and Education Cen-

tre, Skin and Cancer Foundation, Melbourne, VIC, Australia
Cameli Norma San Gallicano Dermatological Institute, Rome, Italy
Martin O’Malley Department of Applied Ethics, Friedrich-Schiller-Univer-

sity, Jena, Germany
Michael O’Malley Center for Health and Environment, UC Davis, Davis,

CA, USA
Department of Pesticide Regulation, California Environmental Protection
Agency, Sacramento, CA, USA
Jart A. F. Oosterhaven Department of Dermatology, University Medical

Anthony D. Ormerod Department of Applied Medicine, Department of

Dermatology, University of Aberdeen, Aberdeen, UK
Marcel C. Pasch Department of Dermatology, Radboud University Nijme-

gen Medical Centre, Nijmegen, GL, The Netherlands
Maria Antonia Pastor-Nieto Department of Dermatology, University Hos-

pital of Guadalajara, Alcalá de Henares University, Madrid, Spain
A. N. Patel Department of Dermatology, Nottingham NHS Treatment Centre,

Nottingham, UK
Stefanie E. Pentinga Department of Dermatology, St. Antonius Hospital,

Utrecht, The Netherlands
xxxviii Contributors
Maria Pesonen Occupational Medicine, Finnish Institute of Occupational

Jana Präßler Department of Dermatology, University Hospital Jena, Jena,
Germany
Claire Quah Occupational Medicine Unit, Department of Medicine, Changi
General Hospital, Singapore, Singapore
Hanspeter Rast Division of Occupational Medicine, Suva (Swiss National
Accident Insurance Fund), Luzern, Switzerland
Monika Raulf Institute for Prevention an Occupational Medicine of German
Social Accident Insurance, Institute of the Ruhr-Universität Bochum,
Bochum, Germany
Rasika Reddy Department of Dermatology, Veterans Affairs Medical Cen-
ter, San Francisco, CA, USA
UT Southwestern Medical Center in Dallas, Texas, USA
R. Riala Department of Dermatology and Allergology, VU University Med-
ical Center, Amsterdam, The Netherlands
E. J. Roberts Nottingham Circle NHS Treatment Centre, Nottingham, UK
Marc Rocholl Institute for Health Research and Education, Department of
Dermatology, Environmental Medicine and Health Theory, University of
Osnabrück, Osnabrück, Germany
Geertruida L. E. Romeijn Department of Dermatology, University Medical
Paolo Romita Department of Biomedical Science and Human Oncology,
Thomas Rustemeyer Department of Dermatology and Allergology,
VU University Medical Center, Amsterdam, The Netherlands
Thomas Ruzicka Department of Dermatology and Allergology, Ludwig
Maximilian University, Munich, Germany
Carmen Maria Sălăvăstru Colentina Clinical Hospital, “Carol Davila”
University of Medicine and Pharmacy, Pediatric Dermatology, Bucharest,
Romania
Rik J. Scheper Department Pathology, VU University Medical Center,
Sibylle Schliemann Department of Dermatology, University Hospital Jena,
Friedrich-Schiller-University, Jena, Germany
Axel Schlieter FEH/AH – H306, Corporate Health Management, BASF SE,
Ludwigshafen, Germany
Anne Schmidt Büro für Berufsdermatologie, Nürnberg, Germany
Contributors xxxix
Jochen Schmitt Zentrum für Evidenzbasierte Gesundheitsversorgung

(ZEGV), Medizinische Fakultät Carl Gustav Carus, TU Dresden,
Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dres-
den, Dresden, Germany
Claudia Schröder-Kraft Institute for Interdisciplinary Dermatologic Pre-
vention and Rehabilitation (iDerm) at the University of Osnabrueck and
Dermatologic Centre, Trauma Hospital, Hamburg, Germany
N. Y. Schürer Department of Dermatology, Environmental Medicine and
Marie Louise A. Schuttelaar Department of Dermatology, University Med-
ical Center Groningen, University of Groningen, Groningen, The Netherlands
Jakob Ferløv Schwensen National Allergy Research Centre, Department of
Denmark
Geetanjali Sethi Wexner Medical Center at The Ohio State University,
Columbus, OH, USA
Mili Shah Department of Dermatology, Royal Liverpool Hospital, Liver-
pool, UK
Christoph Skudlik Department of Dermatology, Environmental Medicine
and Health Theory, University of Osnabrück, Osnabrück, Germany
V. Smith Salisbury District Hospital, Salisbury, UK
H. Smith Department of Dermatology, Nottingham Circle Treatment Centre,
Nottingham University Hospital, Nottingham, UK
Retno W. Soebaryo Faculty of Medicine, Department of Dermatology and
Venereology, Universitas Indonesia, Jakarta, Indonesia
Stephanie Soost Department of Dermatology, Venerology and Allergy,
Charité – Universitätsmedizin Berlin, Berlin, Germany
Peter H. Soyer Dermatology Research Centre, School of Medicine, The
University of Queensland, Brisbane, QLD, Australia
Dermatology Department, Princess Alexandra Hospital, Brisbane, Australia
Radoslaw Spiewak Department of Experimental Dermatology and Cosme-
tology, Faculty of Pharmacy, Jagiellonian University Medical College,
Krakow, Poland
Institute of Dermatology, Krakow, Poland
Markus F. C. Steiner GO Heath Services, NHS Grampian Occupational

Health Service, Aberdeen, UK
Harma Stenveld Centrum voor Huid en Arbeid, Velp, The Netherlands
Mariko Sugiura Department of Environmental Dermatology and

Allergology, Daiichi Clinic, Nagoya, Aichi, Japan
xl Contributors
Keiji Sugiura Department of Environmental Dermatology and Allergology,

Daiichi Clinic, Nagoya, Aichi, Japan
Cord Sunderkötter Universitätsklinik und Poliklinik für Dermatologie und

Venerologie, Universitätsklinikum Halle (Saale), Halle (Saale), Germany
Päivikki Susitaival Department of Dermatology, North Carelia Central Hos-

pital, Joensuu, Finland
Katri Suuronen Occupational Medicine, Finnish Institute of Occupational
Christiane Szliska Department of Dermatology, Bethesda Hospital,
Freudenberg, Germany
James S. Taylor Department of Dermatology, Desk A-61, Dermatology-
Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
Cleveland Clinic Lerner College of Medicine of Case Western Reserve Uni-
versity, Cleveland, OH, USA
Hermann-Josef Thierse Department of Dermatology, Venereology and
Allergology, University Medical Center and Medical Faculty Mannheim,
University of Heidelberg, Center of Excellence in Dermatology, Mannheim,
Germany
Current address: Department of Chemical and Product Safety, German Federal
Institute for Risk Assessment, Berlin, Germany
Jacob P. Thyssen Department of Dermatology and Allergy, Herlev-Gentofte
George-Sorin Ţiplica Colentina Clinical Hospital, “Carol Davila” Univer-
sity of Medicine and Pharmacy, Dermatology 2, Bucharest, Romania
Akiva Trattner Department of Dermatology, Rabin Medical Center, Petah
Tiqwa, Israel
Tel Aviv University, Tel Aviv, Israel
Ron A. Tupker Department of Dermatology, St. Antonius Hospital,
Nieuwegein, The Netherlands
Jukka Uitti Occupational Health and Occupational Medicine, Faculty of
Medicine and Life Sciences, University of Tampere, Tampere, Finland
Team of Occupational Health Care, Finnish Institute of Occupational health,
Tampere, Finland
Wolfgang Uter Department of Medical Informatics, Biometry and Epidemi-
ology, University of Erlangen/Nürnberg, Erlangen, Germany
Roy Gerth van Wijk Section of Allergology, Department of Internal Med-
icine, Erasmus MC, Rotterdam, The Netherlands
Markku Vanhanen Finnair Health Services, Helsinki, Finland
Niels K. Veien University of Aarhus, Kolding, Denmark
Contributors xli
Juan Vilaplana Barcelona, Spain

B. Mary E. von Blomberg Department Pathology, VU University Medical
Center, Amsterdam, The Netherlands
Angelique N. Voorberg Department of Dermatology, University Medical
J. E. Wahlberg Stockholm, Sweden
Penpun Wattanakrai Division of Dermatology, Department of Medicine,
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Elke Weisshaar Department of Clinical Social Medicine, Occupational and
Environmental Dermatology, University of Heidelberg, Heidelberg, Germany
Thomas Werfel Department of Dermatology and Allergy, Klinik für
Dermatologie und Venerologie, Hannover Medical School, Hannover,
Germany
Aaron Wiener University of California (UCSF), San Francisco, CA, USA
Annika Wilke Institute for Health Research and Education, Department of
Dermatology, Environmental Medicine and Health Theory, University of
Osnabrück, Osnabrück, Germany
Mark S. Wilkinson The Leeds Centre for Dermatology, Leeds Teaching
Hospitals Trust, Chapel Allerton Hospital, Leeds, UK
J. D. L. Williams Contact Dermatitis Investigation Unit, Salford Royal NHS
Foundation Trust, Hope Hospital, Salford, Lancashire, Manchester, UK
Marjolein Wintzen Department of Dermatology, VUmc Medical Center,
Catriona I. Wootton Department of Dermatology, Circle Nottingham, Not-
tingham, UK
Margitta Worm Division of Allergy and Immunology, Department of Der-
matology, Venerology and Allergy, Charité – Universitätsmedizin Berlin,
Berlin, Germany
Britta Wulfhorst MSH Medical School Hamburg, University of Applied
Sciences and Medical University, Hamburg, Germany
Ian Yamaguchi Department of Dermatology, University of California Med-
Maryam Yazdani van Altena & de Jongh bedrijfsartsen bv, Amsterdam, The
Netherlands
Mirjana Ziemer Department of Dermatology, Venerology and Allergology,
University Hospital Leipzig, Leipzig, Germany
J. E.Wahlberg: deceased.
xlii Contributors
Erik Zimerson Department of Occupational and Environmental Dermatol-

ogy, Lund University/Skåne, University Hospital, Malmö, Sweden
François Zimmermann Occupational Health and Safety Research Institute

(INRS), Vandoeuvre-Les-Nancy, France
Part I
General Aspects of Occupational
Dermatology
Immunology and Barrier Function of the
Skin 1
Thomas Rustemeyer and Manigé Fartasch
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3 Barrier: Structure and Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4 The Role of the Epidermal Barrier Regarding Irritant and Allergic
Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5 The Role of the Epidermal Barrier Regarding Type I (Immediate) and
Type IV Sensitization of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.1 Epidermal Barrier and Type I Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.2 Epidermal Barrier and Type IV Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5.3 Relationship Between Area of Barrier Exposure and Dose in Induction and
Elicitation of Contact Hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
6 Susceptibility of Individuals to Sensitization and Irritation . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Keywords 1 Core Messages

Atopic eczema (AE) · Cornified cell envelope ·
Epidermal permeability barrier · Filaggrin · • A disturbed epidermal barrier may lead to irri-
Keratohyalin · Netherton’s syndrome (NS) · tant contact dermatitis.
Transepidermal water loss (TEWL) • An enhanced penetration through skin barrier
may facilitate sensitization.
• Immunological effects induced by pre-
T. Rustemeyer (*)
irritation and barrier alteration may fur-
Department of Dermatology and Allergology, VU
University Medical Center, Amsterdam, The Netherlands ther lead to the induction of allergic Type
e-mail: t.rustemeyer@vumc.nl IV-contact dermatitis and Type I (immediate
M. Fartasch type reaction) reactions or aggravate allergic
Department for Clinical and Experimental Occupational reactions.
Dermatology, Institute for Prevention and Occupational
Medicine of the German Social Accident
Insurance/Institute of the Ruhr-University,
Bochum, Germany
e-mail: fartasch@ipa.ruhr-uni-bochum.de
© Springer Nature Switzerland AG 2020 3

S. M. John et al. (eds.), Kanerva’s Occupational Dermatology,
https://doi.org/10.1007/978-3-319-68617-2_1
4 T. Rustemeyer and M. Fartasch
2 Introduction 3 Barrier: Structure

and Biochemistry
The cutaneous permeability barrier largely resides
in the outer layers of the epidermis, the stratum The SC consists of protein-enriched differentiated
corneum (SC). The SC forms an effective barrier extremely flattened and enucleated keratinocytes
between the organism and the environment pre- (Warner et al. 1995) filled with keratin and
venting invasion of pathogens and fending off bounded with cornified envelope and cytoskeletal
chemical and physical assaults, as well as the elements, as well as corneodesmosomes and lipid-
unregulated loss of water and solutes. enriched lamellar-arranged intercellular domains
It is both metabolically active and interactive surrounding the corneocytes (Fig. 1). The
with the underlying epidermal cell layers. Hence, cornified cell envelope, a protein/lipid polymer
it is important to consider SC as a dynamic feature structure, resides below the cytoplasmic mem-
rather than a fixed, inflexible barrier layer (see brane on the exterior of the corneocytes. The
recent reviews and commentaries Elias and nucleated parts of the epidermis (Fig. 1) also
Feingold (2006), Hoath (2001), Menon and contribute to the barrier through tight, gap, and
Fartasch (2010), and Menon (2003)). adherens junctions, as well as through desmo-
Furthermore, the topic of the function and for- somes and cytoskeletal elements (so-called
mation of the epidermal permeability barrier and the tonofibrils and the keratohyalin).
changes regarding its biophysical properties con- During epidermal differentiation lipids are syn-
tinues to be an important issue to understand regu- thesized in the keratinocytes of the lower parts of
lation and development of the normal and abnormal the epidermal cells (stratum spinosum) and finally
epidermis (Fartasch 1997, 2004, 2005) and the per- – in the upper parts of the epidermis (stratum
turbation of the epidermal permeability barrier, pre- granulosum/stratum corneum interface) extruded
viously speculated to be just a symptom involved in into the extracellular domains via lamellar bodies
skin diseases, is currently considered to be a primary (LB; Syn: keratinosomes, membrane-coating
pathophysiologic factor for many skin diseases. granules, and Odland bodies), where they form
A defective barrier function is characterized by extracellular lipid-enriched layers. As most drugs
an increased transepidermal water loss (TEWL), and occupational substances applied onto the skin
might be seen in disease entities with the distur- permeate in part along the lipid domains, the lipid
bance of terminal differentiations (keratinisation organization is considered to be very important
disorders like different types of ichthyosis) and in for the skin barrier function. Due to the excep-
inflammatory reactions of the epidermis, which tional stratum corneum lipid composition, with
influences epidermal proliferation and leads to long chain ceramides, free fatty acids, and choles-
incomplete cornification (like contact dermatitis, terol as main lipid classes, the lipid organization is
atopic dermatitis or psoriasis). In all cases the different from that of other biological membranes.
distribution, structure, and biochemistry of the In stratum corneum, two lamellar phases are pre-
intercellular lipid compartment of the SC, which sent. Moreover, the lipids in the lamellar phases
are vital for the barrier function, are influenced form predominantly crystalline lateral phases, but
leading to an impairment of the water diffusion most probably a subpopulation of lipids forms a
barrier of the skin and probably facilitate penetra- liquid phase (Bouwstra and Ponec 2006). The
tion of various substances. Changes in epidermal Ceramides A and B are covalently bound to
differentiation of the corneocytes and lipid com- cornified envelope proteins of the SC and form
position lead to a disturbed skin barrier, which the backbone for the subsequent addition of free
allows the entry of environmental allergens, ceramides, free fatty acids, and cholesterol in the
immunological reaction, and inflammation in SC. Filaggrin – which forms the matrix of the
atopic dermatitis. A disturbed skin barrier is corneocytes – is cross-linked to the cornified
important for the pathogenesis of contact derma- envelope and aggregates keratin filaments into
titis, ichthyosis, psoriasis, and atopic eczema. macrofibrils. Formation and maintenance of
1 Immunology and Barrier Function of the Skin 5
Fig. 1 (a) Stratum corneum (SC)/Str. granulosum inter- with the upper membrane of the stratum granulosum cell
face: The upper layer of stratum granulosum shows lamel- and extrude their polar lipid content into the intercellular
lar bodies (arrow) which are extruded in the intercellular space. (d) After a transformation process the lipids are
spaces. (D) Desmosomes. (b) Stratum corneum shown by finally arranged into lipid bilayers. (b) and (d) RuO4
conventional OsO4 staining. (c) The lamellar bodies fuse staining
barrier function is influenced by cytokines, 30 , Irritation of the skin is accompanied by a

50 -cyclic adenosine monophosphate and calcium. complex array of epidermal and dermal meta-
bolic responses. Previous studies have shown
that structurally unrelated chemical irritants
induce a different pattern of cellular damage to
4 The Role of the Epidermal the viable parts of the epidermis when topically
Barrier Regarding Irritant applied to human skin (Willis et al. 2001;
and Allergic Contact Dermatitis Fartasch 1997). Further, the role of the epidermal
barrier and its repair seems to be especially cru-
Contact dermatitis (Johansen et al. 1998), one of cial for the epidermal responses since studies
the most common skin diseases, has a great socio- have shown that the epidermal keratinocyte
economic impact (Uter et al. 1998), especially as actively participates in the modulation of inflam-
irritant contact dermatitis (ICD), is a frequent matory reactions induced by the injuring agent
occupational disease, and represents a major (Nickoloff and Naidu 1994; Tsai et al. 1994; von
health risk. den Driesch et al. 1995; Wood et al. 1992).
Additionally, there seems to be a precise 5 The Role of the Epidermal

relationship between barrier function (after bar- Barrier Regarding Type
rier disruption) and cytokine expression I (Immediate) and Type IV
(Nickoloff and Naidu 1994; Wilmer et al. Sensitization of the Skin
1994). The primary response to the irritation
with the resulting barrier disruption should 5.1 Epidermal Barrier and Type
be the attempt to restore the protective barrier I Reaction
so that penetration of environmental hazards and
further alteration of the keratinocytes are Normally, aeroallergens do not make contact
prevented. with antigen-presenting cells, such as Langerhans
The occurrence of allergic contact dermatitis cells (LCs) in epidermis or other dendritic
(ACD) with previous or simultaneous irritation cells in subepithelial tissues, owing to the effec-
seems also to be common and this interaction tiveness of the cornified envelope, tight junctions
has been investigated using human, animal, between cells in the epidermis, and the barrier
and in vitro skin models (Agner et al. 2002; function of the basal lamina (details see
Bonneville et al. 2007; Brasch et al. 1992; also ▶ Chap. 14, “Mechanisms of Allergic Con-
Grabbe et al. 1996; Jacobs et al. 2006; tact Dermatitis,” by Rustemeyer).
McLelland et al. 1991; Pedersen et al. 2004). But factors such as genetic, physical, chemical,
Irritation and barrier alteration might faci- and enzymatic activities of certain allergens like
litate the occurrence (induction) of allergic Der P 1 (de Jongh et al. 2008a, b), barrier alter-
Type IV-contact dermatitis and Type I (immedi- ation by mechanical or chemical trauma produced
ate type reaction) reactions or aggravate allergic by house dust mites that affect one or more com-
reaction (Bonneville et al. 2007). As mecha- ponents of this multilayered barricade might
nisms not only an enhanced penetration through increase the opportunities for allergens to pene-
skin barrier is discussed but also immunological trate into the epidermal layer and make contact
effects (Agner et al. 2002; Basketter et al. 2007; with Langerhans cells which will initiate a T
Brasch et al. 1992; Grabbe et al. 1996; helper type II (Th II) response involving T cells,
Jacobs et al. 2006; McLelland et al. 1991; B cells, and immunoglobulin E (IgE) production,
Pedersen et al. 2004). depending on the cytokine environment and/or
Combined effects of more allergens, more other intrinsic properties of the host immune
irritants, or allergens and irritants together are response. This has been supported by morpho-
reported to produce an altered response logic investigations using laser scanning method
compared to when applied separately (see which have shown that the LHCs are also situated
Review Pedersen et al. (2004)). Single versus in the upper epidermis with their dendrocytes
repeated applications also elicits differential making contact with the lower regions of the SC
cytokine expressions in skin (de Jongh et al. (Bauer et al. 2001) and thus facilitating contact
2007). The combined exposure of allergens with foreign proteins which penetrate through
and irritants may potentially influence irritant small fissures in the barrier. Once initiated, this
effects as well as allergenicity of the subs- response is long lasting, with IgEs binding to mast
tances. Several types of interaction may cells in the skin, the lung, and other mucosae.
exist: (1) an additive response, (2) a syner- Subsequent exposures of the host to allergens
gistic response, and (3) an antagonistic res- will activate mast cells, leading to allergic sys-
ponse (quenching), (Pedersen et al. 2004). temic symptoms such as conjunctivitis, rhinitis,
In conclusion, the hapten-induced skin asthma, urticaria, and angioedema (Incorvaia
contact irritation conditions the develop- et al. 2008). Recent hypothesis (Callard and
ment and the severity of ACD (Bonneville Harper 2007; Hudson 2006) also discuss an asso-
et al. 2007). ciation between barrier dysfunction and
IgE-mediated skin disorders (Type I reactions, epidermis. Even standard patch testing using an
immediate type) such as urticaria/angiodema occlusive patch test chamber, which leads to bar-
which can be systemic in their expression and rier disruption due to hyperhydration (Proksch
respiratory symptoms (with and without the com- and Brasch 1997) lead to altered LC ratios. Addi-
bination with atopic dermatitis). tionally, barrier disruption may in itself activate
T-cells (Nishijima et al. 1997), indicating a link
5.2 Epidermal Barrier and Type IV between the physical barrier and the immune
Reaction barrier.
Studies using skin culture models have also
Penetrating substances responsible for Type shown that both skin irritation and contact aller-
IV-contact dermatitis show certain physico- gens at nonirritating concentrations can accelerate
chemical parameters and the ability for a certain LC migration (Jacobs et al. 2004) to the draining
chemical reactivity (Basketter et al. 2007; lymph nodes, indicating potential for initiating
Kimber et al. 2003). Chemicals that possess the sensitization in vivo (see ▶ Chap. 107, “Identifi-
capacity to cause skin sensitization are reactive cation of Skin Irritants and Allergens by In Vivo
(electrophilic) or at least the precursors of an and In Vitro Methods”).
electrophile with a size less than 700 Da. The
chemical species (haptens) covalently bound to
skin protein then forms an antigen to which the 5.3 Relationship Between Area
immune system responds, and with sufficient of Barrier Exposure and Dose
exposure might lead to sensitization (Basketter in Induction and Elicitation
et al. 2007). However, it is hypothesized that for of Contact Hypersensitivity
this process to occur secondary stimuli (danger
signals) are also necessary (Basketter et al. 2007; One of the key questions is why do certain indi-
Bonneville et al. 2007; McLelland et al. 1991) viduals develop allergic sensitization by vehicles
and the sensitizing potency is linked to their whereas the larger majority of people tolerate
ability to produce pro-inflammatory signal contact with those substances without conse-
release which manifests clinically as ability for quence (Friedmann 2006). Of course, some
skin irritancy. They are capable to activate innate chemicals are more potent as sensitizers. A differ-
immunity causing irritant contact dermatitis ent exposure dose can be a factor; way of
and/or acquired specific immunity inducing exposure, duration of exposure, and frequency of
allergic contact dermatitis (Saint-Mezard et al. exposure are all factors that might influence
2004) and seem to stimulate Langerhans cells the ability to induce a sensitization. Clearly
(LHC) – and induce their migration and matura- studies with potent experimental sensitizers
tion in antigen or non-antigen-dependent manner (2,4-dinitrochlorobenzne (DNCB), 2,4 dinitro-
(Gallucci et al. 1999; Jacobs et al. 2006; McFad- fluornemzeme (DNFB)) have shown that an
den and Basketter 2000). important factor seems to be the penetrating dose
Further, the presence and density of per unit area (Friedmann 2007) as key determi-
Langerhans cells play an important part in the nant of sensitization and with increasing concen-
induction of allergic type IV reactions. The con- tration of allergen (e.g., DNCB v. 0.063%) a clear
stant ratio of epidermal Langerhans cells to other dose-response relationship (Friedmann et al. 1983;
epidermal cells in healthy human skin Friedmann 2007) is seen, whereas the total dose
(1 Langerhans cell keeps 53 epidermal cells may vary over a wide range. Therefore crucial
under immune surveillance (Bauer et al. 2001)) factors seem to be what is happening on the skin
is altered by experimental barrier disruption surface. A number of molecules of the antigen will
through acetone or sodium lauryl sulfate which diffuse into the stratum corneum, and in the case of
increases the Langerhans cell density within the ointments, drugs etc. the number being determined
by the concentration in the vehicle and the partition reaction is seen. Immunologically induced
coefficients and relative solubility of the substance alterations in epidermal differentiation result in
in the vehicle and the SC. increased epidermopoises (Jensen et al. 2004;
Proksch et al. 1990). Additionally, recent
hypothesis discuss an association between bar-
6 Susceptibility of Individuals rier dysfunction, filaggrin mutation in subgroups
to Sensitization and Irritation of atopic eczema (associated with allergic
asthma, rhinitis, Type-I-IgE sensitisation, early
There are very strong interindividual variations in onset and persistence into adulthood of
susceptibility to irritation which might be either coexisting ichthyosis vulgaris (O’Reagan and
explained by the differences in skin barrier Irvine 2008). There has always been ongoing
properties as shown by analyzing SLS permeation discussion if the barrier in non-eczematous skin
rate through stratum corneum (de Jongh et al. of atopics is disturbed and thus facilitates pene-
2006) but also due to the variations regarding the tration. Recent studies have shown that penetra-
inflammatory response (Judge et al. 1996). A tion of SLS is increased in uninvolved skin of
combination between individual susceptibility to patients with atopic eczema (Jakasa et al. 2006).
allergies (Type IV) and irritant reactions has been They also found that penetration coefficient
shown in persons who show cytokine gene poly- of polyethylene glycols (PEGs) of varying
morphism (IL1 genotypes, TNF-alpha genotypes) molecular sizes through atopic skin was twice
(Blomeke et al. 2008; de Jongh et al. 2008a, b; as high compared to normal skin. In some
Westphal et al. 2003). cases, the epidermis of nonaffected atopic skin
There is also clinical evidence that certain shows signs of suppressed synthesis of
genetic disorders with barrier impairment keratohyalin (Profilaggrin) with a histologically
show only an increase in type I reactions perceptible reduction in thickness of granular
and not type IV. This is known for the barrier layers (Fartasch et al. 1998; Jensen et al. 2004).
defect in Netherton’s syndrome (NS), a rare Yet, recent molecular biological studies show a
autosomal recessive disorder characterized by firm association between ichthyosis vulgaris
a generalized inflammatory skin condition, a and loss-of-function mutations in the filaggrin
specific hair shaft abnormality (trichorrhexis (FLG) gene as carried by 16.7–56% of all
invaginata) and invariably, atopic manifesta- individuals with atopic dermatitis (Palmer et al.
tions. NS shows loss of SC cohesion 2006). Additionally, recent studies have
(desmoglein) due to defective LEKTI expression highlighted an association of FLG mutations in
(loss of function mutations in SPINK5 atopics with nickel sensitization (Type IV
chrom.5q31) (Chavanas et al. 2000) and proba- sensitization) and with reactions with
bly secondarily induced altered lamellar body jewelry but with lack of association with Type
secretion and stratum corneum membrane struc- IV sensitizations to other common haptens
tures (Fartasch et al. 1999). As a consequence, (Novak et al. 2008). Since filaggrin is a precur-
there is a loss of SC adhesion affecting skin sors of natural moisturizing factors (NMF) inside
barrier functions. NS shares several clinical fea- of the corneocytes, the relation with penetration
tures with atopic eczema (AE) and greater of small allergens is not clear (Kezic 2008).
inflammatory reactivity.
AE, a common chronic inflammatory skin
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Percutaneous Penetration
2
Austin Jiang, Howard I. Maibach, Aaron Wiener, and
Rasika Reddy
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3 Factors Affecting Percutaneous Penetration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4 In Vivo Methods for Determining Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4.1 Radioactivity in Excreta and Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4.2 Surface Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4.3 Surface Disappearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.4 Biological/Pharmacological Response and Impedance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.5 Stripping Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5 Human Skin Flap Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6 In Vitro Methods for Determining Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7 Current Recommendations on Percutaneous Penetration Methods . . . . . . . . . . 15
A. Jiang (*)
University of Cincinnati College of Medicine,
Cincinnati, OH, USA
e-mail: austinjiang13@gmail.com
H. I. Maibach
Department of Dermatology, University of California,
e-mail: Howard.Maibach@ucsf.edu
A. Wiener
University of California (UCSF), San Francisco, CA, USA
e-mail: AIWiener@ucsc.edu
R. Reddy
Department of Dermatology, Veterans Affairs Medical
Center, San Francisco, CA, USA
UT Southwestern Medical Center in Dallas, Texas, USA
e-mail: rasikareddy1019@gmail.com

https://doi.org/10.1007/978-3-319-68617-2_2
12 A. Jiang et al.
8 Influence of Vehicle on Percutaneous Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

9 Skin Cleansing and Decontamination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Keywords 2 Introduction
Impedance · Skin metabolism · Skin
decontamination · 15 factors of percutaneous Workplace chemical exposure especially when
penetration repetitive over weeks, months, and years has led
to systemic (internal organ) toxicity such as bladder
cancers and sterility. This chapter provides an intro-
1 Core Messages duction into the readily available techniques for
quantification of some of the 15 steps to percutane-
• Many intrinsic and extrinsic factors affect ous penetration. It is suspected that some so-called
percutaneous absorption rates. idiopathic diseases will eventually be documented
• Percutaneous absorption is measured in to be due to such occupational skin exposure. This
vivo through different methods, including summary also provides an introduction to the meth-
radioactivity measurements in the blood odology so that occupational health workers can
and excreta, surface recovery, surface dis- most efficiently collaborate with laboratories
appearance, biological and pharmacolo- performing such assays. Methods described here
gical responses, the stripping method, and are relevant to animal and man.
human-skin-flap method.
• In vitro methods include measuring absorption
rates through excised skin into a receptacle 3 Factors Affecting Percutaneous
designed to mimic actual dermatological Penetration
conditions.
• Measuring the radioactivity in a subject’s Many factors, both intrinsic and extrinsic, influence
blood and excreta is commonly practiced, the absorption of chemicals through skin (Table 1).
and involves administering a compound Dose, duration, and surface area of exposure have a
often radiolabeled, in order to measure the clear role in the extent of percutaneous absorption. A
amount of the original dose that has pene- large degree of regional variation exists depending
trated the skin. on the body site contaminated. This is due to the
• Surface recovery and disappearance methods differences in hydration levels, lipid and sebum con-
involve administering a compound on the skin tent, and the hair follicle density of the skin (Dancik
and measuring the rate of recovery from et al. 2015). Whether or not the skin is damaged or
the surface of the skin or the rate of its affected by a dermatological condition also has an
disappearance. impact on the absorption. Increased local and sur-
• The stripping method deals with measuring rounding room temperature enhances percutaneous
the concentration of a chemical in the stratum absorption (Dancik et al. 2015), as does increased
corneum through successive tape applications relative humidity (Zhu et al. 2015). UVexposure has
and removals. an impact on percutaneous absorption as well, and
• Efforts are being made to standardize the most further research is needed to establish this effect.
commonly used in vitro assay. Skin metabolism of chemicals also has
• The vehicle by which a compound is transferred an impact on percutaneous absorption. Some
to the skin has an effect on its absorption rate. chemicals require metabolism in order to fully
2 Percutaneous Penetration 13
Table 1 15 Factors of percutaneous penetration (Ngo and detection after topical application, it may be
Maibach 2012) necessary to use radiotracer methodology. The
1. Physiochemical properties of penetrant administered compound is usually labeled with
2. Vehicle effects 14C or tritium and is applied to the skin. Measure-
3. Dose, duration, surface area, and frequency ments of radioactivity are taken from the blood,
4. Sub-anatomical pathways urine, or urine and feces combined. Radioactivity
5. Regional variability measurements include a mixture of both the
6. Population variability applied compound and metabolites (Wester and
7. Surface conditions
Maibach 2002). Since the compound in question
8. Health and integrity
can be retained in the body or exit through
9. Substantivity and binding
methods other than the measured excreta (sweat-
10. Distribution
ing, breathing), the amount of radioactivity
11. Exfoliation
12. Wash effect
detected is corrected by measuring the amount
13. Metabolic and photochemical transformation of radioactivity excreted after parenteral
14. Excretion kinetics administration.
15. Method of determination The equation for determining percutaneous
absorption is expressed as:
Total Reactivity After Topical Administration

penetrate the skin. Sugino et al. demonstrated 100 ¼ %
Total Radioactivity After Parental Administration
that dialkyl phthalates, when applied to the (1)
skin, were only able to penetrate beyond the
epidermis and dermis if hydrolyzed into Measurements of radioactivity in the blood
phthalate monoesters (Sugino et al. 2017). If this of a subject or animal have given similar results
hydrolysis was inhibited, then the dialkyl to those obtained through excreta (Wester
phthalates remained in the stratum corneum. and Maibach 2002). A limitation on using
When the phthalate monoesters were applied radioactivity as a means of measuring absor-
directly into the skin, there were lower levels of ption is that metabolism by the skin is not
penetration of phthalate monoesters compared to accounted for.
when the dialkyl phthalates were applied. Other
chemicals may undergo similar skin metabolism
to those in this example; the impact of skin metab-
4.2 Surface Recovery
olism on other chemicals is an area requiring
further study.
This method of determining percutaneous
absorption involves measuring the amount of
compound that penetrates into the skin. It is
4 In Vivo Methods for assumed that the difference between the
Determining Absorption applied dose and the residual dose collected
after the trial period is the absorption.
4.1 Radioactivity in Excreta and Finding accurate results with this approach
Blood is difficult, since materials are able to leave
the surface of the skin without penetra-
Percutaneous absorption in vivo is commonly ting; thus full recovery of the residual compound
determined by chemical measurements (and/or is never assured. Properties of the radio-
radioactivity) taken in a subject’s or animal’s isotope, penetrant, and vehicle place limits on
blood or excreta. Since levels of a compound are how useful this method can be (Wester and
often found to be below the level required for Maibach 2002).
14 A. Jiang et al.
4.3 Surface Disappearance of a chemical in the stratum corneum after a 30-min

application period. Through linear extrapolation, the
Using appropriate instrumentation, it is possible percutaneous absorption is predicted for application
to measure the disappearance of a 14C-labeled periods longer than 30 min. The chemical is applied
compound from the surface of the skin. Disap- to the skin of animals or humans, and after the
pearance of 14C is due to both the movement of application period, the stratum corneum is removed
the compound into the skin, and the quenching by successive tape application and removal
effect of beta rays bouncing back into the measur- (Rougier et al. 2002). A linear relationship between
ing instrument, which places a limitation on the stratum corneum’s content of a tested chemical
this kind of measurement. Placing a sheet of the and the percutaneous absorption using standard
stratum corneum over a quantity of radiolabeled radioactive excretion methods has been established.
chemical and then measuring the radioactivity This method has considerable advantage over other
with an external device will exhibit this effect methods in the fact that non-radiolabeled assays
(Wester and Maibach 2002). may be tested, and urinary and fecal excretions
become unnecessary. This method requires more
research to establish more accurate limitations
4.4 Biological/Pharmacological (Wester and Maibach 2002).
Response and Impedance
In this method of determining percutaneous absorp- 5 Human Skin Flap Method

tion, a biological assay is substituted for a chemical
assay. The great limitation of this method is that In a developing close-to-in vivo method,
assays are limited to compounds that will elicit a human skin harvested from patients undergoing
response that can be easily and accurately measured. abdominoplasty is used to measure percutaneous
Results from this methodology are more qualitative absorption. The skin is attached to a perfusion appa-
than quantitative (Wester and Maibach 2002). ratus in experimental conditions mimicking physi-
Another method to estimate in vivo percutane- ological conditions. The chemical is applied to the
ous absorption in animals is whole body autora- perfused skin, and the amount of the chemical in the
diography. This procedure provides a picture of perfusate is measured. Initial studies have shown
absorption followed by the involvement of other that this method has the potential to be considered
body tissues (Wester and Maibach 2002). more representative of in vivo studies than ex vivo
Measuring the bioimpedance of a transdermal human skin studies (Ternullo et al. 2016). This
substance is a novel method of measuring method requires future research in establishing this
percutaneous absorption. This method entails effect. A significant limitation to this method is the
measuring the resistance of the skin before availability and procurement of live human skin.
and after application of a conduction substance.
There is a linear relationship between the amount
of the injected substance and the impedance 6 In Vitro Methods for
spectrum in vivo studies with human subjects Determining Absorption
(Arpaia et al. 2017). This method requires further
investigation into reducing interindividual Skin removed from humans or animals can be used
reproducibility. to measure percutaneous penetration of chemicals.
The skin is stretched over the opening of a collecting
receptacle, a Franz cell, with the epidermal side
4.5 Stripping Method facing up. The chemical in question is applied, and
fluid in the receptacle is assayed at intervals to
The stripping method determines percutaneous ab- measure the penetration. The collecting fluid used
sorption through measurements of the concentration is usually water or saline. Either the entire thickness
of the skin or just the epidermis may be used for in 7 Current Recommendations on
vitro assays. Some variations on this method require Percutaneous Penetration
that the excised skin be covered with fluid Methods
containing the chemical, but the preferred method
is to expose one side of the skin to the air, while the In vitro assays using human skin have become
underside is bathed in saline or other receptacle the preferred method for measuring percutane-
fluids. Since diffusion requires a concentration gra- ous penetration (WHO 2006; EFSA 2012). The
dient, some receptacles have been designed to allow skin of common laboratory animals (rats, guinea
repeated replacement of the receptacle fluid. The pigs, etc.) has demonstrated a significantly
fluid is usually continuously stirred and maintained higher penetration potential than that of human
at a temperature appropriate to the chemical in ques- skin (Jung and Maibach 2015). Nonetheless, in
tion (Maibach and Patrick 2001). the United States, the US Environmental Protec-
This method is advantageous to in vivo assays tion Agency maintains a requirement to conduct
because it allows highly toxic chemicals to be in vivo studies when determining dermal absorp-
tested, but just like any other method, it has limitation for pesticides. The North American Free
tions. Because the skin must be stored before its use Trade Agreement (NAFTA) recommends a triple
in an assay, it cannot be assumed that the skin will pack approach for human health risk assess-
metabolize chemicals in the same manner as living ments for pesticides: studies with in vitro rats,
skin. When using full-thickness skin, the dermis in vivo rats, and in vitro humans (NAFTA
can influence the absorptive process. This influence 2008). A workshop was held in 2012 in Gaithers-
may be minimized by heat separating the dermis burg, Maryland, USA, in order to work
from the stratum corneum; however, the viability of toward standardizing the in vitro assay for pesti-
the skin may be destroyed in the process. Often, the cide risk assessment. The workshop identified
suitability of each specimen of skin is verified certain protocol elements that were a source
through a measurement of the penetration of of variation between in vitro assays that
titrated water through the tissue, prior to a chemical included characteristics of skin used, receptor
assay (Maibach and Patrick 2001). fluid choice, and barrier function testing
Multiple studies have been done to find an method. Extensive evidence-based recom-
alternative in vitro method that addresses con- mendations for the protocol of human skin
cerns of viability and standardization with the in vitro assays were made at the conclusion of
Franz cell (Herbig et al. 2015; Planz et al. 2016), this workshop, which included standardizing
as well as concerns of realistic applicability of this skin variables, skin preparation, model prepara-
method for risk assessment (Clarke et al. 2015). tions, substance application methods, and
Future studies are needed to further establish any measurement methods.
of these various methods.
How relevant are in vitro penetration assays as
related to in vivo data in humans? Lehman summa- 8 Influence of Vehicle on
rized the extensive comparisons and identified 11 out Percutaneous Absorption
of 92 comparisons as being readily interpretable in
terms of this point (Lehman et al. 2011). The original Substances added to a formula can influence
article should be read in detail; nevertheless, Lehman the release, absorption, and action of an applied
states that the 11 studies suggest a reasonable con- drug. Experiments have shown that doses
cordance when taking into account the anatomic administered through different vehicles will ini-
exposure site, vehicle, and dose. This important tially have differing absorption rates. As time
question clearly requires further documentation/val- passes, the influence of the vehicle decreases,
idation, as few human in vivo studies are being and the absorption rate becomes constant for all
performed – with the exception of transdermal vehicles. Vehicles have the ability to increase or
drugs being registered by the American FDA. decrease water levels in the stratum corneum,
16 A. Jiang et al.
resulting in increased or decreased penetration. References

Additionally, it is hypothesized that a multiple-
dose administration of a vehicle can “reactivate/ Arpaia P, Cesaro U, Moccaldi N (2017) Noninvasive mea-
surement of transdermal drug delivery by impedance
solubilize” the original chemical preventing it
spectroscopy. Sci Rep 7:44657
from binding to the skin, as well as push the Chan HP, Zhai H, Hui X, Maibach HI (2012) Skin decon-
chemical into and through the skin (Wester and tamination. Toxicol Ind Health 29(10):955–968
Maibach 2001). Clarke JF, Cordery SF, Morgan NA et al (2015) In vitro
method to quantify dermal absorption of pesticide res-
idues. Chem Res Toxicol 28(2):166–168
Dancik Y, Bigliardi PL, Biglairdi-Qi M (2015) What
9 Skin Cleansing and happens in the skin? Integrating skin permeation kinetics
into studies of developmental and reproductive toxicity
Decontamination following topical exposure. Reprod Toxicol 58:252–281
EFSA (2012) European food safety authority panel on plant
While it is largely assumed that washing with protection products and their residues. Scientific opinion
soap and water can decontaminate a chemical – guidance on dermal absorption. EFSA J 10:1–30
Herbig ME, Houdek P, Gorissen S, Zorn-Kruppa M,
from the skin, the skin and the body are often Wladykowski E, Volksdorf T, Grzybowski S, Kolios
subjected to enhanced penetration because the G, Willers C, Mallwitz H, Moll I, Brandner JM (2015)
decontamination will increase absorption of the A custom tailored model to investigate skin penetration
chemical. The occurrence of this “wash-in” in porcine skin and its comparison with human skin.
Eur J Pharm Biopharm 95:99–109
effect is dependent upon the identity of the Hui X, Lamel S, Qiao P, Maibach HI (2013) Isolated
chemical that has contaminated the skin (Zhu human/animal stratum corneum as a partial model for
et al. 2015). Soap and water washing is effective 15 steps in percutaneous absorption: emphasizing
at removing visible dirt and odor; however, it decontamination, Part I. J Appl Toxicol 33(3):157–172
Jung EC, Maibach HI (2015) Animal models for percuta-
may not be the best as a skin cleanser, especially neous absorption. J Appl Toxicol 35:1–10
in the case of fat-soluble materials (Maibach and Lehman PA, Raney SF, Franz TJ (2011) Percutaneous
Patrick 2001). absorption in man: in vitro-in vivo correlation. Skin
Upon chemical exposure to the skin, there Pharmacol Physiol 24:224–230
Maibach H, Patrick E (2001) Chap 22, Dermatotoxicology.
are many methods of skin decontamination In: Hayes AW (ed) Principles and methods of toxicol-
that one has to choose from. These include ogy. Taylor and Francis, Philadelphia, pp 1039–1084
physical removal, solvation, chemical alteration, NAFTA (2008) Dermal absorption group position paper on
adsorption and absorption, and friction (Chan use of in vitro dermal absorption data in risk assess-
ment. Unpublished; available upon request: North
et al. 2012). The method of decontamination American Free Trade Agreement Dermal Absorption
to be selected is dependent on the chemical Working Group, 1–3
identity. The efficacy of these decontamination Ngo M, Maibach H (2012) Chap 6, 15 Factor of
methods is continually being evaluated, and percutaneous penetration of pesticides. In: Knaak JB,
Thimchalk C, Tornero-Velez R (eds) Parameters
current knowledge can be found in the refer- for pesticide QSAR and PBPK/PD models for human
ences (Chan et al. 2012; Hui et al. 2013; Phuong risk assessment. American Chemical Society, Washing-
et al. 2016). ton, DC, pp 67–86
Phuong C, Maibach HI (2016) Effect of massage on per-
cutaneous penetration and skin decontamination: man
and animal. Cutan Ocul Toxicol:1–4
10 Conclusion Planz V, Lehr C-M, Windbergs M (2016) In vitro models
for evaluating safety and efficacy of novel technologies
for skin drug delivery. J Control Rel 242:89–104
Taken together, human/animal in vivo percutan- Rougier A, Dupuis D, Lotte C, Maibach HI (2002)
eous penetration remains a vast territory still Chap 16, Stripping method for measuring percutaneous
requiring extensive investigation. This chapter absorption in vivo. In: Bronaugh RL, Maibach HI (eds)
Topical absorption of dermatological products. Marcel
opens the door; Ngo and Maibach provide a look
Dekker, New York, pp 241–245
into complexities yet to be investigated (Table 1) Sugino M, Hatanaka T, Todo H, Mashimo Y et al (2017)
(Ngo and Maibach 2012). Safety evaluation of dermal exposure to phthalates:
metabolism-dependent percutaneous absorption. Toxi- Wester RC, Maibach HI (2002) Chap 9, In vivo
col Appl Pharmacol 328:10–17 methods for percutaneous absorption measurement.
Ternullo S, de Weerd L, Flaten GE, Holsæter AM, Škalko- In: Bronaugh RL, Maibach HI (eds) Topical absorption
Basnet N (2016) The isolated perfused human skin flap of dermatological products. Marcel Dekker, New York,
model: a missing link in skin penetration studies? Eur pp 145–149
J Pharm 96:334–341 WHO (2006) Dermal absorption, in Environmental
Wester RC, Maibach HI (2001) Chap 7, Principles and Health Criteria. Geneva, Switzerland. ISBN 92-4-
practice of percutaneous absorption. In: Barel AO, 157235
Paye M, Maibach HI (eds) Handbook of cosmetic Zhu H, Jung EC, Phuong C et al (2015) Effects of soap-
science and technology. Marcel Dekker, New York, water wash on human epidermal penetration. J Appl
pp 53–59. Part 3: Safety considerations Toxicol 36(8):997–1002
Quality of Life (QoL) in Relation to
Occupational Skin Diseases 3
Tove Agner
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3 How Is QoL Assessed? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.1 Examples of Available Self-report Questionnaires . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4 QoL in Occupational Skin Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5 QoL Score Used for Regulation of Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
HR-QoL · Occupational skin disease · Contact
dermatitis During the last decades, there has been an
increased focus on research in health-related
quality of life (HR-QoL). This concept gener-
1 Core Messages ally refers to the perception of the effects of a
disease and its impact on the patient’s daily
• Different instruments for assessment of HR- functioning and incorporates the patient’s per-
QoL are compared and discussed. The influ- sonal perspective including the impact of dis-
ence of demographic and disease-related fac- ease on everyday life activities and life
tors on HR-QoL is discussed, and the satisfaction. Research in HR-QoL has rapidly
importance of including HR-QoL instruments become an important outcome variable in der-
as outcomes in clinical trials is emphasized. matology research, where today also other
aspects such as the total burden of the disease
are being taken into account. HR-QoL instru-
ments may also be used in the clinical setting
as part of severity assessment. Especially
T. Agner (*) within the area of occupational skin diseases,
Department of Dermatology, Faculty of Health Science, evaluation of HR-QoL is important, since fac-
Bispebjerg Hospital, University of Copenhagen, tors such as sick leave and job change or job
Copenhagen NV, Denmark
e-mail: Tove.Agner@regionh.dk loss may significantly influence the patient’s

https://doi.org/10.1007/978-3-319-68617-2_3
20 T. Agner
perception of the severity of the disease. Vari- During the last decade, there has been an
ous instruments for assessment of HR-QoL will increased focus on research in HR-QoL. This
be discussed in this chapter. research incorporates the patient’s personal per-
Severity assessment of occupational hand spective including the impact of disease on every-
eczema (OHE) is important in clinical settings as day life activities and life satisfaction. Since
well as in research. Traditionally, severity of skin Finlay and Khan first introduced the Dermatology
diseases is evaluated from the clinical appearance of Life Quality Index (DLQI) as a practical clinical
the disease by the doctor. However, this evaluation measure for disease severity (Finlay and Khan
may very well be misleading. The clinical picture 1994), research in QoL has rapidly become an
reveals only the current situation, and not the fre- important outcome variable in dermatology
quency of eruptions, does not include the subjective research. Also other aspects such as the total bur-
perception of symptoms such as pain and itch, or den of the disease, including the economical costs
psychosociological factors such as restraints on lei- borne by the society, have increasingly been taken
sure activities, sick leave from work, impaired social into account (Diepgen et al. 2007).
contact, time-consuming treatments, and even
embarrassment. The clinical symptoms may also
bother different people to a very different degree: 3 How Is QoL Assessed?
While some people as an example tend to live quite
well with a mild or even moderate eczema, other HR-QoL is usually assessed using patient ques-
people may find it extremely bothering, either due to tionnaires, either emailed or posted to patients or
limitation in handling of ordinary daily living activ- given to patient to fill in before, during, or after
ities or due to cosmetic reasons, and some may find consultation. Three different instruments are used:
it to cause a social handicap.
The relation between self-rated severity and Generic questionnaires. This type of questionnaire
severity assessment based on standardized medical gives a global assessment of the impact on HR-
certificates issued by dermatologists in a popula- QoL. These questionnaires are not specific for
tion of 758 patients with occupational hand eczema dermatological diseases, and incorporate infor-
was studied, and major differences in the criteria mation about influence of the general health
for self-rated severity versus dermatologist-rated status on QoL. Generic questionnaires can be
severity were found (Cvetkovski et al. 2005). used across different patient populations,
While 40% of the patients responding to a ques- enabling researchers to compare QoL in skin
tionnaire described themselves as having severe diseases with other medical conditions (Harlow
eczema, only 18% were judged as severe by the et al. 2000; Moberg et al. 2009).
dermatologists. These data make it clear that dis- Dermatology-specific questionnaires. These ques-
ease should be evaluated from more angles than tionnaires are designed to assess the impact on
just the classical medical angle, in research projects QoL in different skin conditions and are there-
as well as in the daily clinical work. fore able to describe specific effects in derma-
Public health has been defined as “the science tology. This type of questionnaire allows
and art of promoting health,” based on the under- comparison between the impact on QoL
standing that health is a process engaging social, between different skin diseases (Finlay and
mental, spiritual, and physical well-being Khan 1994; Finlay 1998; Chren et al. 1996;
(Kickbusch 1989). Health-related quality of life Anderson and Rajagopalan 2001). This instru-
(HR-QoL) generally refers to the perception of the ment has also been developed for children with
effects of a disease and its impact on the patient’s skin diseases (Lewis-Jones and Finlay 1995).
daily functioning. HR-QoL is the perceived func- Disease-specific questionnaires. Disease-specific
tioning in physical, psychological, and social questionnaires focus on one particular skin
dimensions and is therefore a more holistic assess- condition, for example, hand eczema (Ooster-
ment than the clinical examination. haven et al. 2017).
3 Quality of Life (QoL) in Relation to Occupational Skin Diseases 21
3.1 Examples of Available Self- Dermatology-Specific Quality of Life (DSQL)

report Questionnaires (Anderson and Rajagopalan 2001)
The DSQL consists of 52 items and is esti-
Generic Questionnaires mated to take 15 min to complete. The items
SF36 (Short Form 36) (Harlow et al. 2000) cover seven different subscales: physical symp-
The SF-36 is a multipurpose, short-form health toms, activities of daily living, social functioning,
survey with only 36 questions. It yields an 8-scale work/school functioning, self-perception, general
profile of functional health and well-being scores mental health, and vitality.
as well as psychometrically based physical and
mental health summary measures. Disease-Specific Questionnaires (Related to
EQ-5D (http://www.euroqol.org/; Moberg Occupational Eczema)
et al. 2009) The Quality of Life in Hand Eczema Question-
The EQ-5D is a standardized instrument for naire (QOLHEQ) covers the domains of (i) symp-
use as a measure of health outcome. Applicable toms, (ii) emotions, (iii) functioning, and (iv)
to a wide range of health conditions and treat- treatment and prevention (Ofenloch et al. 2014;
ments, it provides a simple descriptive profile Oosterhaven et al. 2017).
and a single index value for health status. The
EQ-5D is a generic instrument that has been For assessment of HR-QoL in dermatology, the
developed and refined by an international best validated instruments/questionnaires are
group of researchers since 1987. Respondents DLQI and Skindex-29 (Chren et al. 1997; De
complete the EQ-5D by choosing one of three Korte et al. 2002; Zachariae et al. 2000; Agner
severity levels on five questions covering et al. 2013). Components from the generic
five dimensions: mobility, self-care, usual activ- questionnaire, the SF-36, have been used to
ities, pain/discomfort, and anxiety/depression. supplement a number of dermatology-specific
Responses on the five dimensions are used to questionnaires, and recently the use of EQ-5D
create an index, a single value for each health has also been positively evaluated (Moberg
profile. et al. 2009).
Dermatology-Specific Questionnaires
DLQI (Finlay and Khan 1994; Finlay 1998) 4 QoL in Occupational Skin
The DLQI consists of ten items (score range Disease
0–30) covering six categories: symptoms and
feelings, daily activities, leisure, work/school, The most commonly notified and recognized
personal relationships and treatment, and takes occupational skin disease in Scandinavia as well
3–5 min to complete. Score 0 means that QoL is as in most European countries is hand eczema,
totally unaffected by the disease, while a score of which comprises more than 90% of all occupa-
30 is maximum. Scores above 10 are generally tional skin diseases. No major changes in the
accepted as severe influence on QoL of the disease incidence of occupational hand eczema have
(Cvetkovski et al. 2006). The minimal clinical taken place for the past few decades, despite pre-
important difference in DLQI was recently vali- ventive efforts and legislative regulations. In
dated (Basra et al. 2015). Scandinavia, the one-year prevalence of hand
Skindex-29 (Chren et al. 1996) eczema is 9.5% (Meding and Järvholm 2004),
Skindex-29 consists of 29 items and one addi- and it is estimated that 10% of all cases of hand
tional item concerning adverse effects of treat- eczema is due to occupational exposures (Lerbaek
ment. It consists of three separate subscales et al. 2008). The prognosis is generally poor, in
covering symptoms, functioning, and emotions. particular for occupational cases (Shah et al. 1996;
The response format is a five-point Likert scale. Wall and Gebauer 1991; Meding et al. 2005). In
Completion time is estimated to be 5 min. some cases, hand eczema adversely affected
22 T. Agner
patients’ social lives. Hand eczema may constitute atopic eczema were independent risk factors for
a considerable problem for the individual, since it low QoL, and sick leave was also found to have a
may disturb sleep and hamper leisure activities significantly negative influence on QoL. Severity
and, as an occupational skin disease, it may lead of hand eczema, as assessed by the HECSI scoring
to sick leave and eventually result in a change of system (Held et al. 2005), was found significantly
occupation (Fowler 2008; Braun and Dotterud inversely related to HR-QoL, while subgroups
2016). Individuals with more severe, recurrent, of hand eczema were not related to QoL (Diepgen
or protracted hand eczema can endure serious et al. 2009).
psychosocial symptoms and a substantially The effect of allergic contact dermatitis on QoL
impaired QoL (Brans et al. 2016; Cvetkovski was investigated (Kadyk et al. 2003). A total of
et al. 2006). 428 subjects with allergic contact dermatitis were,
It has also been investigated if people with at varying times after diagnosis, mailed the
hand eczema showed symptoms of depression; Skindex-16 dermatology-specific questionnaire,
however, symptoms of depression could not modified to include an additional five items
directly be connected to hand eczema (Cvetkovski pertaining to occupational impact. The results
et al. 2006). An independent association was showed that occupationally related allergic con-
found between severe OHE and severely affected tact dermatitis was associated with worse QoL
QoL, and also low socioeconomic status was and that hand involvement also had a significantly
independently associated with low QoL negative impact on QoL. Subjects that had
(Cvetkovski et al. 2006) (Table 1). changed jobs because of allergic contact dermati-
In a study, with participation of ten different tis had more severe QoL impairment than any
patch test clinics from different European coun- other group analyzed. Patients with allergic con-
tries, QoL was investigated in patients with hand tact dermatitis of the face were significantly more
eczema, using the DLQI instrument (Agner et al. bothered by the appearance of their skin. Early
2008, 2009). A total of 416 (252 women and 164 diagnosis was shown to have a positive influence
men) were included, DLQI was 8.0 for women of QoL. It was concluded that allergic contact
and 7.0 for men, although the severity of hand dermatitis has an appreciable effect on QoL, espe-
eczema was assessed significantly higher for men cially when it affects the hands and the face or is
than for women. High age and personal history of occupationally related. Of the four scales included
Table 1 Factors influencing HR-QoL in patients with occupational hand eczema (OHE)
Factors
influencing QoL Influence on QoL Reference
Severity Severe OHE is associated with low QoL Agner et al. 2008; Cvetkovski et al. 2006; Petersen
et al. 2014; Cazzaniga et al. 2016
Age High age is related to low QoL Agner et al. 2008; Cvetkovski et al. 2006
Gender More impaired QoL for females than for Agner et al. 2008; Wallenhammar et al. 2004;
males Petersen et al. 2014; Cazzaniga et al. 2016
Socioeconomic Low socioeconomic status is associated Cvetkovski et al. 2006
status with low QoL
Atopy Previous or current atopic eczema is Agner et al. 2008; Cvetkovski et al. 2006
associated with low QoL
Sick leave Sick leave is associated with low QoL Agner et al. 2008
Allergic contact The effect of allergic contact dermatitis is Kadyk et al. 2003; Diepgen et al. 2009; Cazzaniga
dermatitis discussed et al. 2016
Early diagnosis Early diagnosis has a positive influence on Kadyk et al. 2003
QoL
Change of job Associated with low QoL Kadyk et al. 2003; Carøe et al. 2018; Cazzaniga
et al. 2016
in our study, the emotions scale suffered the medicaments may be used has been introduced
greatest effect. Emotional impact is therefore an by the authorities. Severity assessment of the dis-
important measure of QoL in allergic contact der- ease has become important within this discussion,
matitis patients (Kadyk et al. 2003). and here also the impact of the disease on HR-
A comparison between a generic questionnaire QoL has been looked upon (Smith et al. 2009;
(SF-36) and the dermatology-specific question- Ingram et al. 2009; http://www.nice.org.uk/
naire (DLQI) for assessment of HR-QoL in TA177; Rodgers et al. 2010).
patients with hand eczema was performed Assessment of disease severity for work-
(Wallenhammar et al. 2004). The QoL was signif- related skin disease/occupational hand eczema is
icantly negatively affected by hand eczema, mea- important when new treatment options become
sured with both SF-36 and DLQI. The SF-36 available and when multidisciplinary care for
showed more impaired HR-QoL for females than hand eczema is introduced (van Gils et al. 2009).
for males, in the mental health dimension, HR-QoL has become an increasingly important
whereas no gender-related differences were aspect of this, but new instruments have become
detected with the DLQI, and it was concluded available which evaluates also the effect of treat-
that in this aspect the SF-36 was superior ment from the patient’s point of view. The “Patient
(Wallenhammar et al. 2004). Benefit Index” (PBI) is a validated instrument for
Another population-based study also used a the assessment of such benefits in patients with
generic questionnaire, the EQ-5D (Moberg et al. skin diseases, where patients rate the importance
2009). A questionnaire was sent to 57,009 ran- of specific treatment needs before treatment and
domly selected individuals aged 18–84 years. The benefits achieved after treatment (Augustin et al.
questionnaire included a validated question 2009). This instrument has also been introduced
concerning hand eczema (“have you ever had for evaluation of treatment benefit in patients with
hand eczema”), as well as the EQ-5D. The study hand eczema (Blome et al. 2009).
confirms that HR-QoL measured with the EQ-5D Counting the HR-QoL in the total assessment
is negatively affected in individuals with hand of severity of skin disease, including work-
eczema. The mean EQ-5D index was significantly related skin diseases, has become an important
lower for those with hand eczema than for those part of outcome measures for epidemiological
without, both in the group as a whole and within studies and RCT-studies and is also used increas-
all age and gender subgroups. This indicates that ingly in the clinical setting, where treatment
hand eczema has an impact on HR-QoL for all guidelines may sometimes demand that HR-
those affected. The EQ-5D index was of the same QoL should be assessed. Dermatology-specific
size as those for psoriasis and asthma, all three questionnaires, supplemented with some ques-
common diseases with an impact on public health tions from generic questionnaires, have been
(Moberg et al. 2009). reliable tools; however, today a specific tool
directed at hand eczema patients has developed
and should be included.
5 QoL Score Used for Regulation
of Therapies
References
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Pharmacoeconomics of Occupational
Diseases 4
Matthias Augustin
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3 Basic Considerations on Economic Issues in Occupational Skin Diseases . . . 28
3.1 Definition and Evaluation of Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
3.2 Definition and Evaluation of Quality of Life and Patient Benefits . . . . . . . . . . . . . . . . 29
3.3 Pharmacoeconomic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4 Special Pharmacoeconomic Aspects in Occupational Skin Diseases . . . . . . . . . . 30
4.1 Cost Factors in Occupational Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.2 Quality of Life and PRO in Occupational Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.3 Predictors of Costs in Occupational Diseases from the Societal Perspective . . . . . 32
4.4 Cost-Effectiveness Data on Interventions in Occupational Skin Diseases . . . . . . . . 33
4.5 Conclusions from the Economic Data on Occupational Skin Diseases . . . . . . . . . . . 33
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Abstract impact on work, the annual costs are in the

Due to its increasing frequency and the wide- same range or even exceed those for chronic
ranging consequences for the affected inflammatory skin disease like psoriasis and
patients, occupational skin diseases are of atopic eczema. Moreover, significant limita-
great socioeconomic importance. In light of tions of quality of life are reported for patients
this, clinical and epidemiological research is with occupational skin diseases. The stress for
devoted increasingly to the effect of the dis- these patients in many studies exceeds that of
ease on quality of life and to costs. In all other skin diseases and also for chronic
studies published to date, there is a marked diseases.
economic relevance of occupational skin dis-
eases. Depending on the severity and the Keywords
Direct costs · Health-related quality of life
(HRQoL) · Indirect costs · Intangible costs ·
M. Augustin (*) Patient-reported outcomes (PRO) ·
Institute for Health Services Research in Dermatology and
Pharmacoeconomics
Nursing (IVDP), University Medical Center Hamburg-
Eppendorf (UKE), Hamburg, Germany
e-mail: m.augustin@uke.de

https://doi.org/10.1007/978-3-319-68617-2_4
28 M. Augustin
1 Core Messages 3 Basic Considerations

on Economic Issues
• From the economic point of view, occupational in Occupational Skin Diseases
skin diseases are relevant to the payers, the
patients, and the society. Medical economy or health economy is an empir-
• Major cost drivers are treatment costs (direct ical and theoretical, interdisciplinary science that
costs), cost for losses of work productivity aims at recording the production and allocation of
(indirect costs), and the patients’ burden of health services related to resource consumption
disease (intangible costs). and costs. The focus in this is a balanced use and
• From the societal view, the great number of distribution of goods, such as personnel, appara-
persons affected by occupational skin disease tus, medications, hospitals, and preventive and
is crucial. diagnostic measures, and the attendant efficiency,
• Effective treatments for occupational skin effectiveness, quality, and fairness in dealing
diseases reduce the cost burden and increase with them.
work productivity and the patients’ quality Pharmacoeconomics is a subarea of health eco-
of life. nomics. It evaluates the costs and cost-benefit
• Preventive measures can be cost-effective if ratios of drugs and – in a larger sense – of thera-
applied in time and provided to persons at peutic procedures. Medical interventions are eco-
defined risks. nomically sound if the costs are in an appropriate
• Cost-benefit evaluation of interventions for ratio to the benefits. “Benefit” is determined either
occupational skin diseases requires a long- in the form of medical parameters (such as skin
term assessment period. scores), monetary units (such as costs of disease),
or intangible values (such as quality of life,
satisfaction).
It must be emphasized that from an economical
2 Introduction point of view, there is no intervention which is per
se “too expensive”. The price is only to be viewed
Due to its increasing frequency and the as in a favorable or unfavorable relationship to the
wide-ranging consequences for the affected achieved benefit. For this reason, a balance is
patients, occupational skin diseases are of needed between the costs accrued and the benefit
great socioeconomic importance. In light of achieved by an intervention.
this, clinical and epidemiological research
is devoted increasingly to the effect of the
disease on quality of life and to costs. This 3.1 Definition and Evaluation
chapter presents the status of research in these of Costs
two areas.
In all studies published to date, there is a According to international rules, costs in health
marked economic relevance of occupational economics are generally divided into three cate-
skin diseases. Depending on the severity and gories (Table 1): direct costs, indirect costs, and
the impact on work, the annual costs are in the intangible costs.
same range or even exceed those for chronic Direct costs are costs for the health service
inflammatory skin disease like psoriasis and (public or private health insurance system,
atopic eczema. Moreover, significant limitations national health system) and costs for the patients
of quality of life are reported for patients with (out-of-pocket expenses). They directly derive
occupational skin diseases. The stress for these from diagnostic, therapeutic, and preventive
patients in many studies exceeds that of procedures.
other skin diseases and also of other chronic Indirect costs included the secondary impact
diseases. of a disease due to losses of productivity and
4 Pharmacoeconomics of Occupational Diseases 29
Table 1 Forms of costs in pharmacoeconomic Table 2 Causes of relevant direct (1, 2) and indirect
evaluations (3) costs in occupational skin diseases
Cost form Perspective 1. Payer
Direct costs Costs in connection with treatment (insurance/
(a) Costs for the payers health service) 2. Patient 3. Economy
(b) Costs for the patient (out-of-pocket Drugs Self-medication Lost working
expenses) days
Indirect Costs to the economy arising from illness UV therapy Care products Loss of
costs productivity at
work
Intangible Nonmonetary costs (e.g., quality of life
costs impairment) Outpatient fees Prescription fees Costs for
(consultations) changes of
Hospitalization Patient-paid workplace
transportation
functional capacity. For this, they are accounted
Auxiliary Extra dietary
as costs for the national economy. Finally, materials costs
“intangible costs’’ are raised to the patients for Preventive Extra costs for
their burden of disease and losses of quality measures protective
of life. (facultative) measures
In discussing costs, it is thus necessary to cite Informational
material
the cost perspective. In many clinical studies, only
the costs of the drugs, that is, only a part of the
direct costs, are recorded. From the point of view
of the health insurance system, the total treatment 3.2 Definition and Evaluation
costs are relevant but not the direct costs for the of Quality of Life and Patient
patient. From the perspective of the economy, the Benefits
ability of the patient with occupational dermatitis
to work and his productivity are of interest. This The term “quality of life” (QoL) is a construct
may raise a conflict of interest since payments which cannot be directly measured (Bullinger
from the health insurances for treatment of occu- et al. 1993). However, it is of crucial importance
pational diseases (raising direct costs for them) in outcomes measurement, being one of the major
may lead to improved work ability (reducing indi- criteria for benefits from medical interventions.
rect costs for the employers). For this, economists Parameters like QoL which need to be obtained
prefer to assess health economic parameters from directly from the patient are called “patient-
a global societal perspective which includes all reported outcomes” (PRO).
distinct perspectives. In its general sense, QoL includes all condi-
In general, direct costs in health care derive tions necessary for the well-being of an individual
from fees to doctors or hospitals and from in society. In a narrower sense, it reflects the well-
costs for medication and other health devices being of a person in relation to his state of health.
(Spilker 1996). Moreover, transportation and In such sense, QoL is termed “health-related
other nonmedical costs can also be of importance. quality of life” (HRQoL). Among the factors in
Table 2 shows a summary of important cost- health-related QoL are “physical health,” “emo-
inducing factors in the direct costs. tional health,” “social life,” and “functional
International comparison shows that there capacity in everyday living” (Brock 1996;
are considerable differences in health systems Schipper et al. 1996). The “health-related quality
and in the mechanisms of cost reimbursement of life” can further be differentiated into “generic”
for patients with occupational skin diseases. quality of life, referring to general health condi-
Direct and indirect costs and their perspectives tions, and “disease-specific quality of life” which
strongly depend on the national health system, reflects the particular QoL situation in a given
the health market, and the reimbursement system. disease.
30 M. Augustin
The patients’ quality of life has been emphasized published by the German Dermatological Society
increasingly as a target criterion in almost every (DDG) as guidelines (Augustin et al. 2004).
area of medicine over the past decades. In addition Another approach for assessing patient benefits
to the clinical course and effects of costs, quality of in the care for patients with occupational diseases
life is increasingly included as an outcomes param- is the recording of patient-defined goals and
eter in economic studies (Spilker 1996). their achievements by “goal attainment scaling.”
Data on quality of life are needed not only in A particular method of such has been developed
clinical studies but also in everyday practice. It is for use in dermatology (Augustin et al. 2009) and
self-explanatory that in treating a patient with atopic especially in chronic hand eczema (Blome et al.
dermatitis, we obtain an impression of whether that 2009). In this PRO technology, the patients rate
patient’s quality of life is impaired or the extent to their preferences for potential treatment goals
which the planned treatment measures will have an before intervention. After the intervention, the
effect on this. The patient’s quality of life has always grade of achievement of the single items is
been the focus of clinical treatment in this respect, measured. A single, weighed index including all
even when it was not so explicitly stated in the past. preferences and outcomes (Patient Benefit Index,
Moreover, quality of life is a decisional param- PBI) indicates the overall patient benefit.
eter in health economics and health politics in
order to distribute the limited resources of the 3.3 Pharmacoeconomic Analyses
health system as fairly as possible where they are
needed. It is an expressed health-political objec- Economic evaluation is the comparison of two or
tive in all modern societies to apply the necessary more alternative courses of action in terms of both
financial resources to maintain or reinstate the their costs and consequences (Drummond and
quality of life in chronically ill patients. In McGuire 2001). It is obvious that the interpretation
order to do this, reliable data will be needed in of the costs for a medical procedure is depending on
the future on which to base these so-called cost the benefit that can be achieved. Thus, a validated
allocations. comparison of the input (in monetary units) and the
Assessing quality of life is based on the output (in monetary or other units) for any treat-
patient’s subjective view. Thus, it can only be ment or medication is necessary.
measured by interrogating the patient or his rela- This input-output comparison can be performed
tives (proxies). For methodological reasons, QoL on any level of the health system, e.g., the treatment
is mostly assessed by standardized questionnaires of a single patient, the cost-effectiveness of a drug,
instead of interviews. These questionnaires can be the performance of a clinic, or the health system in
generic or disease specific, the first permitting total. Depending on the parameters to be compared,
QoL assessment in a great range of diseases or the analysis of costs versus outcome is called cost-
even healthy persons, the latter being more ade- benefit analysis (costs vs. costs), cost-utility analysis
quate for the evaluation of problems specific to a (costs vs. quality of life), or cost-effectiveness anal-
certain disease. Hence, the choice of the right QoL ysis (costs vs. clinical parameters, like healing rate).
questionnaire is strongly depending on the partic-
ular purpose and on the study design.
Numerous instruments have been published for 4 Special Pharmacoeconomic
the assessment of quality of life in dermatology and Aspects in Occupational Skin
allergology, some being also feasible for occupa- Diseases
tional diseases. These include Skindex-29, DLQI
(Dermatology Life Quality Index; Chren et al. 4.1 Cost Factors in Occupational
1996), DSQL (Dermatology-specific Quality of Skin Diseases
Life; Anderson and Rajagopalan 1997), and
DQOLS (Dermatology Quality of Life Scales; Mor- The number of scientific publications on the costs of
gan et al. 1997). The standards and methodology of occupational skin diseases (OSD) is small. In the
assessing quality of life in skin diseases have been United States, costs for OSD were estimated to be
Photographic guide: max. severity

1024
1,000
800 743
600 578
EUR
466
422
400
322 325
296
232 211
200 159
113 104 106 132
80
0
clear/almost clear moderate severe very severe
Outpatient costs UV therapy costs

Drug costs* Inpatient costs
(n = 223) *incl. emollients
Fig. 1 Costs-of-illness of patients with chronic hand eczema according to disease severity and cost groups (Augustin
et al. 2011)
1.2 billion US$ (Blanciforti 2010). In another study Important expenditure factors in CHE were
from Oregon, the average cost per claim of occupa- medication used (especially topical steroids and
tional skin diseases was 3552 US$, and the average systemic therapy), frequent doctor’s appoint-
disability time was 23.9 days (McCall et al. 2005). ments, inpatient treatment days, own expenses
Estimates or extrapolations indicate annual for care products, and sick days.
costs of disease of hundreds of million Euro Costs strongly correlated with the disease
each year in the EU. Most of these cost estimates severity of the last 12 months (Fig. 1).
take only into account the direct costs from the Extrapolated for Germany, these data and data
payers’ perspective and indirect costs but not the from other studies show total costs resulting from
out-of-pocket expenses and the intangible costs. CHE of about 500 Mio € per year just for the SHI.
In previous studies, a few authors have In another study section, these costs were com-
published additional data on the costs-of-illness pared with costs for patients being reimbursed by
of occupational skin diseases in defined patient the occupational health insurances (Berufsgenos-
groups: In a single-center study, Diepgen et al. senschaften, BG). The results showed that annual
(2013b) demonstrated a very high cost impact of costs for patients with chronic hand eczema being
about 9000 € for patients of the German occupa- covered by the BG are strikingly higher than those
tional health insurances. for patients of the SHI (Diepgen et al. 2013a).
In a German multicenter study on a represen- However, the subgroup of patients of the SHI
tative random sample of patients with chronic associated with work impairments shows almost
hand eczema (CHE) insured by the statutory the same amount and pattern of costs as the BG
health insurances (SHI), the annual costs of dis- patients (Fig. 2): Direct costs for managing
ease amount to an average of 2128 € for a patient patients in the work-impaired group and work-
with CHE; 1512 € of these costs (71%) are direct diseased group (BG) were 3164 € and 3309 €,
costs for the statutory health insurances, 230 € respectively, around double the costs for manag-
(11%) costs for the patient, and 386 € (18%) for ing non-working and work-unaffected in the
the indirect costs. work-impaired group of patients.
32 M. Augustin
Fig. 2 Annual total, direct 8000

and indirect per patient
costs for CHE treatment 7000 6731
according to CHE impact
on work (Diepgen et al. 6000
2013a)
5036
EUR per year

5000 3422
4000 1872
3000
2000
1442
1271
1000
0
Non-working Work-unaffected Work-impaired Work-diseased
patients (GKV) patients (GKV) patients (GKV) patients (BG)
(N = 72) (N = 105) (N = 46) (N = 87)
Direct costs Indirect costs (=productivity loss)
4.2 Quality of Life and PRO et al. 2009). Regarding distinct patient-defined ben-
in Occupational Skin Diseases efits, a noninterventional study on patients with
chronic hand eczema, including occupational back-
A variety of studies have shown that the quality ground, revealed a marked overall benefit from
of life of patients with occupational skin diseases, alitretinoin treatment, as measured with the PBI
in particular chronic hand eczema, is markedly (Blome et al. 2009) (Fig. 3).
reduced (Matterne et al. 2009; Rabin and Fraidlin In total, the following are the evidences on
2007; Soder et al. 2007; Cvetkovski et al. 2006; quality of life and patient benefits in occupational
Hutchings et al. 2001; Lau 2011b). In summary, it skin diseases:
can be stated that significant limitations compared
to healthy persons were found in most studies • Clinically relevant losses of QoL due to the
published on quality of life (Lau et al. 2011a). skin condition
However, in a single publication on persons with • Marked improvements following guideline-
occupational latex allergy, there were no relevant compliant treatment
reductions of QoL (Nienhaus et al. 2008). • Significant potential for improvements after
Conversely, there is at least some evidence the introduction of skin-preventive measures
that the QoL of patients with hand eczema and
atopic eczema significantly improved in con- 4.3 Predictors of Costs
trolled clinical studies by means of various der- in Occupational Diseases from
matological treatment procedures. Among these the Societal Perspective
are ciclosporin A (Harper et al. 2000; Salek et al.
1993), tacrolimus (Drake et al. 2001), dermato- A major economic factor for the global costs of
logical standard therapy with behavioral therapy occupational skin diseases in a country is their
(Lange et al. 1999), balneotherapy (Kubota et al. epidemiology. Several publications indicate both
1997), and UV therapy/photopheresis (Granlund the high prevalence and incidence in Western
et al. 2001; Mohla et al. 1999). countries (Dickel et al. 2001; McDonald et al.
Also preventive interventions in occupational 2006; Turner et al. 2007; Apfelbacher et al.
skin diseases induced improved QoL (Apfelbacher 2008; Thyssen et al. 2010).
Fig. 3 Distribution of
benefits achieved from 60 84.3% of the patients achieved benefit
treatment of chronic hand
eczema with oral
alitretinoin, as measured 50
with the Patient Benefit
Index (PBI), n = 219
40
Frequency (n)
Mean: 2.7 ± 1.4
30
20
10
0
0 1 2 3 4
Patient Benefit Index
Moreover, the comorbidity and associated dis- prevention programs in OSD which included cost
eases must be taken into account, such as atopic assessments (van Gils et al. 2011).
risk factors (Nilsson et al. 1985; Coenraads and However, some clinical drug studies have
Diepgen 1998; Dickel et al. 2003). These addi- documented cost-effectiveness of interventions
tional conditions may aggravate the course of for occupational skin diseases:
occupational disease and thus be an indicator of Blank et al. showed the cost-effectiveness of
higher cost impact. oral alitretinoin in the treatment of chronic hand
Given the chronic nature of occupational skin eczema in Switzerland (Blank et al. 2010). Annual
diseases, the long-term outcomes and the preven- costs of alitretinoin treatment were 2212 €. Using
tion of recurrences are also of relevance (Cherry a long-term Markov model, the incremental cost-
et al. 2000; Mälkönen et al. 2009, 2010). Specific effectiveness ratio resulted in 14,816 €/QALY
preventive programs – if effective and accepted by gained, compared to standard care which is con-
employers and employees – cannot just be clini- sidered an acceptable ratio.
cally effective (Holness and Nethercott 1995; Findings of acceptable cost-effectiveness
Dickel et al. 2002; Dulon et al. 2009; Held et al. ratios were also reported by Rodgers et al. apprais-
2002; Winker et al. 2009; Kütting et al. 2010) but ing the cost-effectiveness of alitretinoin for NICE
also improve the economic prognosis of disease. (Rodgers et al. 2010; Paulden et al. 2010).
4.4 Cost-Effectiveness Data 4.5 Conclusions from the Economic

on Interventions Data on Occupational Skin
in Occupational Skin Diseases Diseases
Most of the interventional studies on OSD have not The following conclusions can be drawn:
been analyzed economically (Flyvholm et al. 2005).
Accordingly, in a previous systematic review, van • The great budget impact and the impairment of
Gils et al. have not found any publication on quality of life of patients with occupational
34 M. Augustin
skin diseases should be the impetus for quali- edn. Lippincott-Raven, Philadelphia, pp 487–510.
fied and inclusive disease management. (Revised)
Bullinger M, Anderson R, Cella D, Aaronson N (1993)
• The wide-ranging socioeconomic conse- Developing and evaluating cross-cultural instruments
quences of occupational skin diseases justify from minimum requirements to optimal models. Qual
high investments in research, prevention, and Life Res 2(6):451–459
therapy. Cherry N, Meyer JD, Adisesh A, Brooke R, Owen-Smith V,
Swales C, Beck MH (2000) Surveillance of occupa-
• A considerable proportion of costs could tional skin disease: EPIDERM and OPRA. Br J
be saved by effective preventive measures. Dermatol 142:1128–1134
For the sake of better efficiency, they Chren MM, Lasek RJ, Quinn LM, Mostow EN, Zyzanski
should be structured and provided by trained SJ (1996) Skindex, a quality-of-life measure
for patients with skin disease: reliability, validity,
dermatologists. and responsiveness. J Invest Dermatol
107(5):707–713
Coenraads PJ, Diepgen TL (1998) Risk for hand eczema
References in employees with past or present atopic dermatitis.
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Cvetkovski RS, Zachariae R, Jensen H, Olsen J, Johansen
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(2008) Occurrence and prognosis of hand eczema in (2001) Occupational skin diseases in Northern Bavaria
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study. Contact Dermatitis 58:322–329 Dermatol 145:453–462
Apfelbacher CJ, Soder S, Diepgen TL, Weisshaar E (2009) Dickel H, Kuss O, Schmidt A, Diepgen TL (2002) Impact
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60(3):144–149 Dickel H, Bruckner TM, Schmidt A, Diepgen TL (2003)
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Dermatol 165(4):845–851 (2001) The impact of tacrolimus ointment on health-
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Occupational Dermatology: Ethical
Aspects 5
Nikolaus Knoepffler and Martin O’Malley
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3 Fundamental Ethical Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4 Some Hard Cases and the Role of the Physician . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.1 The Structural Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.2 The Occupational Health Practitioner (OHP) Within the Four-Fold Matrix
of Ethical Responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.3 The Problem of a Duty of Complete Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
5 Specific Ethical Case and Resolution for Occupational Dermatology? . . . . . . . 46
5.1 The Case: Skin Cancer Caused by Occupational UV Irradiation . . . . . . . . . . . . . . . . . 47
5.2 Start of a Solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.3 Solution by the Framework of Rules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Abstract Legal regimen and ethical guidelines are

Occupational dermatology is a professional similar in that they build upon consensus social
field at the intersection of essentially four eth- values, without which they are both illegiti-
ical realms: society, business, medical profes- mate and ineffective. Among the key insights
sion, and the individual. is the obligation to not just workers and
The fundamental ethical frameworks of employers but also to society and the profes-
most important occupational health ethical sion, i.e., to the social values and laws that
guidelines build upon the consensus principles share wide consensus and to the principles
of human dignity and human rights. and standards that have established the well-
earned respect for medical care.
The “International Code of Ethics for Occu-
pational Health Professionals” (ICOH Code
N. Knoepffler (*) · M. O’Malley
2014) provides resources for an adequate eth-
Department of Applied Ethics, Friedrich-Schiller- ical approach to occupational dermatology.
University, Jena, Germany Divided loyalties should be resolved not by
e-mail: n.knoepffler@uni-jena.de; reducing health surveillance or the flow of
martin.omalley@uni-jena.de

https://doi.org/10.1007/978-3-319-68617-2_5
38 N. Knoepffler and M. O’Malley
information between medical professionals • Among the key insights is the obligation to not
and workers but by establishing fully transpar- just workers and employers but also to society
ent guidelines: Medical officials should be able and the profession, i.e., to the social values and
to attain the information they need to ensure laws that share wide consensus and to the prin-
the safest possible workplace, and workers ciples and standards that have established the
should be assured that their rights and privacy well-earned respect for medical care.
are not violated. • Divided loyalties should be resolved not by
Medical professionals have the duty to reducing health surveillance or the flow of
refrain from revealing information from information between medical professionals
employers when that revelation is a violation and workers but by establishing fully transpar-
of workers’ informed consent or when such an ent guidelines: Medical officials should be able
action would endanger the trust in their integ- to attain the information they need to insure the
rity and impartiality. Workers have the duty to safest possible workplace, and workers should
share responsibilities for their health as is be assured that their rights and privacy are not
shown in two examples (genetic predisposi- violated.
tion, exposure to UV radiation). • Medical professionals have the duty to refrain
from revealing information from employers
when that revelation is a violation of workers’
Keywords informed consent or when such an action
Autonomy · Beneficence · Bioethics · Equity · would endanger the trust in their integrity and
Genetic predisposition · Human rights · impartiality.
Human dignity · Justice · Non-maleficence ·
Occupational health · Privacy · Professional
ethics · Values 2 Introduction
Occupational dermatology is a professional field

1 Core Message at the intersection of essentially four ethical
realms: society, business, health profession, and
• Occupational dermatology is a professional the individual. Each realm makes distinct ethical
field at the intersection of essentially four eth- demands upon the health professional. Society
ical realms: society, business, medical profes- makes demands in the form of social values and
sion, and the individual. the explicit determinations of legal codes. Busi-
• The fundamental ethical frameworks of most ness forms a distinct ethical realm that deals with
important occupational health ethical guide- contractual obligations, market pressures, and
lines build upon the consensus principles of professional standards. The health profession is
human dignity and human rights. a distinct realm even within the context of a busi-
• Legal regimen and ethical guidelines are simi- ness setting. Doctors, nurses, and other practi-
lar in that they build upon consensus social tioners have a duty to uphold the integrity and
values, without which they are both illegiti- reputation of good clinical practice. This is inde-
mate and ineffective. pendent of their context of employment (business)
• Ethical literature in the field is scant and and goes beyond what is merely required by the
focuses too narrowly upon dilemmas posed law (society). Finally, it is useful to consider the
by the medical professional’s conflicting loy- ethical demands of individuals as a realm distinct
alties to workers and employers. from that of society. All four realms are integrally
• The “International Code of Ethics for Occupa- related, but they are distinguished, as philoso-
tional Health Professionals” (ICOH Code phers say, by their ends. That means that they
2014) provides resources for the most optimal each have distinct interests and goals. Ideally,
ethical approach to occupational dermatology. these goals are in harmony, but experience teaches
5 Occupational Dermatology: Ethical Aspects 39
us that they often come into conflict. Ethics is the the law reflects their fundamental moral convic-
study of the nature and resolution of such conflicts tions – or at least does not violate them. This
according to established principles, practices, principle of legitimacy also applies to the specific
values, and procedures of resolution. ethics of health practitioners.
Rapid developments in science, medicine, Business ethics deals with proper relationships
and society necessitate legal regulations to and responsibilities within market-based enter-
operationalize the basic ethical framework for prises. The end (or purpose) of society is human
occupational dermatology. Laws are essential to flourishing and business is oriented toward the
deal with the hard cases that push established creation of value in a competitive context. That
moral actions and principles into conflict. Laws created value is not exactly the same thing as the
set standards and stabilize expectations generation of profit for shareholders, but profit
according to basic moral convictions within generation is necessary in business. Whether the
functioning societies. Laws prevent cases from workplace is a business, a non-for profit, or gov-
being determined according to expediency or ernmental organization, finite resources limit
inflamed public opinions. And laws insure that organizations’ goals and options. Occupational
even the hard cases can be resolved according to dermatology has a responsibility to respect the
processes that respect and reflect the moral con- business context and the boundaries it presents.
victions of a pluralistic society. Yet law is only This ethical responsibility for the health practi-
one aspect of social ethics. Social ethics also tioner coexists with the ethical demands of pro-
involves the common moral values that tran- fessional medical codes. Doctors and nurses enjoy
scend ideological differences – religious and a privileged level of respect in western societies –
secular. These values are distinct from the legal and for good reason. People trust they act in the
process, but they are integrally associated with patients’ best interests because the medical pro-
the law. Both aspects of social ethics are relevant fession has zealously maintained standards of
for occupational dermatology when resolving honorableness and competence over many
hard cases because the law may not sufficiently decades. These standards impose an obligation
represent the full force of social values. How, for on the practitioner that is distinct from both the
example, can a worker with a genetic disposition social and business realms. Finally, the individual
for certain dermatological diseases be protected realm will be spelled out below but is essentially
in his working place, when the law prohibits the comprised of the principles of human dignity and
employer from requiring genetic testing? How human rights – principles that are now universally
can a worker be protected in some countries, recognized in such documents as the Universal
where the law does not punish the use of danger- Declaration of Human Rights (UDHR) and influ-
ous substances? ence the discussions of occupational health-care
Social ethics provide the general ethical con- coverage and protection of the workforce (NAS
text for occupational dermatology or any other 2016).
professional person. Legal systems in modern For the practitioner of occupational dermatol-
democracies will not be perfect, but citizens ogy, the balance of these four ethical realms
must be able to accept that they are governed by demands a core understanding of not only the
laws that represent their interests and values. They realms themselves and the principles that govern
must also believe they share some participatory them. It also requires an appreciation that the
access to the continuing development of those achievement and maintenance of such an ethical
regulations. This is a way of saying that the law balance parallels the process of achieving and
has legitimacy. Legitimacy does not imply that the maintaining a medical proficiency. As Aristotle
system of law represents a situation of perfect famously taught, ethics is not merely the compli-
justice, especially in a pluralistic society with ance with restrictive guidelines; it is the science
divergent notions of justice. The effectiveness of of achieving the moral virtues necessary for
the law depends upon a people’s conviction that living well.
The discussion below begins with a fundamen- human being shares a fundamental equality and
tal ethical framework and then argues that the fundamental human rights. No single philosophical
existing codes in occupational health ethics rep- or theological foundation was given to establish
resent an overlapping consensus that meets the this ethical framework of the UDHR, even though
demands of each of the four essential spheres it is certainly possible to do so (see Knoepffler
outlined in the ethical matrix above. Next, specific 2004, 33–49). Rather, the ethical framework was
questions relevant for occupational dermatology a historical achievement tied to the tragic experi-
will be addressed, especially with respect to its ence of human degradation. This contingent con-
relationship to the wider field of occupational text of the principle’s creation does not imply that
medicine: What is the role of the physician in the principle itself is contingent. The context
respect to patient (worker), employer, and other merely shows the background which lead to the
stakeholders? What are the responsibilities of formulation of an internationally recognized ethical
worker and employer? What kind of therapies principle. Hence, it is not a legalistic fallacy to
can be required of a worker? The discussion con- consider that the principle of human dignity
cludes with controversial questions regarding attained its status as a fundamental ethical “princi-
genetic screening of workers for specific disposi- ple” precisely in the experience of human degrada-
tions for dermatological diseases. It considers tion during the period of National Socialism.
whether some people should be excluded from The fundamental principles of human dignity
some work in order to prevent them from getting and human rights, once established by nearly unan-
diseases. imous international consent, lead to the recognition
of the right of bodily integrity and welfare. Note the
unambiguous formulation in the preamble of the
3 Fundamental Ethical World Health Organization (1946, 2007):
Framework
The enjoyment of the highest attainable standard of
health is one of the fundamental rights of every
Judgments in difficult bioethical cases are essen- human being without distinction of race, religion,
tially dependent upon the ethical framework uti- political belief, economic or social condition.
lized. Thus it is important to be quite clear from the
Government organizations like the European
beginning that the ethical framework being pro-
Agency for Safety and Health at Work, National
posed here is one built upon the principle of
Institute for Occupational Safety and Health
human dignity which has been established in inter-
(USA), or the Work Safety and Health Council in
national charters (UDHR) and national laws and
Singapore and the Information Center of Occupa-
which has achieved a distinct level of international
tional Safety and Health in Israel all try to adopt
consensus (see Knoepffler 2004, 7f; Knoepffler and
what was stated by the Joint ILO/WHO Committee
O’Malley 2010, 2016). The preamble of the UDHR
on Occupational Health at its first session in 1950
recognizes “the inherent dignity and of the equal
and revised at its twelfth session in 1995:
and inalienable rights of all members of the human
family is the foundation of freedom, justice and Occupational health should aim at: the promotion
peace in the world.” This document was drafted and maintenance of the highest degree of physical,
in response to the cruel and inhuman beliefs of mental and social well-being of workers in all occu-
pations; the prevention among workers of depar-
National Socialism, which rationalized the sacrifice tures from health caused by their working
of individual rights and personal dignity as neces- conditions; the protection of workers in their
sary for the interests of the majority. The principle employment from risks resulting from factors
of human dignity stands as both a rejection of adverse to health; the placing and maintenance of
the worker in an occupational environment adapted
human debasement and a universal recognition of to his physiological and psychological capabilities;
fundamental human worth. Every human being has and, to summarize, the adaptation of work to man
value simply because they are human. Every and of each man to his job.
In 2009 the Board of the German Society for to allowing sick leave and providing injury com-
Occupational Medicine and Environmental Med- pensation, to name just two general examples.
icine e.V. (DGAUM) and the Bureau of the Asso- Even the expansion of consideration to multiple
ciation of German Company and Factory Doctors loyalties neglects the ethical demands upon
e.V. (VDBW) formulated a code of ethics for the occupational health professional (OHP)
occupational medicine (DGAUM/VDBW 2009). concerning the health profession and society in
In article 2 they commit themselves explicitly to general.
the UDHR and their respective principles: There is a reciprocal relationship between
health-outcome effectiveness and respect for
“Those doctors, scientists and medical ancillary health professionals. Thus even though the par-
staff entrusted with occupational medicine respon-
sibilities agree to conform to internationally
ticular circumstances of occupational medicine
accepted ethical principles, as defined in the Uni- may impose complex ethical responsibilities on
versal Declaration of Human Rights and in German the OHP, the field of the medicine poses a legit-
constitutional law, as well as to follow the specific imate and independent set of responsibilities
ethical principles applicable to medicine in their
professional behavior. The principle of each being
upon the practitioner. Guidotti (2008) rejects
treated equally always applies.” the disparagement of the profession posed in
such accounts as Draper’s “The Company
The preamble consequently states Doctor: Risk, Responsibility, and Corporate Pro-
fessionalism” (2003). Whether you follow
“The goals of occupational medicine are to promote
and maintain health and, in particular, to participate
Guidotti’s positive history or Draper’s more crit-
in the early detection of health impairments because ical account of occupational medicine, the point
of work and in the restoration of the health and stands that the reputation of the field is of critical
employability of people in the workplace. This is importance for the integrity of the work of OHPs.
facilitated, for example, through targeted medical
and occupational toxicology, epidemiology and
No one is served by hazy ethical guidelines,
psycho-social research and, in practice, through violated boundaries, or the instrumentalized
comprehensive ‘occupational health management’ medical-practice understanding of a narrow
as is demanded of all participants and stakeholders guild mentality. The challenge is to optimally
in the promotion of health in the workplace.”
preserve the value-creating and value-preserving
Ethics codes are very good at laying out the loyalties and responsibilities of both business
positive goals of occupational medicine that can and the self-regulating health profession.
be essentially boiled down to the maintenance of We now turn to some practical examples of
workers’ good health through preventative and ethical dilemmas posed by occupational derma-
active measures. This is all fine and good, but as tology to explain the principles outlined above.
recent literature shows, there is a perceived lack of
concrete and useful ethical guidance (see Kuhn
and Gensch 2009; London 2005; Brandt-Rauf 4 Some Hard Cases and the Role
1989). This and other literatures point to multiple of the Physician
loyalties of workers and employers as the essen-
tial problem. Workers have expectations of health 4.1 The Structural Problem
service that include confidentiality and care (see
Baur et al. 2009; Bercovitch and Long 2007; As we have seen, the principles of human dignity
Budnik and Baur 2009). This is understandable and human rights underlie the central importance
given Brant-Rauf’s argument that ethical conflicts of human life and bodily integrity, as well as the
in occupational medicine are typically understood right to self-determination. There are essentially
only according to traditional medical role models. two aspects of human rights, the physical and the
Less emphasis is paid to expectations of volitional, that frame a tension in the hard ethical
employers bearing different interests with respect cases of occupational dermatology.
A possible tension exists between the physical to self-determination and choose a career that
or “objective” claim to life and bodily integrity leaves them relentlessly exposed to the sun, for
and the volitional or “subjective” claim to free- example. But even that is a situation where the
dom that is associated with the right to self- preconditions and risks are blatantly manifest.
determination, which the principle of human Employers, however, have an interest in attaining
dignity also safeguards. The claim to freedom is the healthiest workers possible, for both the pos-
subjective in the sense that the person has the itive contribution and lack of risk they offer an
freedom to choose his own good, at least to the organization. Thus, every employment situation
degree that these choices to not infringe upon the poses a cost-benefit analysis that is dependent
self-determination of other people. The right to upon workers’ health fitness and the risks posed
self-determination prioritizes the freedom of indi- by particular occupations. Ethical guidelines gen-
viduals over and against the structures of poten- erally require a reasonable disclosure of fitness
tially overreaching corporate and government from prospective employment candidates and,
structures. Protected freedoms can allow individ- from employers, a reasonable disclosure of an
uals to make bad or even tragic choices in occupation’s potential risks. The ICOH Code
selecting the place where they work. People can 2014 describes this level of reasonableness in
choose risky careers, for example. Nevertheless, terms of a general aim of contributing to the
modern liberal systems of law deem the restriction “establishment and maintenance of a safe and
of freedom to be a greater evil. healthy working environment for all.”
Subjective rights protect the individual in a Problems potentially emerge when relevant
sphere of freedom, within which the individual information is excluded from the employment
may act according to her or his own desires, if fitness analysis. A worker poses such a problem
those actions do not infringe upon the rights and with an undisclosed and infectious dermatological
freedoms of others. This is the classic definition of disease in an employment that includes close-
a right, subjectively understood. Ideally, we range contact with other workers. The problems
should not act in ways that are detrimental to our of scarce information or neglect of healthy work-
well-being. However, we do not have an ethical ing conditions are posed when the negative effects
duty to protect our lives and bodies to the greatest of limiting information are not associated with the
possible degree according to some “objective” perpetration of such actions. For example, there is
criteria. We have a right to life and bodily integ- a disassociation of actions and the negative effects
rity. And we can freely choose a particular course of that action when a worker spreads an infection,
of action such as working in a hazardous occupa- but the cost of that infection is shouldered by the
tion that risks our lives and bodily integrity. Some health insurer and the employer, but not the pri-
(or even most) in society may judge this to be mary infector. The negative external effects go to
dumb or even morally problematic, but the greater other stakeholders like insurances (money of
social evil is posed by society’s limit of our free- other insured people) or the state (taxpayer’s
dom to choose dumb things – at least to a certain money).
degree. Despite the freedom that individuals have There is an inherent structural inefficiency
to endanger themselves, health professionals, posed by the fact that workers are protected by
employers, and the social order have an obligation state laws in their withholding of certain medical
to uphold the rights protecting workers’ health, conditions and in their refusing to be submitted to
bodily integrity, and general welfare. certain health tests. Most western countries, for
Just to mention some examples: Individuals example, do not require workers to submit to
may possess preconditions to disease or injury genetic testing even if that testing could reveal
and nevertheless choose employment that poses genetic predispositions to diseases associated
distinct and peculiar risks to workers with such with elevated risks for environmental factors pre-
preconditions. Fair-skinned people with family sent in a desired place of employment. The person
histories of skin cancer may exercise their right has a right “not to know.” Even if the person
knows the genetic predisposition, there is a further structure involved (cf. London 2005), and
protection such that such knowledge need not be (c) maintaining the integrity of the profession.
handed over. That is not all – though this consideration is
Using the example of genetic testing for certain neglected in most occupational medicine. A
dermatological hereditary predispositions: If the fourth party is involved, too, namely, the insur-
worker refuses to be tested, he is not obliged to do ance industry and society as a whole that shoul-
so. If a disease surfaces, the costs are then paid by ders the financial and other burdens for the
the holder of the health-insurance policy. Whether externalities caused by the information deficits
the employer or the insurance agency foots the present in the attaining of workers for risk-prone
bill, there is a cost shift to the larger society when careers. Therefore, the OHP should understand
the resources from the common are dedicated to the ethical responsibilities due society as well.
this treatment, rather than used for some other
social good. Further, the employer has a high 4.2.1 The OHPs Multiple Relationships
incentive to choose workers most fit for their of Accountability
work, i.e., they provide the greatest contribution As outlined in Figure 1 above, the OHPs ethical
and fewest risks. But if the costs of either provid- matrix includes four essential realms of responsi-
ing increased health care and/or for replacing a bility. The health provider is responsible to main-
worker are minimized through insurance leverag- tain the balance among all four while respecting
ing or socialized medicine, there is a proportionate human dignity and human rights and promoting
disincentive to actively attain healthy workers. the four values of beneficence, non-maleficence,
autonomy, and justice (or equality) (Westerholm
2007; Beauchamp and Childress 2013).
4.2 The Occupational Health
Practitioner (OHP) Within (1) With respect to the worker as patient, there is
the Four-Fold Matrix of Ethical the classical obligation of respecting the
Responsibilities autonomy of the patient, following the values
and principles included in the ethical medical
Health practitioners may only reflect upon the codes, which prioritizes the health and well-
ethics of their fields when they find themselves being of the patient. As patient, the worker
in situations of conflict. Then, they must go about enjoys privileges of confidentiality and the
resolving their particular dilemma according to respect of informed consent, which insures
some ethical-resolution strategy. Entering into self-determination. These are all elements of
such deliberation, it is important to have a func- the value of autonomy.
tional definition of health such as “the capacity (2) With respect to the employer, there is the clas-
and ability to achieve vital life goals” sical obligation of respecting the norms and
(Westerholm 2007; cf. Knoepffler and Daumann regulations of the corporation – as the OHP is
2017, 13–18; cf. Westerholm et al. 2004). Next, a loyal cooperator of the enterprise paying the
one assembles all the information relevant to a health provider’s salary. The values of justice,
case, whether medical, psychological, social, or classically defined as “to each his own,”
other. The skill set for ethical evaluation is analo- insures the ethical consideration of the business
gous to basic science-based medical practice. and all those within and external to it who
After outlining the relevant values including dig- benefit from its productive functioning.
nity, rights, autonomy, competency, institutional (3) In respect to society/stakeholders, he has the
well-being, etc., the practitioner can use the ethi- classical obligation of a citizen in preventing
cal matrix provided above to determine the spe- exploitation and contributing to public health.
cific spheres of loyalty that deserve attention. The (4) And finally, there is the duty to uphold the
OHP is responsible to (a) the worker as patient, reputation and standards of the health profes-
(b) the employer/enterprise/or institutional sion. Practitioners have a duty to promote
Society Business
• Obey Public Laws • Respect Contractual Relationships, Which
• Respect Social Values Must be Transparent
• Promote Public Health • Assess and Limit Potential Health Risk
• Promote Organizational Value with Healthy
Staff and Safe Environment
Ethical Matrix
Worker Medical Profession

• Protect Human Dignity and Human Rights • Practice According to Professional Standards
• Respect Personal Autonomy and Privacy and Oaths
• Respect Different Cultures • Respect Independence, Integrity and
• Generate Resources for their Families Reputation of Medical Profession
Fig. 1 Matrix of ethical responsibilities for occupational health professional
good health, beneficence. Moreover, whether Conflicts arise when these loyalties indicate
or not the OHP has taken an oath to do no contradicting paths of action. The high rate of
harm, they are bound to this value of non- skin cancer in occupational dermatology makes
maleficence. it a good example. “In 2014, skin diseases
according to BK no. 5101 and No. 5102 thus
4.2.2 The Potential for Loyalty accounted for 33.6% of all reported occupational
Conflicts diseases in Germany” (Diepgen 2016), and in
The OHP should never enter into a strictly com- 2015 skin cancer was added as an occupational
mercial relationship with an organization to act disease with the revision of the German ordinance
solely in its best interests. Such a one-sided loy- on occupational diseases. Let us assume that a
alty compromises the OHPs responsibilities to the physician knows about the following risk: Pre-
other three ethical realms. Most importantly, it disposed workers have a high probability of incur-
jeopardizes the OHP’s relationship with the ring skin cancer by being exposed to sunlight. If it
worker and the commitment to the workers’ best is in the (acknowledged) interest of the worker
interests. Hence, there is no real relationship of and employer to know about the predisposition,
health professional with a “patient.” It may be then there is no conflict. There is also no conflict
necessary for an OHP to act overtly and prejudi- when the rules or laws in a specific country allow
cially as a representative of the employer’s inter- the employer to demand a testing of the possible
ests, but such a position would necessarily be fully future worker concerning this specific predisposi-
apparent to the worker. Such a role would argu- tion. This is independent from the question
ably be only analogously a “health” role. Such a whether the possible worker desperately needs
situation does call into question the situations the job or not.
where it is assumed that the occupational physi- A conflict arises, however, in the case where a
cian is bound by the medical code and therefore worker with a genetic disposition for skin cancer
acting both in the best interest of the patient and in is in grave financial need and testing for the spe-
the best interest of the organization. cific predisposition is not obligatory or the test is
legally prohibited, as is the case for genetic diag- could seek legal remedies for broken patient con-
nosis in some regions. Germany’s law on gene fidentiality and damage done to future wage
diagnosis, for example, prohibits employers earnings.
from asking any questions regarding genetic pre- Both options leave the physician in a dilem-
dispositions. If the patient informs the physician matic situation. The solution consists in keeping
about the predisposition under the reasonable pre- confidentiality, because this is the foremost duty
sumption of confidentiality, the physician is according to the ethical framework of human
bound by that confidentiality. A physician may dignity and human rights. This solution respects
only make use of persuasion to convince the the self-determination of the person, and is con-
patient not to apply for the position. In other sistent with the framework of medical values
countries where no such laws apply, the following worldwide, as well as the legal framework in
conflict situations are possible: most countries. Nevertheless, it is important
Option 1: The physician does not break the that existing legal frameworks plainly address
confidentiality. this problem to protect the physician and the
The worker has a relatively high risk to get the employer, not only the worker as vulnerable
disease and thus carries a high risk to bodily (cf. Emanuel 2002). Instead, each party involved
integrity. The employer, too, bears a high risk to in the hiring process bears specific responsibili-
be hurt economically. Depending upon the ties, and these responsibilities should be as
region’s health-care structure, the long-term ill- clearly delineated as possible. This protects the
ness has to be paid by society or the participating rights of the employer, the worker, and physi-
members of the respective insurance. There is also cian. Finally, advocating for fair rules and laws is
another problem. Let us assume that after some the responsibility of each group, as citizens, and
years of work, the worker attracts the disease he especially physicians and the medical commu-
was predisposed for and then tells the employer nity as specialists.
that the physician was confidentially informed
about his condition when he applied. The physi-
cian may fear that the employer will “punish” him 4.3 The Problem of a Duty
for not telling him even though he was bound to of Complete Information
maintain the confidentiality and the employer is
not allowed to do so. Laws may protect OHPs, but But what set of rules is adequate? On the one
there are indirect ways for businesses to apply hand, it should be noted that OHPs are not pri-
punishment, e.g., denying career advancements marily enmeshed in such conflictual situations
and salary increases. and that the great bulk of their work is applying
Option 2: The physician breaks the technical and scientific knowledge to establish
confidentiality. preventative safety and health policies and condi-
If the physician breaks the confidentiality, tions and that this is beneficial to all four ethical
which is permissible in some countries, trust in constituencies. Nevertheless, the potential for
the relationship and in the profession is damaged. conflict means that the OHP ought to have respon-
The long-term result will be that no patient will sibilities and loyalties clearly outlined for workers
reveal anything beyond the mere minimum and management. The most conflict-ridden issue
required, and nothing will be revealed that could of divided loyalties should be resolved NOT by
jeopardize job applications or security. The result reducing health surveillance or the flow of infor-
will be that the distrusted physician is not able to mation between medical professionals and
try to convince someone not to apply for a posi- workers. Rather, conflict resolution should be
tion. This places the worker at a health risk achieved by establishing fully transparent bound-
because the OHP lacks necessary information. aries: Medical officials should be able to attain the
Further, the OHP and the business are placed in information they need to insure the safest possible
legal jeopardy because prospective applicants workplace, and workers should be assured that
their rights and privacy are not violated. Where A more optimal solution (suggested by ICOH
OHPs have obtained demonstrably relevant health Code generally and especially #12, p. 21) is the
information needed to make prudent medical strict choosing of biological monitoring and
decisions with respect to hazardous working con- investigations that have been proven valid and
ditions, the findings must be discretely relayed relevant “for the protection of the health of the
without revealing specific details of the examina- worker concerned, with due regard to their sensi-
tions (ICOH 2014, Principle #6, p. 19). Further, tivity, their specificity, and their predictive value.”
medical professionals have the duty to refrain This is not just a process of marginal cost-
from revealing information from employers effectiveness analysis, although that analysis is
when that revelation is a violation of workers’ certainly relevant. And there is room for flexibility
informed consent or when such an action would among regions dependent upon their relative
endanger the trust in their integrity and impartial- wealth. A good solution is for OHPs and the larger
ity. The ICOH Code is quite clear that to protect medical community to coordinate efforts to dis-
this independence, OHPs should insist that it be cover most high-risk predispositions and diseases
written into their contracts as standard practice relevant to occupational populations. Employers
(#19, p. 24). should only be allowed to demand a screening for
There are good reasons for applicants revealing these agreed-upon respective predispositions and
all health information important for the position, diseases. There is no inherent reason why genetic
and physicians should screen to exclude as much diseases and predispositions should be treated
risk as possible. If this is the case, there is no differently from conventional predispositions
inherent reason why genetic information must be and diseases. Likewise, protections against dis-
dealt with differently if two conditions can be met: crimination and mandatory base-line medical
(1) that it can be reasonably demonstrated to pre- insurance coverage should insure that genetic
dict predisposition to injury or disease and (2) that information is likewise not the cause of unfair
injury or disease is reasonably grave and closely exclusions from the job market for workers. If
related to performing the occupational tasks. the fear or danger of discrimination is proven to
Genetic screening need not be prohibited if it is be well founded, perhaps such genetic testing
analogous with consisting regulations concerning could be conducted by third-party health-care pro-
nongenetic diseases and dispositions. A prohibi- viders, who would maintain the genetic informa-
tion to reveal genetic information might appear to tion independently from the place of employment.
be ethically problematic for various reasons:
• Persons with diseases or predispositions 5 Specific Ethical Case

for diseases considered conventional have and Resolution
to reveal a great deal of private information, for Occupational Dermatology?
some of may not be currently understood.
Therefore, they are not equally treated. The discussion to this point deals with general
• Persons with genetic diseases or predisposi- topics of occupational health – a relevant discus-
tions for diseases have the incentive mentioned sion given that, e.g., 33.6% of all of work-related
above to exploit the system, if they are in illnesses are skin related (Diepgen 2016). The
desperate need of employment. discussion below focuses specifically upon occu-
pational dermatology. Marks et al. (2002) shows
But if potentially valid and relevant monitoring that occupational skin disease is multifactorial in
and investigations are excluded for these two rea- origin. It results from the interaction of pre-
sons, we face a situation of workers shielding disposing risk factors in workers together with
medical information that places them and others agents within the work environment such as
at potential risk. chemicals, abrasions, plants, animals, sunlight,
radiation, heat, cold, moisture, and others. The 5.2 Start of a Solution
identity of such material causal agents suggests
that occupational skin disease is an affliction that Diepgen outlines the complexity involved in
can be prevented with careful control of the work attributing occupational UV exposure to cancer
environment. Knowing disease prognoses is espe- causation:
cially relevant to medical-ethical reflection.
The following case presents a potential Given the many factors affecting the development
of skin cancer, derivation of a dose measure in terms
dilemma for the OHP and a pathway to an ethical of a science-based dose-response relationship as
treatment of the dilemma using the framework minimum exposure and cut-off criterion is not pos-
suggested above. sible based on the epidemiological literature. How-
ever, scientific data and clinical experience allow
for the basic assumption that additional occupa-
tional UV exposure of 40% at the site of tumor
5.1 The Case: Skin Cancer Caused development suggests predominantly occupational
by Occupational UV Irradiation causation. (Diepgen 2016)
Skin cancer caused by occupational UV irradia- The criteria developed to ascertain workplace
tion is a dermatological disease that afflicts sig- responsibility for specifically BK 5103 attempt to
nificant percentage of workers in especially balance unavoidable workplace UV radiation
agriculture and construction industries. In Ger- exposure against factors beyond the responsibility
many, for example, Diepgen (2016) estimates of an employer. Thus skin tumors must be in areas
that BK 5103 (“Squamous cell carcinoma or mul- exposed to the sun under ordinary circumstances,
tiple actinic keratoses of the skin caused by natu- and this presumes the use of protective measures
ral UV irradiation”) will account for 8000–10,000 required by the employer such as protective head
cases annually. covering. With regard to personal worker respon-
This medical scenario is unfortunate, but in sibility, signs of recreationally exposed skin dam-
terms of the disease itself and medical ethics, it is age due to UV radiation exposure may be a
not especially problematic for the occupational relevant clue regarding determining cancer causa-
health practitioner (OHP). Additional context tion. Additionally, nonoccupational risk factors
factors, however, introduce complications rele- such as immunosuppression, phototherapy, and
vant to ethics. Some populations possess dispro- other factors may also be considered. However,
portionate susceptibility to skin disease. skin phototype may not play an essential role in
Personal-choice factors regarding preferred out- factor determination, even though it should
door recreation and level of precautionary pro- always be provided in BK notification. Thus per-
tection in non-work contexts (sunscreen, hats, sonal responsibility remains relevant, and protec-
etc.) add relevant risk to skin-cancer develop- tions are built in against discrimination of
ment. Skin cancer manifestation can take many populations based upon skin color. Determining
years or even decades after occupation-relevant certain causal relationships between UV radiation
exposure to UV radiation. Add to this scenario exposure and disease is virtually impossible, and
the hypothetical operation of an industry in an thus scientifically determined general rules pro-
economically deprived area employing workers vide general guidance, such as presuming that
from a large pool of available, but unskilled and occupational exposure to UV radiation is at least
non-unionized laborers, and operating with 40% additive to nonoccupational exposure. The
small profit margins in a not-so-rosy economic BK 5103 criteria are based on averages of general
climate of escalated market competition. The population activities and allow for inclusion of
OHP must outline an ethical approach to dealing relevant exceptions or circumstances for deter-
with this scenario that appropriates the guide- mining causation, such as extended holidays in
lines of the ICOH Code. tropical regions. The basic “logic” of disease
reporting is to structure a process whereby the best difficulty of finding clear causal responsibility is
possible causal argument can be made, with an so difficult that establishing definitive proof of
understanding that there is much that is inherently employment responsibility in specific cases is
either unknowable or at least not practically dis- quite a burden and introduces inherent cause-
coverable about skin cancer causes. establishing inefficiencies into a system that is
better served by devoting resources to cause pre-
venting and disease treating. Thus, rules should be
5.3 Solution by the Framework constructed to incentivize preventative measure,
of Rules and disease should be paid for in a way that shares
risk. One possible solution path is for industries
The logic of the reporting process discussed above with high typical for UV radiation exposure (agri-
allows for a judgment based upon the arguments culture, forestry, fishery, building construction,
presented, though the information necessary for road construction, outdoor adventure touring) to
such a report is structured such that reporting provide insurance premiums for their workers
parties are incentivized to provide information based upon the added risk that the industry pre-
benefiting their own specific loyalties. Thus, sents, together with premium-reducing incentives
workers might be reluctant to report vacations in in the form of measurable risk-reducing policies.
regions with high UV radiation, and employers This system-wide approach on the level of rule-
might be motivated to implement rules that, formation takes the burden from individual med-
whether they are implementable or not, protect ical providers.
the employer from exposure to compensable
risk. Further, if personal risk is determined on
the basis of the general population’s average sun References
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(d) The effectiveness of occupational preventa- dermatology. J Ger Soc Dermatol. https://doi.org/
10.1111/ddg.13128
tive measures
Emanuel EJ (2002) Introduction to occupational medical
(e) The effectiveness of initial and continuous ethics. Occup Med 17(4):549–558
screening measures Guidotti TL (2008) Occupational medicine and the con-
struction of “difficult reputations”. New Solut 18
(3):285–298
Given these details, an optimal integration of
ICOH (International Commission on Occupational Health)
the ethical approach presented here is to incentiv- (2014) International code of ethics for occupational
ize the preventative measures d and e. Further, the health professionals. http://www.icohweb.org/site/
multimedia/code_of_ethics/code-of-ethics-en.pdf. Last Marks JG, Elsner P, DeLeo VA (2002) Etiology of occu-

accessed 28 Jun 2018 pational skin disease. In Contact and occupational der-
Knoepffler N (2004) Menschenwürde in der Bioethik. matology, 3rd edn. Mosby St. Louis, pp 303–313
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Gesundheitswesen. Alber, Freiburg (i. B.) coverage and occupational health and safety for the
Knoepffler N, O’Malley M (2010) Human dignity: regula- informal workforce in developing countries. The
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(3):63–76 Westerholm P (2007) Professional ethics in occupational
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tive in medical ethics. In: Luetge C, Mukerji N (eds) 45:19–25
Order ethics: an ethical framework for the social market Westerholm P, Nilstun T, Ovretveit J (2004) Practical
economy. Springer, Switzerland, pp 311–328 ethics in occupational health. Radcliffe Medical Press,
Kuhn J, Gensch R (2009) Ethical aspects of workplace Oxford
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itsforschung-Gesundheitsschutz 52(5):535–552 Vol. 14, p. 185, reproduced in: World Health Organi-
London L (2005) Dual loyalties and the ethical and humans zation: Basic Documents. Forty-sixth Edition (Geneva:
rights obligations of occupational health professionals. WHO, 2007)
Am J Ind Med 47:322–332
History of Occupational Dermatology
6
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
2 From the Ancient Times . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.2 From Greece to Ramazzini . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.3 Some Reports of Occupational Dermatology During
the Eighteenth Century . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
2.4 A Major Discovery in the Eighteenth Century: The Cancer of the Scrotum
Among Chimney Sweepers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
3 The Birth of Dermatology in the Nineteenth Century . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.1 The Birth of Dermatology as a Separate Scientific Discipline During
the Nineteenth Century: Its Impact on Occupational Dermatology . . . . . . . . . . . . . . . 55
3.2 Josef Jadassohn, the Father of Patch Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
4 The Life of Occupational Dermatology in the Twentieth Century . . . . . . . . . . . . 56
4.1 Books Dedicated to Occupational Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
4.2 A Breakthrough in Occupational Dermatology: Poul Bonnevie’s
Pioneering Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.3 Later Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.4 Recent Books Related to Occupational Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Historical aspects · Patch testing · Irritant
contact dermatitis · Allergic contact • Bernardino Ramazzini (1633–1714) is
dermatitis · Occupational dermatoses · Visits undoubtedly the father of modern occupational
in factories medicine.
• De morbis artificum diatriba is the first treatise
dedicated to occupational medicine, but
cases of occupational dermatology are poorly
described.
J.-M. Lachapelle (*) • A major discovery in the eighteenth century
Department of Dermatology, Catholic University of
was the cancer of the scrotum among chimney
e-mail: Jean-marie.Lachapelle@uclouvain.be sweepers.

https://doi.org/10.1007/978-3-319-68617-2_6
52 J.-M. Lachapelle
• The birth of dermatology during the nineteenth stories collected in this book are too anecdotal and
century had a limited impact on occupational imprecise, and it seems difficult to adhere to the
dermatology. proposed conclusions.
• Josef Jadassohn is the father of patch testing Nevertheless, from the ancient Greek and
(1895–1896). Roman civilizations, the statements advanced
• A breakthrough in occupational dermatology: by two greats of that time have to be kept in
Poul Bonnevie’s pioneering work. memory (Foussereau 1991; Foussereau et al.
• Many books have been dedicated recently to 1982):
occupational dermatology.
Hippocrates (circa 460–377 B.C.) considered
environmental influences as possible causes of dis-
eases (Cadwick and Mann 1950). His observations
were prophetic but his conclusions somewhat
2 From the Ancient Times tangential.
Galen (A.D. 133–200) preceded the Environ-
2.1 Introduction mental Protective Agency by 1900 years; he
considered the noxious effect of air pollution
in his work De Temperamentis. (Siddiqui and
Michel Valentin wrote a detailed and very well- Cormane 1976)
documented history of occupational medicine
(Valentin 1978) (Fig. 1) and ergonomics, starting
from the Egyptian period till the end of the sev- 2.2 From Greece to Ramazzini
enteenth century. It is a gold mine of knowledge
for historians, but, in all respects, it lacks of real 2.2.1 Bernardino Ramazzini, the Father
interest for medical doctors. Indeed, the various of Occupational Medicine
Bernardino Ramazzini (1633–1714) is undoubt-
edly the father of modern occupational medicine.
First of all, he appears to have been “one of the
outstanding physicians of Italy of the time.” He
practiced during all his life in Modena (Emilia)
and was consulted by a vast number of patients;
this was due to his scientific approach of the
problems and his practical expertise. Obviously,
he tried – as far as he could – to find out the
presumable cause of the diseases encountered in
daily life, but, of course, the general knowledge
and the tools for appropriate diagnosis were very
limited at that time!
When consulting his numerous writings, the
reader is surprised by his encyclopedic medical
erudition. Ramazzini was aware of the views and
statements expressed by his Greek and Roman
predecessors. He knew also very well the discov-
eries of the Arabic physicians, such as Rhazès or
Avicenne (Ammar 1965). He fully agreed with
some of them; but, sometimes, he argued strenu-
ously against some precepts he considered
nonsense.
Ramazzini was obviously an admirer of Hip-
Fig. 1 Bernardino Ramazzini pocrates and seemed fascinated by his anamnestic
6 History of Occupational Dermatology 53
approach, when Hippocrates was facing a new

patient, sitting under the famous tree (still alive!)
in Kos Island (Greece).
Nowadays, Hippocrates’ questions, formu-
lated two millennia ago, are still a part of the
current propaedeutic heritage:
(a) What are your complaints?

(b) Do you have any idea about the events that
could have been responsible for their onset?
(c) When did the symptoms start?
But Ramazzini had an additional question,
very important for the real impact of occupa-
tional medicine in daily life:
(d) What is your current job?
Which were your previous jobs?
Can you tell me about the place you are
living?
Is there a particular environmental nuisance?
This means that Ramazzini was very concerned
by the occupational and social status of his patients,
and this led him to study occupational diseases in a
roundabout way (Wright and Goldman 1979).
Fig. 2 Ramazzini’s treatise: De morbis artificum diatriba
2.2.2 The First Treatise
on Occupational Medicine: De Fourcroy (1755–1809), to translate Ramazzini’s
Morbis Artificum Diatriba opus into French. This translation was reedited
Ramazzini began his lectures at the University in 1990 (de Fourcroy 1990), with a preface by
of Modena on diseases of artisans in 1690. Bernard Kouchner.
The first edition of his book: De morbis
artificum diatriba (“About occupational dis- 2.2.3 What About Occupational
eases”) was published at Modena in Dermatology in Ramazzini’s
1700 (Ramazzini 1700). The book was very Treatise?
innovative in its presentation and its contents Reading de Fourcroy’s translation of Ramazzini’s
(written in Latin). treatise, one is taken by surprise by the fact that
It was divided into 40 chapters, each one skin diseases were so poorly described, as com-
being dedicated specifically to a well-defined pared to other work-related diseases. However,
occupation. Ramazzini emphasized the connec- one must remember that dermatology was not
tion of many diseases with work conditions considered at that time a “speciality by itself.”
and urged that medical students study ways The work-related diseases were so dramatic that
to protect workers. A second edition, skin lesions were considered ancillary. Most of
expanded upon 52 chapters, was published in the diseases described were life-threatening,
1703 (Fig. 2). due to heavy poisoning by metals, for instance.
The success of the treatise was so important Nevertheless, quoted in Table 1 are some work-
among the medical community throughout related skin diseases that were classically
Europe that the French Royal Society asked a observed in the beginning of the eighteenth
young brilliant doctor (circa 1780), Antoine de century.
54 J.-M. Lachapelle
It is clear that most skin conditions had not the eighteenth century (Wright and Goldman
been identified as such in 1700 (i.e., eczemas, 1979). They were described as “dermatitis,”
psoriasis, acne, various types of tumors, etc.). mainly of the hands, forearms, and face. Some
Therefore, the terms used in Table 1 provide a examples are quoted at random: cases of dermati-
flavor of popular medicine. tis due to lacquer varnish, laundry soaps, mercury,
wax in shoe makers, etc.
In the United States, poison ivy dermatitis
2.3 Some Reports of Occupational (unknown in European countries) was very fre-
Dermatology During quent among foresters and agricultural workers.
the Eighteenth Century A. Rostenberg Jr. published a wonderful paper
entitled An Anecdotal Biographical History of
Some reports referring to occupational dermatol- Poison Ivy (Rostenberg 1955). He explained at
ogy were published, somewhat isolated, during length how not only medical officers but also
agricultural experts were implied in the problem-
Table 1 Work-related skin diseases quoted in solving of the disease, which was a real disaster in
Ramazzini’s treatise: De morbis artificum diatriba (1700)
some parts of the country. Experimental studies
Occupations Skin diseases (including applications of various parts of the
Bakers and millers Rheuma, i.e., seborrhoeic
plant onto the skin) were conducted in many
yellowish secretions around the
eyes (from Meibomius’ glands) places, but all those efforts were forgotten for a
Swollen and “painful hands” long period of time.
Breastfeeding Impetigo of the breasts (with
nurses pustules)
Scabies, etc. 2.4 A Major Discovery
Fishers (sea fishers Wounds in the Eighteenth Century: The
and river fishers) Leg ulcers Cancer of the Scrotum
Pustular reactions Among Chimney Sweepers
Gilders Mouth ulcers due to mercury
vapors
During the eighteenth century, the most impor-
Gold diggers Chrysoderma
Horsemen Hemorrhoids
tant discovery in occupational derma-
Anal clefts tology was the recognition of the occurrence of
Laundry women and Irritant contact dermatitis of the cancers of the scrotum (defined later as squa-
soap workers hands and forearms attributed to mous cell carcinomas) among chimney
repeated friction and direct sweepers. This discovery was due to Sir
contact with caustic substances Percival Pott (1775), in London. At that time,
Midwives Hand ulcers
chimney sweepers were selected very young
Syphilis (at risk). Treponema
pallidum was not identified at
(even at the age of 5), in relation with their
that time, and the term “verola” small size, and they worked for many years in
was commonly used the same job.
Masons, bricklayers Cement burns In his careful studies, Pott noticed that the
Persons standing Varices tumors appeared at a late stage, when workers
constantly at work Leg ulcers were aged 30–35 years. He considered that skin
Pharmacists Lesions on the hands and tumors were consecutive to a long exposure to
forearms: pruritus, papules,
scratch marks, etc. (these terms
soot, lack of protective clothing, and poor
most probably prefigured personal hygiene. In the next century, it was recog-
“eczematous” lesions, either nized that a number of coal tar products and certain
irritant or allergic) forms of mineral oils in different industries could
Salt workers Leg ulcers due to acids cause cutaneous cancers (Decoufle 1982).
Schwartz et al. (1957) believed that coal tar The contribution of the English school at the
derivates were the most frequent causes of occu- same period was in retrospect more important for
pational cancer, with 35% caused by tar, 54% by the future of occupational dermatology.
pitch, and 5% by heavy tar oil. Nowadays, Thomas Bateman (1778–1821) worked in asso-
thanks to preventive measures, all these patho- ciation with Robert Willian (1757–1812), the illus-
logical events have almost completely trious founder of the British Dermatology, at the
disappeared. Public Dispensary in London, an association which
was to become far more than one of teacher and
pupil, for Bateman became Willian’s most trusted
assistant, and the tremendous work of the latter
3 The Birth of Dermatology interrupted by death (1811) was brought to its
in the Nineteenth Century logical conclusion by Bateman in his masterful
and most influential A Practical Synopsis of Cuta-
3.1 The Birth of Dermatology neous Diseases (Bateman 1814). As with Socrates
as a Separate Scientific and Plato, it is difficult to determine where the
Discipline During work of one ends and the other’s begins.
the Nineteenth Century: Its His description of eczema (he called it eczema
Impact on Occupational rubrum) is very precise:
Dermatology
The disease is preceded by a sense of stiffness,
burning, heat, and itching, in the part where it
The knowledge of skin diseases and tumors commences. These sensations are soon followed
blossomed in the beginning of the nineteenth by an appearance of redness, and the surface is
century, almost simultaneously in many somewhat rough to the touch. This, however, is
not a simple erythema: for on examining it
European countries. Attempts were made to
minutely between the light and the eye, or with a
classify adequately the elementary lesions that convex glass, the roughness is found to be
were observed on the skin of patients. Authors occasioned by innumerable minute, red pellucid
described carefully the morphological charac- vesicles, which have been mistaken for papules. In
2 or 3 days, these vesicles, if they are not ruptured,
teristics of each type of lesion; they also pro-
obtain the size of a pin’s head, and the included
duced remarkable color drawings that they serum then becoming somewhat opaque and
collected together in books of illustrations or milky, the character of the eruption is obvious.
in treatises. But there was still a pitfall: the When the vesicles begin to loose their transpar-
ency, they generally burst and discharge from
etiology of most dermatoses was unknown,
numerous points a thin acid fluid, which seems to
and apart from the credit paid for the classifica- irritate the surface. . ..
tion (like a stamp collection), no real progress
could be reached. Von Hebra (1816–1880) marked the beginning
Jean-Louis Alibert (1768–1837) is consid- of etiologic research by demonstrating that
ered the father of French Dermatology. Alibert’s eczematous dermatitis could be induced by the
tree of dermatoses is very famous but is of application of croton oil on normal skin (Finnerud
course obsolete nowadays (Alibert 1833). The 1952). He utilized pathology to study a clinical
tree of skin disorders is the testimony of dermatologic problem. Prior to his experiment, it
Alibert’s innovative work in picture form. As a was generally held that eczema was caused by
result of the evolution of scientific knowledge morbid conditions of fluids of the body. While
over the past century, it has, of course, been demonstrating that eczema could result from
superseded. Henceforth, it belongs to the histor- external substances, he realized that such a mech-
ical patrimony of the Hôpital Saint-Louis to anism did not explain all skin diseases. He
which the name of Alibert will be forever linked maintained that occupational exposure “per se”
(Tilles 1989; Lachapelle et al. 1995). was not the cause of psoriasis.
56 J.-M. Lachapelle
3.2 Josef Jadassohn, the Father

of Patch Testing
With the morphology and some pathophysiology

established, some method of diagnostic confirma-
tion was needed. Josef Jadassohn (1863–1936)
developed the patch test, in 1895–1896
(Jadassohn 1896).
As recorded by Sulzberger in 1940 in his clas-
sic textbook, the key message of Jadassohn’s
paper was the fact that he recognized the process
of delayed hypersensitivity to simple chemicals
(Sulzberger 1940). He was the first to make a
distinction between irritant and allergic reactions
(the term “allergy” was not used at that time, since
it was coined only in 1906 by von Pirquet).
4 The Life of Occupational

Dermatology in the Twentieth
Century
4.1 Books Dedicated

to Occupational Dermatology Fig. 3 Robert Prosser White
4.1.1 The Prosser White Book It will be readily agreed that this volume is a
Robert Prosser White (1855–1934) (Fig. 3), monument to the author’s painstaking thoroughness
who worked during all his life in the borough and patience and unflagging industry in collecting
of Wigan, a city located at the North East of records from the widest range of periodical litera-
Liverpool, cumulated many official functions as ture, while many of the facts quoted, being from
dermatologist and factory physician. His main “private communications,” testify to the worldwide
interest was to describe and understand the vari- reputation his devotion to the subject had secured.
ous facets of occupational dermatoses. He was Prosser White was also a figure of incredible
most probably the first one to visit all factories modesty. He wrote in the preface of the 3rd edi-
of this industrialized area of Great Britain but also tion: “Success has been neither complete nor
smaller trades and shops where different activities given content. The little learned unfolds the
were practiced. Very early in his carrier, he wanted more to learn. Until the whole is known, these
to communicate his expertise in the field and ills will stay.”
decided to write a book (first edition, 1915), It has to be noted that the use of the patch test
which was immediately appreciated and three fur- to diagnose more precisely the link between the
ther editions were edited later on. culprit allergen(s) and the occupation is not
We refer to the 4th edition (Prosser White mentioned.
1934), which is a masterpiece, not only His memory is still celebrated in the United
related to the knowledge of occupational derma- Kingdom. Each year, the British Association of
toses but also to the characteristics of work- Dermatologists organizes a special session called
places. Obviously, there were no measures of “The Prosser White Oration.” The lecture is deliv-
prevention at that time. The list of diseases is ered by an invited speaker renowned in the field of
impressive. occupational dermatology.
4.1.2 Other Books Table 2 List of occupational dermatoses quoted in

Ronchese (1948) wrote a classical book entitled Gougerot-Carteaud’s book (1952)
Occupational Marks and Other Physical Signs: A Achromiasa
Guide to Personal Identification. His approach Acne (common)a
was interesting and quite original, but, of course, Actinic dermatitis
it had no practical implications. It is therefore not Anthraxa
too surprising that it was rarely quoted in most Bullous dermatoses
textbooks of dermatology. Burns
Chloracnea
Gougerot and Carteaud (1952) published
Chrome and/or nickel ulcer
(in French) a book simply called Occupational
Erysipeloid
Dermatoses. Its reading is intriguing for two rea-
Erythroderma
sons: (a) the section devoted to “eczemas” is lim-
Frostbites
ited to 22 pages and, (b) on the other hand, Glanders, farcya
132 pages are dedicated to all other occupational Hoffmann and Habermann’s lichenoid melanodermaa
dermatoses. They are listed in alphabetical order Keratoderma
(Table 2). Some of these have completely Mycoses
disappeared in industrialized countries. Occupational cancers
Onychoses and perionyxis
Pruritus and prurigo
4.2 A Breakthrough Purpura
in Occupational Dermatology: Pyoderma
Poul Bonnevie’s Radiodermatitis and radiumdermatitisa
Pioneering Work Rhagades
Riehl’s melanosisa
The work initiated and developed by J. Jadassohn Syphilisa
was pursued to a large extent by Bruno Bloch Tattoos
Tuberculosis
in Basel and in Zurich. Patch testing has become
Urticaria
so important that some authors refer to the
Vacciniaa
“Jadassohn-Bloch” technique. One of Bloch’s a
Dermatoses that have completely or almost completely
trainees at the time was Poul Bonnevie, from disappeared in industrialized countries
Copenhagen, who spent some time in Zurich.
Bonnevie was also an occupational physician, and
he soon realized how patch testing could be useful related to work activities, i.e., turpentine, forma-
in the field of occupational dermatology. His book, lin, potassium dichromate, nickel sulfate, brown
edited simultaneously in German and in Danish in soap, coal tar, wood tars, pyrogallol, para-
1939, is a masterpiece of concision and knew a phenylenediamine, and paramidophenol.
great success (Bonnevie 1939). It is fascinating that about 30 years later, some
Bonnevie was the father of a “standard series” of allergens are still in the limelight (Table 4).
patch tests, now called “baseline series” (Table 3). Adhesive plaster is, at that time, often aller-
This “standard” or “baseline” series was used genic (due to the presence of colophony).
unchanged, and Marcussen (1962) published an The material used today for patch testing is
extensive statistical analysis of the results col- hypoallergenic.
lected in Denmark.
The series was not dedicated in particular to
occupational dermatology but was a selection of 4.3 Later Events
the allergens, mainly encountered in the environ-
ment of that time. Nevertheless, it is obvious that The recent history of occupational dermatology is
some of them were primarily, but not exclusively, closely linked with the historical and scientific
58 J.-M. Lachapelle
Table 3 The standard series of patch tests proposed by

Bonnevie (1939) and slightly modified by Marcussen
(1962) (mainly in terms of nomenclature and also with
the addition of Primula)
1. Turpentine (50% olive oil)
2. Colophony resin (10% olive oil)
3. Balsams of Peru (25% lanolin)
4. Salicylic acid (5% lanolin)
5. Formalin (4% water)
6. Mercuric chloride (0.1% water)
7. Potassium dichromate (0.5% water)
8. Silver nitrate (2% water)
9. Nickel sulfate (5% water)
10. Resorcin (5% petrolatum)
11. Primula obconica
12. Sodium perborate powder (10% water)
13. Brown soap (as is)
14. Coal tar (pure)
15. Wood tars
16. Quinine HCl (1% water)
17. Iodine (0.5% ethanol)
18. Pyrogallol (5% petrolatum)
19. Paraphenylenediamine (2% petrolatum)
20. Paramidophenol, i.e., 4-amino-3 nitrophenol (2%
petrolatum)
21. Adhesive plaster (as is)
Fig. 4 Sigfrid Fregert
Table 4 Bonnevie’s series: allergens still present in the

current standard series (Cadwick and Mann 1950)
contact dermatitis. The birth of national groups
1. Colophony throughout the world boosted the discipline.
2. Balsams of Peru Working parties on occupational dermatology
3. Formaldehyde were created, i.e., by the ECSD. Moreover, some
4. Potassium dichromate
departments, exclusively devoted to occupational
5. Nickel sulfate
dermatology, were opened in different countries.
6. Paraphenylenediamine
A prominent member of the ICDRG was
7. Primula (optional)
Sigfrid Fregert (1919–2016) (Fig. 4) particularly
8. Adhesive plaster
specialized in occupational dermatology. His
book: Manual of Contact Dermatitis (Fregert
advances in the field of contact dermatitis. 1981) is a very concise piece of work, very
The creation of international groups of contact famous all over the world. His approach was
dermatitis, such as the ICDRG (International Con- very similar to that initiated by Prosser White: he
tact Dermatitis Research Group), the NACDG visited a lot of factories and was interested to
(North American Contact Dermatitis Group), know the various chemicals used at each work-
the ACDS (American Contact Dermatitis Soci- place with the aim to discover, in case of contact
ety), the EECDRG (European Environmental dermatitis, new irritants and/or allergens, by the
and Contact Dermatitis Research Group), and use of patch tests. These were more and more
the ECDS (European Contact Dermatitis Society), numerous, as emphasized in a historical review
led to a blossom of knowledge in the field of (Lachapelle 2010).
4.4 Recent Books Related Diagnostischen Wertes der Ekzemproben. Busch,

to Occupational Dermatology Copenhagen
Cadwick J, Mann WN (1950) The medical works of
Hippocrates. Blackwell Scientific, London
Several books have been written in recent de Fourcroy A (1990) Bernardino Ramazzini
years about occupational dermatology. A French (1633–1714). Des maladies du travail (De morbis
treatise on occupational and environmental artificum diatriba – 1700) with a preface by Bernard
Kouchner. Alexitère Editions, Paris, 340 pp
dermatology has been published (Lachapelle Decoufle P (1982) Occupation. In: Scottenfeld P,
et al. 1992) based on Gougerot and Carteaud’s Fraumeni JF Jr (eds) Cancer epidemiology
book (1952); it has been entirely actualized and prevention. W.B. Saunders, Philadelphia, pp
and adapted to modern life, including sports’ 318–335
Finnerud CW (1952) Ferdinand von Hebra and the Vienna
activities and regulatory aspects, with a compar- school of dermatology. Arch Dermatol Syphilol
ison between the French and the European 66:223–232
legislation. Foussereau J (1991) Guide de dermato-allergologie pro-
Robert Adams was a great specialist in occu- fessionnelle, Masson, Paris, 452 pp
Foussereau J, Benezra C, Maibach H (1982) Occupational
pational dermatology. His classical book was pre- contact dermatitis. Clinical and chemical aspects.
sent in all libraries. The originality was that, for Munksgaard, Copenhagen, 452 pp
the first time, there were a lot of black-and-white Fregert S (1981) Manual of contact dermatitis, 2nd edn.
photographs, illustrating various workplaces, thus Munksgaard, Copenhagen, 139 pp
Gougerot H, Carteaud A (1952) Dermatoses pro-
allowing the reader to better understand skin prob- fessionnelles. Maloine, Paris, 368 pp
lems encountered in different industrial sectors Jadassohn J (1896) Zur Kenntnis der Medicamentösem
(Adams 1990). Dermatosen. Verhandlungen der Deutschen
Other condensed books appeared in the United Dermatologischen Gesellschaft, V Congress, 1895.
Braumüller, Vienna, pp 103–129
States. Kanerva L, Elsner P, Wahlberg JE, Maibach HI (2000)
But the masterpiece in the field of occupational Handbook of occupational dermatology. Springer,
dermatology is Kanerva’s book (Kanerva et al. Berlin, 1300 pp
2000) that is a real encyclopedia, covering all Lachapelle JM (2010) Giant steps in patch
testing. A historical memoir. Smart Practice, Phoenix,
aspects of occupational life. 169 pp
After Kanerva’s seizure, a second edition was Lachapelle JM, Frimat P, Tennstedt D et al (1992) Précis de
published, and a third is in press, in honor of our dermatologie professionnelle et de l’environnement.
mentor. Masson, Paris, 400 pp
Lachapelle JM, Tennstedt D, Degreef H et al (1995) 2 cen-
turies of dermatology. Jean-Louis Alibert (1768–1837).
Glaxo Belgium, Brussels, 300 pp
Marcussen PV (1962) Variations in the incidence
References of contact hypersensitivities. Trans St Johns Hosp
Dermatol Soc 48:40–49
Adams RM (1990) Occupational skin disease, 2nd edn. Pott P (1775) Cancer scroti. In: Pott P (ed) Chirurgical
W.B. Saunders, Philadelphia, 706 pp observations. Hawes, Clarke and Collins, London,
Alibert JL (1833) Clinique de l’Hôpital Saint-Louis, ou pp 63–68
traité complet des maladies de la peau contenant la Prosser White R (1934) The dermatergoses or occu-
description de ces maladies et leurs meilleurs modes pational affections of the skin, giving descri-
de traitement, orné de 63 planches, 1st edn. Cormon et ptions of the trade processes, the responsible
Blanc, Paris, 390 pp agents and their actions, 4th edn. H.K.Lewis,
Ammar S (1965) En souvenir de la médecine arabe. London, 716 pp
Quelques uns de ses grands noms. Bascone et Touzat, Ramazzini B (1700) De morbis artificum diatriba.
Tunis, 209 pp Impressoris Episcopalis, Modena
Bateman T (1814) A practical synopsis of cutaneous dis- Ronchese F (1948) Occupational marks and other physical
eases, 3rd edn. Longman, London, 344 pp signs. A guide to personal identification. Grune and
Bonnevie P (1939) Actiologic und Pathogenese der Stratton, New York, 176 pp
Ekzemkrankheiten. Klinische Studien über der Ursachen Rostenberg A Jr (1955) An anecdotal biographical history
der Ekzeme unter besonderer Berücksichtigung des of poison Ivy. Arch Dermatol 72:438–455
60 J.-M. Lachapelle
Schwartz L, Tulipan L, Birmingham DJ (1957) Tilles G (1989) La naissance de la dermatologie

Occupational diseases of the skin. Lea and Febiger, (1776–1880). Roger Dacosta, Paris, 320 pp
Philadelphia, pp 726–737 Valentin M (1978) Travail des hommes savants oubliés.
Siddiqui AH, Cormane RH (1976) Dermatologic origins Histoire de la médecine du travail, de la sécurité et de
and developments down to the early 20th century. l’ergonomie. Docis, Paris, 329 pp
J Invest Dermatol 66:122–127 Wright RC, Goldman L (1979) Contact
Sulzberger MD (1940) Dermatologic allergy. Thomas, dermatitis: a historical perspective. Int J Dermatol
Springfield, p 88 18:665–668
Classification of Occupations
7
Wolfgang Uter
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3 “Job Title” Versus Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4 International Standard Classification of Occupations (ISCO-08) . . . . . . . . . . . . . . . 63
5 International Standard Industrial Classification of all Economic
Activities (ISIC Rev.4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
6 Statistical Classification of Economic Activities (NACE Rev.2) of the EC . . . . . 67
7 North American Industry Classification System (NAICS) . . . . . . . . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Abstract Organisation is available. The “International

For the epidemiology of work-related skin dis- Standard Industrial Classification of all Eco-
eases, comprising surveillance and analytical nomic Activities” (ISIC), presently in its fourth
approaches, occupational exposure can be revision, issued by the United Nations Statis-
represented by the occupation (job title) or the tics Division, is globally used to document
industry a person is working in. For both con- industrial sectors; however, in several coun-
cepts, several international and national classi- tries national classification systems are (also)
fication systems exist, which are revised from used. All such classifications have been devel-
time to time. As global classification of occu- oped to serve broad administrative and
pations, the “International Standard Classi- research purposes. For this reason, it is often
fication of Occupations” (ISCO, presently necessary to adapt a classification of occupa-
ISCO-08) of the International Labour tion or industry to medical needs. To this end, a
more refined subcategorization, respecting,
however, the hierarchical structure of the clas-
W. Uter (*) sification it is based upon, and general rules for
Department of Medical Informatics, Biometry and
Epidemiology, University of Erlangen/Nürnberg,
the construction of classification systems, can
Erlangen, Germany be employed to achieve a best possible degree
e-mail: wolfgang.uter@fau.de; of detail. Conversely, some other categories
wolfgang.uter@imbe.med.uni-erlangen.de

https://doi.org/10.1007/978-3-319-68617-2_7
62 W. Uter
(e.g., different types of “office work”) deemed the field of medical diagnoses, the International
largely identical with regard to relevant expo- Classification of Diseases (ICD) by the World
sures may be aggregated. The aim is to achieve Health Organisation (WHO), presently in the
a clinically manageable, reliable catalogue and tenth revision, is an accepted standard. While the
consistent usage aided by clear definitions. classification of disease status concerns the out-
come of epidemiological analyses, the classifica-
Keywords tion of occupational exposure is needed to
Classification · Epidemiology · Exposure · standardize a potential cause of disease.
ILO · Industry · ISCO · ISIC · Job exposure
matrix · NACE · NAICS · Occupation ·
Surveillance 3 “Job Title” Versus Industry
A certain occupation (“job title”) can in this con-

1 Core Message text be regarded as a more or less precise surrogate
marker for a characteristic profile of medically
• Occupational exposure can be represented relevant exposures, e.g., to carcinogens or aller-
either by the occupation (job title) or the indus- gens (Schnitzer et al. 1995). Beyond the simplest
try a person is working in. possible representation of occupational exposure
• Several international and even more national by the job title itself, job titles can be expanded to
classification systems for both occupation and standardized exposure profiles, termed job-expo-
industry exist. sure-matrix (JEM; Goldberg et al. 1993; Plato and
• As global classification of occupations, the Steineck 1993). JEM link information on occupa-
“International Standard Classification of Occu- tion with information on exposure to specific
pations” (ISCO, presently ISCO-08) of the workplace hazards, e.g., for epidemiological risk
International Labour Organisation is available. analyses, if only data on occupation, but no indi-
• The “International Standard Industrial Classi- vidual data on exposure are available. The preci-
fication of all Economic Activities” (ISIC), sion of JEM may vary, depending on whether they
presently in its fourth revision, issued by the are designed for a company or an industrial sector
United Nations Statistics Division, is used to and can therefore be based on a more detailed
document industrial sectors. classification of occupations and better exposure
• Depending on the circumstances, classification information, or whether JEM are applied in
of occupation rather than industry may be pref- population-based studies, where they necessarily
erable, or vice versa, or possibly use of both have to be more general (Goldberg et al. 1993).
classification dimensions. A competing concept of documenting medically
• Regarding all general classifications, medical (dermatologically) relevant descriptors, i.e., expo-
use for representing relevant (skin) exposure sures and their duration and intensity, would be to
has not been a major objective. Hence, addi- classify not the individual occupation of the patient,
tional categories may need to be added, while but the type of industry he or she is working
some original categories can be used on an in. Examples of such classifications and some of
aggregated level. their applications, e.g., employers liability insur-
ances or governmental labor statistics, are listed
below. In many instances both types of classifica-
2 Introduction tions will achieve very similar results, for example,
allowing either the classification of a patient as
The systematic surveillance of a population – “hairdresser” (“ISCO-08” nr. 5141) or as a person
from the world population to the members of a working in “hairdressing and other beauty treat-
small or medium enterprise or community – is ment” (“ISIC Rev. 4” nr. 9602), the latter being
based on a number of classification systems. In probably somewhat less specific. In other cases the
7 Classification of Occupations 63
classification according to industry may be more between countries – mostly depending on the
specific – at least comparing “ISCO-08” and “ISIC degree of industrialization and labor division – a
Rev. 4”: while “ISCO-08” aggregates “miners and truly international meaning of one job title, par-
quarriers” and “laborers,” respectively (nr.8111, ticularly referring to a uniform exposure, can
nr.9311), irrespective of the minerals extracted, sometimes not be assumed.
“ISIC Rev. 4” details already on the second hierar- These limitations have to be kept in mind con-
chical level the material extracted (“mining of coal” sidering any classification of occupations and,
nr05, “mining of metal ores” nr.07 etc.). similarly, of industries. Despite this, the use of
However, in other cases, particularly in large such a classification may be required by certain
industrial plants, e.g., in the automobile industry national regulations for selected purposes. In
(“manufacture of motor vehicles, trailers and addition, and beyond legal requirements, the use
semi-trailers,” “ISIC Rev. 4” nr.29), a whole of a set of well-defined entries of a catalog of
range of different occupations (and very different occupations may facilitate standardized documen-
exposures) is found in one industry, including, tation for epidemiological analyses concerning
among others, cutting and noncutting metal occupational risk factors, e.g., patterns of sensiti-
workers (“ISCO08” nr.72: “Metal, machinery zation (Uter et al. 2001), prevalence or incidence
and related trades workers”), painters (nr.7131 or of dermatitis, etc. Therefore code numbers of the
nr.8122), administrative personnel (nr.1 – sub- “ISCO-08,” the current version, are given in
groups), cleaning (nr.91 – subgroups) and kitchen Table 1, referring to occupations listed in the
(nr.51 – subgroups) staff, which is certainly not “Job Descriptions” section of this book. These
even an exhaustive list of single job titles. Thus numbers may also serve as an identifier or com-
the documentation of occupation, and not of mon denominator of job titles for different lan-
industry, appears preferable in this setting, as it guages, as far as a national adaption of “ISCO-08”
mostly offers more precision (see also Table 1). A exists. Because some of the descriptions refer to
combination of both concepts may have advan- industries rather than occupations, and because
tages in some situations (Schnitzer et al. 1995). most occupations can be related to one (or few)
Even a seemingly precise job title may hide quite type(s) of industries, “ISIC rev. 4” code numbers
varying exposure patterns, as illustrated by a com- have been supplemented additionally (Table 1).
parison between a metal turner in a small workshop
and a turner in a large, fully computer numeric
control (CNC) equipped factory: the former will 4 International Standard
most likely be heavily exposed to cutting fluids, Classification of Occupations
not being able to wear protective gloves because (ISCO-08)
continually working with turning power tools, will
probably use more aggressive hand cleansing Regarding the classification of occupations (job
because of greater soiling, and will sometimes titles), the International Labour Organisation
have no occupational safety or medical officers at (ILO, www.ilo.org), Geneva, maintains the Inter-
hand. The latter turner may mostly feed crude work- national Standard Classification of Occupations
pieces into a completely encapsulated machine, (ISCO). The ILO published the first edition of an
check and pack finished workpieces, only occasion- international classification of occupations in 1952,
ally setting or repairing the CNC lathe, being able to comprising 1727 occupations, based on national
wear protective gloves at all times, and having easy classifications of eight industrialized countries.
access to safety and medical specialists. Revisions followed in 1958, 1968, 1988, and
Such differences may account for considerable 2007 (ISCO-08), the latter being the current version
variability of exposure, and, with this, the need to at the time this chapter is written. ISCO is a natural
employ more general (and imprecise) JEM the reference or starting point for occupational classifi-
more heterogeneous the respective population cations developed and used in the context of occu-
is. As such characteristics may also vary a lot pational medicine. However, the ISCO is a truly
64 W. Uter
Table 1 “ISCO-08” occupational code numbers (differ- low as possible, i.e., as specific as possible. Exclusions in
ent skill levels) and “ISIC rev.4” industrial code numbers, “job title” may not be applicable to the units identified by
resp., as appropriate, for selected occupations and indus- the number(s)
tries, resp. Code numbers selected on a hierarchical level as
ISCO-08 Job title/industrial sector ISIC rev.4
Various Aircraft industry 3030
9312 (n.s.) Air hammer operators 4210 (n.s.)
2230; 2269 (n.s.); 323 Aromatherapists 8690 (n.s)
Various Automotive industry 29
7512 (n.s.) Bakers 1071; part of 56 (n.s.)
5141 Barbers and hairdressers 9602 (n.s.)
5132 Bartenders 5630
5142 (n.s.) Bath attendants 9311 (n.s.)
7318 (n.s.) Batik manufacturing workers 1313 (n.s.)
7241 (n.s.) Battery makers 2790 (n.s.)
6123 Beekeepers 0149 (n.s.)
7115 (n.s.); 8142 (n.s.) Boat builders 301
7231 (n.s.) Brake-lining workers 2930 (n.s.)
7511 (n.s.); 8160 (n.s.) Butchers and slaughterhouse workers 1010
8131 (n.s.) Candle makers 3290 (n.s.)
7115 Carpenters 4100 (n.s.)
8114 Cement workers 2394
7314; 8181 (n.s.) Ceramic and pottery workers 2393
7513 (n.s.) Cheese makers 1050 (n.s.)
3116; 3133; 8131 Chemists 20
5311 Child day-care workers 8510; 8790 (n.s.)
7516 Cigarette and cigar makers and tobacco 1200
workers
Cleaners
7512 (n.s.) Confectionery and candy makers 1073 (n.s.)
Various Construction workers F (41–43)
Cooks
5142 (n.s.) Cosmetologists 9602 (n.s.)
5151; 7133; 911 Detergent workers (cleaning staff) 812
7541 Divers 38 (n.s.)
3114; 742; 8212 Electronic workers 26; 3313
8122 (n.s.) Electroplaters 2592 (n.s.)
5163 Embalmers (including funeral service 9603
workers)
7316 (n.s.) Engravers 2592 (n.s.)
61; 631–3; 9211–3 Farmers and farm workers 011–017
7122 Floor layers 4330 (n.s.)
5211 (n.s.); 522 (n.s.) Florists 4773 (n.s.); 4789 (n.s.)
3143; 621; 9215 Forestry workers 2
3135 Foundry workers 1910
6129 (n.s.); 6224; 7531 Fur farmers and fur industry 014 (n.s.); 0170; 1420
7532 (n.s.); 7535 (n.s.); 8155
7317; 752 Furniture manufacture 3100
2132; 6113; 9214 Gardeners 8130
7125; 7315; 8181 (n.s.) Glass workers 2310; 2670 (n.s.); 3240 (n.s.)
(continued)
Table 1 (continued)
ISCO-08 Job title/industrial sector ISIC rev.4
Greenhouse workers
7224 Grinders and brazers of hard-metal and Part of 25, 28, 29, and 30
stellite
5141 Hairdressers 9602
322; 325 (excl. 3251); 532 Healthcare workers 86 (n.s.)
9312 (n.s.) Highway construction workers 4210 (n.s.)
5152; 9111 House workers
7124 Insulation workers 4329 (n.s.)
7313 Jewelers 321
3119; 3141; 321 Laboratory technicians 7120 (n.s.); 7500 (n.s.); 8690 (n.s.)
7318 (n.s.) Leather industry 15
7222 (n.s.) Locksmiths 4390 (n.s.)
7223 Machinists Part of 25, 28, 29, and 30
2264 (n.s.); 3255 Masseurs 9609 (n.s.)
Various Metal industry 24; 25; 26 and 27 (n.s.); 28; 29; 30 (n.s.);
33 (n.s.)
0 Military personnel 8422
1322; 3117; 3121; 7542; Mining (tunneling) B (n.s.)
8111; 9311 Mountain guides
2652 Musicians 9000 (n.s.)
8113 Oil rig workers 06 (n.s.); 0910 (n.s.)
2212; 2221 Operating room staff 86 (n.s.)
7131–2 Painters, lacquerers, and varnishers 2592 (n.s.); 4330 (n.s.) and others
3431; 8132 Photographers and photo lab workers 7420
9312 (n.s.) Pitch workers 1910
7126 Plumbers and pipe fitters 4322
6122 Poultry processors 0146; 1010 (n.s.)
732 Printers and lithographers 1811
8143; 8171 Pulp and paper workers 17
2144 (n.s.) Railroad shop workers 3020
7121 Roofers 4100 (n.s.)
7536; 8156 Shoe manufacturers and repairers 1520; 9523
7321 Silk-screen workers 1811 (n.s.)
7113 Stonemasons 2396; 4390 (n.s.)
7512 (n.s.) Sugar artists 1073 (n.s.)
1431; 5419; 9129 Swimming pool workers 9311 (n.s.)
7131 (n.s.) Tattoo artists 9609 (n.s.)
7318 (n.s.); 815 (excl. Textile workers 13; 9601
8155–6)
324 Veterinarians 7500
7212 Welders 2592 (n.s.)
In case of multiple code numbers the original classifications should be consulted as to which number (entry) is most
appropriate for the actual classification problem
n.s. nonspecific
universal classification also in the sense that it international trade and commerce, social sciences,
serves a variety of purposes unrelated to medicine, etc. For the application in occupational dermatol-
such as employment statistics, administrative uses, ogy, ISCO-08 partly has a degree of detail which is
66 W. Uter
quite unnecessary, considering the special purpose instance, in the same plastic manufacturing plant.
of representing occupational skin exposure in a However, even within one of these units groups –
manageable and sensible format. For instance, which often encompass several actual occupations
many subtypes of “office workers” are listed. Con- – marked differences in exposure may exist. As an
versely, in some other parts, even more detail than example, in the group of hairdressers (nr.5141)
presented by the 4-digit level (see Table 1) appears exposure to wet work is, at least in some countries,
desirable. This can be accommodated by much heavier for apprentices – entailing a high risk
expanding the respective 4-digit code number of irritant hand dermatitis – than for skilled beauti-
with a fifth (and, theoretically, further) digit with cians. Hence, sole consideration of the information
corresponding definitions, as long as (i) the hierar- “hairdresser” will not precisely reflect individual
chical ordering is preserved and (ii) mutual exclu- exposure. Approaches to some specific problems
siveness of the finest statistical units is maintained. in the classification of actual occupations are
Should a mapping to the original ISCO-08 cata- discussed within the “ISCO-08” (ILO 2007),
logue become necessary, e.g., for reporting pur- which shall not be dealt with here in detail; the
poses, the more detailed entries can simply be principles have been applied to the suggested
aggregated to the corresponding 4-digit level. code numbers (Table 1).
Indeed, it has been suggested by the ILO to use
the ISCO as a model for the development or adap-
tation of national classifications, which may be 5 International Standard
extended to a finer structure. This refinement Industrial Classification of all
could be necessary to represent national character- Economic Activities (ISIC Rev.4)
istics of the labor market or more detailed occupa-
tional descriptions, which are “of particular interest The ISIC was first published in 1948 by the United
. . . for vocational guidance and training, placement Nations Statistics Division (UNSD); the last (fourth)
services, or analysis of occupation-specific morbid- revision was made in 2008 (UN 2008). The ISIC
ity and mortality” (ILO 2007). Thus, as judged by provides a standard classification of economic activ-
its authors, the 619 major groups, sub-major ities arranged so that entities, e.g., persons, compa-
groups, minor groups, and unit groups contained nies, or institutions, can be classified according to
in ISCO-08 may still be too gross – in parts – to the activity they carry out. The categories of ISIC at
serve some special demands, including occupa- the most detailed level (classes) are delineated
tional medicine (see also above). On an interna- according to what is in most countries the customary
tional level, ISCO-08 is used by the ILO for combination of activities described in statistical
statistical analyses published in the “Yearbook of units. The groups and divisions, the successively
Labour Statistics.” broader levels of classification, combine the statisti-
ISCO is generally based both on the concept of cal units according to the character, technology,
“job,” i.e., a certain kind of work performed by one organization, and financing of production. The
person, which is the statistical unit of ISCO-08, and structure is hierarchical, consisting of 21 “Sections,”
of “skill,” i.e., the ability to carry out the tasks and 88 “Divisions,” 238 “Groups,” and 419 “Classes,”
duties of a given job, partly requiring some level of the latter coded in 4-digit codes. This is a massive
formal training. This division is useful not only expansion since the 3rd revision, which comprised
from a social or economical point of view, but 292 “Classes.” Wide use has been made of ISIC,
also from a medical, because exposure patterns both nationally and internationally, in classifying
may vary considerably between, e.g., a chemical data according to kinds of economic activity in the
plant operator (nr.8131), a chemical engineering fields of population, production, employment, gross
technician (nr.3116), a chemical processing plant domestic product, and other economic activities.
controller (nr.3133), a chemical engineer (nr.2145) Other uses include demographic, social, and health
and a chemical scientist (nr.2113), ordered by analysis (e.g., ILO “Yearbook of Labour Statistics,”
ascending level of skill, but all working, for see above).
6 Statistical Classification in a hierarchical structure. The first two digits

of Economic Activities (NACE designate major Economic Sectors, such as Agri-
Rev.2) of the EC culture or Manufacturing. Readers from the
three countries mentioned are referred, e.g., to
In 1970 a “General Industrial Classification of the US Census Bureau (www.census.gov/eos/
Economic Activities within the European Com- www/naics/, last accessed 2017-02-19) for
munities” was published by Eurostat, Luxem- download, further information, and possible
bourg [French: “Nomenclature statistique des applications.
activités économiques dans la Communauté
européenne”, hence the acronym NACE, corres-
ponding to the Swiss “Nomenclature Générale
des Activités économiques (NOGA)”]. This was References
revised in 1990 and 2001 and made generally
EC (2006) Council Regulation (EC) No. 1893/2006
compatible with the ISIC, containing, however, establishing the statistical classification of economic
some extensions as an adaption to European activities NACE Revision 2 and amending Council
demands. On the finest, 4-digit level, NACE Regulation (EEC) No 3037/90, OJ No L 393/1,
hosts 514 statistical units, conceptually corres- 30.12.2006
Executive Office of the President (1987) Standard indus-
ponding to the ISIC classes. NACE is used trial classification manual, 2nd edn. N.T.I.S. Office of
as compulsory standard for Eurostat economic Management and Budget, Springfield
statistics from 1993 onwards (EC 2006) and Goldberg M, Kromhout H, Gunel P, Fletcher AC, Grin M,
regarded as part of the common statistical Glass DC, Heederik D, Kauppinen T, Ponti A (1993)
Job exposure matrices in industry. Int J Epidemiol 22
language being developed. (Suppl 2):S10–S15
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tions: ISCO-08. International Labour Office, Geneva
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eases, united states. Results from the bureau of labor
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WE (1988) Surveillance of occupational skin disease
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23:491–502
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Surveillance in Occupational Contact
Dermatitis 8
Wolfgang Uter
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
3 Occupational Skin Disease as Part of General Occupational Statistics . . . . . . . . . 70
4 Specific Registration of Occupational Skin Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
5 Clinical Contact Allergy Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Abstract been implemented. These are described and

Surveillance of occupational contact dermatitis discussed briefly in the present chapter. In
addresses time trends and subgroups at risk. addition to such on-going schemes, special
Preferably, surveillance should be based on projects provided some insights into the use-
robust, reliable, and valid classification sys- fulness of the different methods used. Clinical
tems both of morbidity and exposure(s). More- surveillance of contact allergy, based on clini-
over, surveillance needs to be detailed enough cal and demographic as well as patch test data
to be valuable, in particular concerning contact collected within (inter)national networks, can
allergy to various defined substances (hap- contribute to surveillance from another per-
tens). Data used for surveillance need a suffi- spective, and usually with some more detail
cient level of methodological standardization, concerning causative allergens.
e.g., for patch testing used to diagnose contact
allergy. Internationally, a number of surveil- Keywords
lance schemes for occupational diseases, Contact allergy · Contact dermatitis ·
including occupational skin diseases, have Epidemiology · Occupational · Surveillance
W. Uter (*)
Department of Medical Informatics, Biometry and
Epidemiology, University of Erlangen/Nürnberg,
Erlangen, Germany
e-mail: wolfgang.uter@imbe.med.uni-erlangen.de;
wolfgang.uter@fau.de

https://doi.org/10.1007/978-3-319-68617-2_9
70 W. Uter
1 Core Message is used in several fields of Public Health. The most

well-known application is probably infectious dis-
• Surveillance of occupational contact dermatitis ease surveillance and cancer surveillance. More-
is the continuous analysis, interpretation, and over, health surveillance is implemented in
feedback of systematically collected morbidity industrial production plants, if analysis of occupa-
and exposure data. tional risks by the employer or legal requirements
• Surveillance may be clinical or population indicates this is necessary (Anonymous 2004).
based, and on an international or national As a prerequisite for valid results, data acqui-
level, or conducted in (usually larger) indus- sition procedures have (i) to follow a standardized
trial plants. protocol and (ii) to ascertain sampling of repre-
• Often, occupational contact dermatitis does not sentative data, if complete, population-wide reg-
separately appear in the general (national) sta- istration is not feasible. Moreover, the sampling
tistics on occupational diseases and injuries; frame has to be large enough to render estimates
however, the proportion of occupational con- of prevalence, incidence, trends, or comparisons
tact dermatitis among all occupational skin between subgroups sufficiently precise and statis-
diseases is consistently estimated to be around tical tests adequately powerful. Regarding occu-
80%. pational contact dermatitis (OCD) as the most
• Special registries or special analyses of “rou- important occupational skin disease (OSD), a
tine” documentation systems including these number of pertinent approaches are outlined in
data enable the assessment of the spectrum of the following sections. Emphasis is on a system-
(occupational) contact allergens in different atic presentation of methods, and not on
occupations. covering completely the results of the surveillance
• Clinical data on the frequency of irritant or instruments.
allergic contact dermatitis, or on the prevalence
of specific contact sensitization, cannot
directly be interpreted as estimates of morbid- 3 Occupational Skin Disease as
ity on the population level. Nevertheless, suf- Part of General Occupational
ficiently standardized patient data are a valid Statistics
basis of surveillance, addressing time trends (in
subgroups) and risk factor assessment. In Germany, as in many other countries, record is
• Consideration of exposure data (be it on the kept by the employers liability insurance of all
simplest possible level of “job titles”) as occupational diseases. Results are reported every
denominator allows some risk estimation, not- year and are nowadays accessible as interactively
withstanding possible selection bias affecting modifiable report tables on the Internet (“BK-
the likelihood of medical consultation. DOK,” see http://www.gbe-bund.de, last accessed
7 March 2017). This regular report provides
insight into the distribution of suspected as well
2 Introduction as confirmed cases of OSD across industrial
sectors. However, to arrive at an estimation of
Surveillance has been defined as “continuous anal- the risk of specific occupations based on this
ysis, interpretation, and feedback of systematically morbidity statistic, additional statistics on the
collected data, generally using methods distin- number of employed persons must be considered
guished by their practicality, uniformity, and rapid- (for Germany: https://www.destatis.de, last
ity rather than by accuracy or completeness. By accessed 7 March 2017).
observing trends in time, place, and persons, In contrast, the US Bureau of Labor Statistics
changes can be observed or anticipated and appro- (www.bls.gov, last accessed 7 March 2017) pro-
priate action, including investigative or control vides not only absolute numbers of “skin diseases
measures, can be taken” (Last 1995). Surveillance or disorders,” as BK-DOK above, but also
8 Surveillance in Occupational Contact Dermatitis 71
incidence rates calculated per standard full-time Table 1 Incidence rates (number of cases/10,000 working
working hours as denominator, and grossly aggre- years) of occupational contact sensitization to three impor-
tant metal allergens according to the Finnish registry of
gated for industrial sectors (https://www.bls.gov/ occupational (skin) diseases, 1991–1997 (Kanerva et al.
iif/, last accessed 7 March 2017). 2000)
Similarly, the Finnish Institute of Occupa- Nickel Chromium Cobalt
tional Health (www.ttl.fi, last accessed 6 March Footwear workers: Tanners, Printers: 0.80
2017) provides figures on OSD subdivided for 2.6 fellmongers
and pelt
• Diagnoses (e.g., in 2002, n = 330 cases of aller- dressers: 12.2
gic contact dermatitis, n = 313 cases of irritant Machine and metal Cast concrete Turners,
products product machinists
contact dermatitis, n = 115 cases of protein assemblers: 2.4 workers: 6.9 and
contact dermatitis and a number of other diagno- toolmakers:
ses among the 965 notified cases) and 0.36
• Incidence of OSD aggregated by industries Electrical and Leather goods Machine and
(e.g., in 2002, 16/10,000 cases in food and teletechnical workers: 4.7 engine
equipment mechanics:
beverages manufacturing work, 14 cases/ assemblers: 2.0 0.17
10,000 in manufacturing work not elsewhere Precision Metal plating
classified and 12 cases/10,000 in agriculture, instrument and coating
forestry and fishing) (Riihimki et al. 2002) mechanics: 1.7 workers: 3.7
Postal officials: 1.5 Bricklayers:
3.4
In Norway, the most commonly affected occu-
pations were mechanics, welders and similar,
healthcare workers, and hairdressers (Alfonso et al.
2015), similar to statistics from other countries. 4 Specific Registration of
However, the reasons for an observed decline Occupational Skin Disease
from 487 notifications in 2000 to 91 in 2013
remained unexplained; under-reporting of OSD In some countries, specialized registration
has been suspected. schemes for OSD have been implemented. In the
However, the information regarding OSD United Kingdom, two voluntary surveillance sys-
which can be provided by routine reporting from tems exist which have been merged for analyses:
general statistics as those mentioned above is very EPIDERM for consultant dermatologists since
general. Hence, occasional special analyses with a 1993 and OPRA for occupational physicians
greater degree of detail, although still limited by since 1996 (Cherry et al. 2000; Turner et al.
the scope of data and classification detail inherent 2007). Specific research topics such as contact
in the respective registration system, have been allergy to rubber accelerators are also addressed
published (e.g., Kanerva et al. 2000; O’Malley (Warburton et al. 2015). This system does not aim
et al. 1988; Schnuch and Butz 1993). at completeness in the sense of registering all
Regarding the important aspect of occupational cases, but rather uses a representative sampling
contact sensitization, a special analysis of the Finn- method and strives for completeness within this
ish Institute of Occupational Health focused on the framework. According to this scheme, contact
incidence rates of occupational allergic contact der- dermatitis is the most common OSD, with 79%
matitis caused by metals (Kanerva et al. 2000). of all registered cases, followed by neoplasia
Relating the numerator of notified cases of allergic (12.8% of cases). The global annual incidence of
contact dermatitis (n = 2543; 1991–1997) with occupational contact dermatitis (OCD) has been
proven contact sensitization to nickel, chromium, estimated as 12.9 cases/100,000 workers in the
or cobalt to the denominator of workers employed first reporting period (Cherry et al. 2000), and
in the respective occupations, the incidence rates 6.8 cases reported by dermatologists and 26.0/
shown in Table 1 are calculated. 100,000 by occupational physicians in a
72 W. Uter
subsequent period (Turner et al. 2007). Interest- employment data, incidence rates in 24 different
ingly, the “high risk” occupational areas, coded occupational groups were estimated. Among
according to the UK Office of National Statistics, 3097 cases of OSD (median age 25 years) in
also varied by specialty: the main 24 occupational groups, a significant
decline in overall incidence of OSD with 10.7
• Dermatologists, via EPIDERM, identified cases per 10,000 workers/year at the beginning
printers (71/100,000 workers employed per and 4.9 cases per 10,000 workers/year at the
year), machine tool operatives (56/100,000), end of the study period was noted. Hair-
and chemical, gas, and petroleum plant opera- dressing was associated with the greatest risk
tives (45/100,000) as most riskful occupations of OSD (97/10,000 workers per year), followed
in men, and hairdressers and barbers (120/ by bakers (33/10,000), florists (24/10,000), and
100,000), assemblers and line workers for pastry cooks (21/10,000). The largest number of
vehicles and other metal goods (35/100,000) notifications concerned hairdressers (n = 997),
and routine laboratory testes (34/100,000) as health care workers (n = 607), and household
high risk occupations in women. and restaurant service workers (n = 288) (Dickel
• Occupational physicians, via OPRA, identified et al. 2001a).
gas and petroleum plant operatives (182/ Evidently, incidence estimates for a trade
100,000), assemblers and line workers for which may be regarded as fairly comparable
vehicles and other metal goods (109/100,000) between nations in the “developed” countries,
and machine tool operatives (69/100,000 namely, hairdressing, vary greatly, if above statis-
workers employed) in men, and biological sci- tics are compared. This may partly be due to
entists and biochemists (75/100,000), routine variation of (i) actual risk of OCD, modified by
laboratory testers (52/100,000) and assemblers the effectiveness of occupational safety regula-
and line workers (34/100,000) in women as tions, (ii) case definitions used, and (iii) the
occupations with a particularly high risk of sensitivity and specificity of the surveillance
OCD (Cherry et al. 2000). scheme used towards that case definition (Mahler
et al. 2017). Therefore, common standards for the
The above differences between dermatologists management, including aspects relevant for sur-
and occupational physicians seem to illustrate the veillance, have recently been developed in a Euro-
impact of the structure of occupational health care pean consensus process (Alfonso et al. 2017).
in a country, where, in this case, workers in the The degree of detail in most of the above
manufacturing industries are covered by occupa- mentioned surveillance schemes, for instance
tional physicians, whereas workers in small scale regarding the role of contact allergens or irri-
production or service units such as hairdressing tants, is mostly limited. The BKH-S and -N pro-
salons are more likely to consult a dermatologist, ject included documentation and analysis of
be it after referral. This may have some impact on contact allergens in different occupations. How-
the results of surveillance based on either spe- ever, as only a limited period was covered, and
cialty, as illustrated above. a relatively small number of cases were
In Germany, a different approach has been included, no analyses regarding time trends and
followed in terms of temporarily implementing subgroups at risk, respectively, were feasible.
a regional, but presumably complete registration This shortcoming can be overcome by utilizing
of suspected cases of OSD (again mostly OCD) routine clinical data collected by a contact
notified to the occupational liability insurance, allergy surveillance network, as described in
first in Northern Bavaria (Dickel et al. 2001a) the next section. Interestingly, within the scope
and later in Saarland (Dickel et al. 2002). A total covered by both systems, results in terms of
of 5285 cases, registered between 1990 and the significance of single contact allergens in
1999, were assessed in Northern Bavaria. Com- certain occupations were quite comparable
bining morbidity data with regionally matched (Dickel et al. 2001b).
5 Clinical Contact Allergy Data occupation and target sensitization by factors such
as age or gender is suspected, age- and sex-stan-
An increasing number of national or multina- dardization, an adjusted, multifactorial analysis
tional contact dermatitis research groups have (e.g., Uter et al. 2001, 2004a), or other suitable
established networks for the collection and con- methods for the control of confounding should be
tinual analysis of patch test data, along with core employed (Uter et al. 2004b).
information from the patients’ history (Uter et al. Moreover, the analysis of time trends enables
2010b, 2016). Allergy testing must be done with the identification of emerging problems (in certain
a sufficient level of standardization and adher- occupational subgroups) which could target fur-
ence to pertinent guidelines, e.g., concerning ther in-depth investigation, or increased preven-
patch testing, the recommendations of the Euro- tive efforts, as appropriate. Conversely, the
pean Society of Contact Dermatitis (Johansen et success of preventive action aiming at the reduc-
al. 2015). The scope of optimum diagnostic tion or elimination of allergen exposure can be
work-up of contact allergic patients along with evaluated by examining the time trend after such
guidance of adequate description as a case action. For example, the withdrawal and subse-
report for publication has been outlined in Uter quent regulation of glyceryl monothioglycolate, a
et al. (2017). component previously used in so called acid
In virtually all networks, data on occupational perming solutions, has led to a sharp decline of
causation of dermatitis (often categorized as “cer- overall sensitization frequency in hairdressers. In
tain,” “probable,” and “not likely,” respectively, or a more detailed age-stratified analysis, sensitiza-
as “exclusive,” “partial,” or “none,” respectively) tion prevalence in the youngest subgroup of hair-
are collected. Contact sensitization to a certain sub- dressers, who entered working life only after
stance (hapten) can usually be characterized as withdrawal of GMTG, prevalence even arrived
currently or previously occupational versus non- at 0% (Uter et al. 2006), see Fig. 1. However, in
occupational in the assessment of clinical rele- other instances, if a compound is not completely
vance. Additionally, the current occupation(s), and and effectively withdrawn, a certain residual
sometimes previous occupations, if relevant, is exposure and sensitization risk may remain. At
documented (see ▶ Chap. 7, “Classification of any rate, the prevalence in those who became
Occupations”). Based on such data, the frequency exposed only recently is the best possible approx-
of certain specific contact allergies in different imation of incidence, based on such routine clin-
occupations can be examined (Pesonen et al. ical data, and thus preferable to evaluate the
2015). If confounding of the association between effects of exposure changes.
Fig. 1 Time course of the 50

prevalence of sensitization up to 20
45
to glyceryl
40 21 −32
monothioglycolate among
hairdressers with 35 33+
occupational contact
dermatitis, subdivided into 30
three age strata. 25
%
(Reproduced with kind

permission from Uter et al. 20
(2006)) 15
10
5
0
95 96 97 98 99 00 01 02 03 04 05
19 19 19 19 19 20 20 20 20 20 20
74 W. Uter
12
11
10
8
Percent positive
2 Professional Subgroup
Food Proc Cleaners
1 Food Proc. Cleaners
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Year of Patch Test
Fig. 2 Time trend of sensitization to the thiuram mix in lines represent fitted regression lines to represent a linear
food handlers and cleaners, respectively. Sensitization subgroup-specific trend. (Reproduced with kind permis-
prevalence is directly age standardized. Straight grey sion from Uter et al. (2010a))
In other cases, clinical surveillance data may frame, which is regarded as largely stable, con-
point to a persisting or even increasing problem. tinual evaluation of these data can provide valid
This has been illustrated by a recent analysis of information on time trends and clustering in sub-
contact sensitization to rubber allergens in occu- groups without direct reference to the popula-
pational contact dermatitis (Geier et al. 2012). tion. Obviously, possible bias induced by
Particularly concerning food processors, the selection effects must be carefully considered
persisting problem of rubber accelerator allergy when relying on clinical routine data.
calls for better allergen declaration and avoid-
ance (Fig. 2).
As patients consulting a dermatologist for
suspected allergic contact dermatitis, to be References
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Occupational Skin Cancer
9
Thomas L. Diepgen and Hans Drexler
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3 Epidemiology of Melanoma and Nonmelanoma Skin Cancer . . . . . . . . . . . . . . . . . 80
4 Types of Occupational Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.1 Nonmelanoma Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.2 Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5 Other Occupational Skin Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
6 Occupational Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.1 Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.2 Polycyclic Aromatic Hydrocarbons (PAHs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
6.3 Ionizing Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
6.4 UV Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
6.5 Malignant Skin Tumors in Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
7 Occupational Skin Cancer According to German Low . . . . . . . . . . . . . . . . . . . . . . . . 88
7.1 BK No. 1108: Diseases Caused by Arsenic or Its Compounds . . . . . . . . . . . . . . . . . . . 88
7.2 BK No. 2402: Diseases Caused by Ionizing Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
7.3 BK No. 5102: Skin Cancer or Skin Alterations Showing a Cancerous
Tendency Caused by Soot, Raw Paraffin, Tar, Anthracene, Pitch, or
Similar Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
T. L. Diepgen (*)
Department of Social Medicine, Occupational and
Environmental Dermatology, University Heidelberg,
Heidelberg, Germany
e-mail: Thomas.Diepgen@med.uni-heidelberg.de
H. Drexler
Institute and Outpatient Clinic for Occupational, Social
and Environmental Medicine, Friedrich-Alexander-
University, Erlangen-Nürnberg, Erlangen, Germany
e-mail: Hans.Drexler@rzmail.uni-erlangen.de;
Hans.Drexler@fau.de

https://doi.org/10.1007/978-3-319-68617-2_10
78 T. L. Diepgen and H. Drexler
7.4 BK No. 5103: Squamous Cell Carcinoma or Multiple Actinic Keratoses

of the Skin Caused by Natural UV Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
8 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
8.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
8.2 Occupational Skin Cancer Prevention Strategies for Outdoor Workers . . . . . . . . . . . 90
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Keywords develop work-related occupational skin

Actinic (solar) keratoses · Bowen’s disease · cancer due to natural UVR exposure, and
Keratoacanthoma · Malignant melanoma · adequate prevention strategies have to be
Nonmelanoma skin cancer · Pitch skin implemented.
disease · Tar keratoses • The three measures that are successful and
of particular importance in the prevention of
nonmelanoma skin cancer in outdoor workers
1 Core Messages are the following:
1. Changes in behavior regarding awareness
• Occupational skin cancer can be induced due to of health and disease resulting from expo-
industrial exposure to chemical carcinogens but sure to natural UV radiation
nowadays more important due to occupational 2. Protection from direct UV radiation by
exposure to UV radiation (UVR). wearing suitable clothing
• Occupational skin cancer is characterized by long 3. Regular and correct use of appropriate
induction periods (years or decades), and its first sunscreens
manifestation is often seen many years after the
occupational exposure or even when the affected
individuals are not more occupationally exposed. 2 Introduction
• Important industrial chemicals are arsenic
and inorganic arsenic compounds, polycyclic Occupational skin cancer is, especially in the
aromatic hydrocarbons (PAHs) with particularly historical sense due to industrial exposure to
high levels in brown coal tars (soft coal tars), coal chemical carcinogens, important, but nowadays,
tars (black coal tars), coal tar pitches, coal tar oils, the relation of skin cancer to occupation is
and coke oven emissions and can cause basal cell often confounded by concurrent sun exposure
carcinomas and squamous cell carcinomas. from leisure pursuits. The term “skin cancer” is
• A published systematic appraisal of the epide- nonspecific. Under such a heading come different
miologic literature and meta-analysis clearly clinicopathological entities with different etio-
indicates that occupational UV-light exposure logic factors, presentation, clinical course, and
is a substantial and robust risk factor for prognosis (Naldi and Diepgen 2007). A distinc-
the development of cutaneous squamous cell tion is usually made between “cutaneous
carcinoma (SCC). melanoma” and “nonmelanoma skin cancer.”
• The actually available evidence of the epide- The term “nonmelanoma skin cancer” includes a
miologic literature could also clearly show a large number of different disorders, especially
significant risk increase for occupationally basal cell carcinoma (BCC) and squamous cell
UV-exposed workers to develop basal cell carcinoma (SCC). Nonetheless, it is common
carcinoma (BCC) compared to nonexposed practice to use it with reference to only two
workers. entities, which, by far, are the most frequent
• There is enough scientific evidence that out- ones, namely, basal cell carcinoma and squamous
door workers have an increased risk to cell carcinoma, also collectively labeled as
9 Occupational Skin Cancer 79
Table 1 Classification of skin cancer (According to Naldi and Diepgen 2007)

Example
Epidermal skin tumors Basal cell carcinoma
Squamous cell carcinoma
Paget’s disease
Keratoacanthoma
Tumors of skin appendages
Hair follicle tumors Pilary complex carcinoma
Sebaceous glands Sebaceous carcinoma
Apocrine gland tumors Apocrine carcinoma
Eccrine gland tumors Sweat gland carcinoma
Microcystic adnexal carcinoma
Eccrine epithelioma
Mucinous eccrine epithelioma
Adenoid cystic carcinoma
Lymphoepithelioma-like carcinoma
Melanocytic tumors Melanoma
Malignant blue nevus
Langerhans cell tumors Histiocytosis X
Mast cell tumors Lymphadenopathic mastocytosis and eosinophilia
Subcutaneous tissue tumors Liposarcoma
Fibrohistiocytic tumors Dermatofibrosarcoma protuberans
Atypical fibroxanthoma
Malignant fibrous histiocytoma
Neoplasms of the vessel wall Angiosarcoma
Kaposi’s sarcoma
Smooth muscle tumors Superficial leiomyosarcoma
Neural and neuroendocrine tumors Granular cell tumor
Neuroendocrine and Merkel cell carcinoma
Cutaneous lymphoproliferative disease
T cell Mycosis fungoides
Sézary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative disorders
B cell Primary cutaneous marginal zone B-cell lymphoma
Primary cutaneous diffuse large B-cell lymphoma, leg type
Precursor hematologic neoplasms
“keratinocyte carcinomas” or “epidermal skin often seen many years after the occupational expo-
cancer.” Besides the abovementioned disorders, sure or even when the affected individual is not
a large number of clinicopathological entities more occupationally exposed.
may be listed as representing “skin cancer” An additional problem related to occupational
(Table 1). skin cancer is the fact that skin cancer
In contrast to most inflammatory occupational nowadays is a widespread disease, especially
skin diseases, especially allergic and irritant contact in Caucasians, and is comparable rarely indu-
dermatitis and contact urticaria, occupational skin ced by occupational carcinogens but by consti-
cancer is characterized by long induction periods tutional (skin type) and lifestyle factors (sun
(years or decades), and its first manifestation is exposure).
This chapter introduces different types of 4 Types of Occupational Skin

occupational skin cancer and discusses its occu- Cancer
pational hazards. In the last paragraph, measures
for the prevention of occupational skin cancer are 4.1 Nonmelanoma Skin Cancer
presented.
The term “nonmelanoma skin cancer” (NMSC)
covers those cancers of the skin (epidermis)
which are not malignant melanomas. The two
3 Epidemiology of Melanoma commonest NMSCs are basal cell carcinoma and
and Nonmelanoma Skin Cancer squamous cell carcinoma of the skin. Both of
these types of malignant tumor arise from the
Melanoma and nonmelanoma (basal and epidermal tissues: squamous cell carcinomas
squamous cell carcinomas) skin cancer (NMSC) from the epidermal keratinocytes and basal cell
are now the most common types of cancer in carcinomas from the basal cells of the epidermis.
the white populations, and the incidence of skin Basal cell carcinoma is the commonest malignant
cancer has reached epidemic proportions (Diepgen tumor in fair-skinned people: it is extremely
and Mahler 2002; Madan et al. 2010). According locally invasive and destructive but only rarely
to population-based studies from Australia, the metastasizes.
incidence rate is over 2% for basal cell carcinoma Different types of basal cell carcinoma
(BCC) in males and 1% for squamous cell carci- can be distinguished clinically: nodular, cystic,
noma (SCC), and there are over 50 new cases of pigmented, superficial (multicentric), morphoea-
melanoma per 100,000 (Buettner and Raasch like, and ulcerative. The nodular and cystic
1998). According to a recently published study variants are usually found on the face and are up
(Pandeya et al. 2017), the person-based incidence to 10 mm or more in diameter. The morphoeic
of keratinocyte cancer excisions in Australia was type shows scarring and a diffuse edge and is
1,531 per 100,000 person-years; incidence often found on the face too, whereas the multi-
increased with age and was higher for men than centric superficial tumors, which can extend to
women (SIR, 1.43; 95% CI, 1.42–1.45). Lesion- several centimeters in diameter, typically occur
based incidence was 3,154 per 100,000 person- on the trunk. Exposure to the sun, to ionizing
years. The estimated age-standardized incidence radiation, and to chemical carcinogens including
rates (ASRs) for BCC and SCC were 770 per tar products can be involved in the causation of
100,000 and 270 per 100,000 person-years, respec- basal cell carcinoma.
tively. In a population-based study in Olmsted Like squamous cell carcinoma, it is more com-
County, Minnesota (USA), the age-adjusted BCC monly found in men than in women. Basal cell
incidence (cases per 100,000 person-years) carcinoma occurs about four times more fre-
was 360.0 (95% CI, 342.5–377.4) in men and quently than squamous cell carcinoma, which is
292.9 (95% CI, 278.6–307.1) in women. The the second most common form of skin cancer.
age-adjusted cSCC incidence (cases per 100,000 Squamous cell carcinoma has a destructive
person-years) was 207.5 (95% CI, 193.9–221.1) in pattern of growth and it metastasizes. It nearly
men and 128.8 (95% CI, 119.4–138.2) in women always arises from characteristic precancerous
(Muzic et al. 2017). Without doubt, skin cancer is lesions; actinic keratoses (AKs) are preinvasive
by far the most common kind of cancer diagnosed squamous cell carcinomas and can therefore be
in many western countries. The chance of devel- regarded as carcinoma in situ. Basal cell carcino-
oping a skin cancer in British Columbia, Canada, is mas and squamous cell carcinomas exhibit both
approximately 1 in 7, over lifetime (Demers et al. epidemiological and biological differences.
2005). The most common skin cancer is basal cell Squamous cell carcinomas and basal cell
carcinoma, followed by squamous cell carcinoma carcinomas are the commonest skin cancers
and melanoma. in spi1;fair-skinned people all over the world
(Wang and Diepgen 2006). In the USA, it has for risk. In contrast to malignant melanomas and
even been estimated that the incidence rate of basal cell carcinomas, the incidence of squamous
NMSCs (basal cell and squamous cell carcinomas cell carcinoma shows an exposure-response curve
combined) is about as high as all other types of without any plateau phase. Benign UV-light-
cancer put together (American Cancer Society induced skin changes (lentigo, telangiectasia,
2006). In the year 2002, some one million and elastosis) also show a strong association
Americans were diagnosed with NMSC. Because with the incidence of squamous cell carcinoma.
of the high morbidity and associated treatment
costs, NMSCs represent a heavy burden on 4.1.1 Risk Factors for NMSC
the health-care system, even though they are Table 2 shows the similarities and differences
not usually associated with very high mortality. in the risk factors for basal cell carcinoma and
NMSC has therefore been included in the top squamous cell carcinoma. Whereas squamous
10 health-care priorities in the USA for this cell carcinomas are clearly associated with
decade, currently occupying place eight. chronic exposure to UV light, occur on areas of
Since the 1960s, the annual incidence of the skin exposed to light, and, in Caucasian
NMSC has increased by 3–8% (Glass and Hoover populations, show clear associations with the
1989; Green 1992). geographical latitude of domicile and measured
Sex-related differences in exposure to the sun UVB radiation, important risk factors for basal
during occupational and leisure activities, the cell carcinomas also include intermittent exposure
use of sun protection, and scalp hair are to sunlight and a genetic predisposition. A deci-
probably reasons for the higher prevalence of sive factor for the development of squamous
nonmelanoma skin cancer in men (Oberyszyn cell carcinoma is the cumulative lifetime UV
2008; Hall et al. 1997). exposure. In contrast to malignant melanomas
Basal cell and squamous cell carcinomas are and basal cell carcinomas, the incidence of
usually considered together under the heading squamous cell carcinoma shows an exposure-
“nonmelanoma skin cancer,” but they present response curve without a plateau phase.
rather different distribution and etiologic factors. Besides UV radiation, other influences such
The two tumors share the difficulties of obtaining as ionizing radiation, exposure to tar and other
reliable incidence data and the limited contribu- carcinogens, smoking, DNA repair defects (such
tion of mortality to understand their distribution as xeroderma pigmentosum), and/or immunosup-
and burden. Incidence estimates for “cancer of pression may induce nonmelanoma skin cancer.
the skin other than melanoma” based on registry Smoking and other types of tobacco use are
data, range from around 0.5/100,000 in Hispanics, clearly associated with squamous cell carcinoma
Blacks, and Asians to more than 100/100,000 of the lip. Malignant tumors of the skin may form
in white people in Switzerland and Ireland in scars. Burns and other firm scar tissue are
(Parkin et al. 2005). However, few cancer regis- predisposed to skin cancer. Most of them are
tries provide reliable data on nonmelanoma skin squamous cell carcinomas or basal cell carcino-
cancer, and ad hoc studies should be better mas, although the former are more common
conducted. (Kowal-Verna and Criswell 2005). Simultaneous
Within populations of European descent, the exposure to UV light and benzopyrenes consider-
incidence of squamous cell carcinoma is lower in ably intensifies the development of cancer.
those with darker skins (Mediterranean skin type). In white transplant recipients, risk of squamous
In Australia and the USA, the incidence of squa- cell carcinoma increases 65–250-fold and risk
mous cell carcinoma increases with proximity to of basal cell carcinoma 10–16-fold compared
the equator. Squamous cell carcinoma of the with the nontransplanted population (Lindelof
skin shows clear associations with geographical et al. 2000; Moloney et al. 2006). The risk of
latitude of the domicile and measured UVB radi- developing actinic keratosis (AK) is about
ation. Lifetime cumulative exposure is decisive 250 times greater in organ transplant recipients
Table 2 Risk factors for nonmelanoma skin cancer (NMSC): basal cell carcinomas and squamous cell carcinomas –
similarities and differences
Risk factor NMSC: squamous cell carcinomas and basal cell carcinomas
Age Clear increase with age
Sex More common in men
Genetics Increased risk with a positive family history of basal cell carcinoma, but not of
squamous cell carcinoma
Phototype Higher incidence in fair-skin types – people who do not tan easily, have many
freckles, get sunburn easily, and have red or blonde hair
Past history of skin cancer 36–52% probability of the occurrence of a new skin cancer within the next 5 years
Ethnic group More common in people of Caucasian origin
Geographical location The incidence increases in Caucasian people with proximity to the equator
Medical causes Chronic ulceration, burn scars, xeroderma pigmentosum, immunosuppression (organ
transplantation), and HPVa infections are associated with increased risk
Occupation Higher incidence of squamous cell carcinoma but also of basal cell carcinoma, in
outdoor workers
Exposure to chemicals and Ionizing radiation, PUVA therapy, and exposure to tar increase the risk. Smoking is a
other substances risk factor for squamous cell carcinoma; arsenic exposure is a more important risk
factor for basal cell carcinoma
Exposure to sunlight
Cumulative The highest individual risk factor for squamous cell carcinoma, less important
(together with other risk factors) for basal cell carcinoma
Sporadic Intensive, intermittent exposure with sunburn and blistering especially in childhood/
adolescence is associated with an increased risk of basal cell carcinoma but not of
a
Human papilloma virus
(Stockfleth et al. 2002; Stoff et al. 2010). The ratio People who already have one squamous
of squamous cell to basal cell carcinoma also cell carcinoma of the skin have an approximately
reverses in iatrogenic immunosuppression, 50% risk of developing a second malignant
because squamous cell carcinomas and actinic skin lesion (nonmelanoma skin cancer) in the
keratosis occur more frequently in transplant following 3–5 years (Hemminki and Dong 2000).
recipients than do basal cell carcinomas.
Although basal cell carcinomas usually occur
in light-exposed areas, unlike squamous cell car- 4.2 Malignant Melanoma
cinomas, they may also occur in areas hardly
exposed to sunlight at all and without any Malignant melanoma (MM) occurs among all ade-
significant actinic damage, such as the trunk. quately studied racial and ethnic groups. Its inci-
UV light is also the most potent causative factor dence is much lower compared to NMSCs but has
for basal cell carcinoma, but its effects are less been rising in fair-skinned populations throughout
evident than in squamous cell carcinoma. the world for several decades (Armstrong and
A carcinogen typically associated with basal Kricker 1994). The incidence of malignant mela-
cell carcinomas is arsenic. An increased incidence noma varies over 100-fold around the world (Naldi
of basal cell carcinomas has been reported with and Diepgen 2007). According to data provided in
a hereditary syndrome of congenital defects Cancer Incidence in Five Continents, the lowest
(basal cell nevus syndrome). A sebaceous nevus rates reported around 1993–1997 were 0.3–0.5/
may enhance the development of basal cell carci- 100,000 person-years, in parts of Asia and in Asian
nomas. Apart from the genetic predisposition, and black people in the USA, while the highest were
intermittent intense exposure to UV light with up to 50/100,000 in Queensland, Australia (Parkin
sunburn is a key risk factor. et al. 2005). Incidence rates have risen significantly
over the last 30–40 years and continue to increase in intermittent exposure and blistering sunburns
the USA, Canada, Australia, and Europe, being per- in childhood and adolescence are associated
ceived as a major public health concern. Geographic with increased risk. However, lentigo maligna
variations with incidence of cutaneous melanoma melanoma (LMM) occurs in sun-exposed sites,
appear to reflect the combined effect of constitutional typically on the face, and is typically associated
characteristics and latitude. Epidemiological data with prolonged cumulative exposure to sunlight,
from the USA and Australia show that melanoma usually over a period of many years, in some-
incidence in white people increases the closer to the body employed in outdoor work. LMM might
equator people live. be considered as an occupational skin cancer
In contrast to nonmelanoma skin cancer, the because there is a “general suitability,” given
greatest numbers of melanomas are found on the that LMM may be caused by prolonged occu-
intermittently sun-exposed areas of the back and pational exposure to natural UV light (Elsner
legs. Increases in incidence in populations of et al. 2014).
European origin have been most pronounced on • Occupation: Higher incidence in indoor
the trunk and other intermittently exposed areas, workers, as well as those with higher education
particularly in men, while the incidence of mela- and income.
noma of the face has remained reasonably stable • Medical conditions: Xeroderma pigmentosum,
over time (Bulliard and Cox 2000; Thorn et al. immunosuppression, other malignancies, and
1990). The anatomical distribution in black peo- previous nonmelanoma skin cancer all increase
ple and people of Asian origin is quite different risk. Previous melanoma is associated with
with most melanomas occurring on the soles of increased risk.
the feet (Cress and Holly 1997).
There are important clinical and epidemiologi- The single greatest predictor of risk for devel-
cal differences in risk factors for the different sub- oping melanoma is the total number of nevi
types of cutaneous malignant melanoma (Gandini et al. 2005b). Studies over the last
(superficial spreading melanoma, nodular mela- decades have revealed a great deal about the way
noma, lentigo maligna melanoma, and acrolentigo nevi develop and the relationship between
melanoma). The following are the most important nevi and melanoma. Interestingly, red-haired chil-
risk factors for malignant melanoma: dren have a reduced count of nevi as compared
to other skin phenotypes but a higher melanoma
• Skin type/ethnicity: Increased incidence in risk, suggesting different pathways to melanoma
those with fair complexions; those who burn development.
easily, tan poorly, and freckle; those who have Intermittent sun exposure and sunburn history
red, blonde, or light brown hair; and those of were shown to play considerable roles as
Celtic ancestry. risk factors for melanoma, whereas a high
• Family history: Occurrence of melanoma in a occupational sun exposure seemed to be inversely
first- or second-degree relative confers associated to melanoma (Gandini et al. 2005a).
increased risk. Familial atypical mole mela- Overall, high occupational exposure is inversely
noma syndrome (FAMMS) confers even associated with melanoma and directly related to
higher risk. the risk of squamous cell carcinoma.
• Nevi: A large number of melanocytic nevi and
giant pigmented congenital nevi confer
increased risk. Melanocytic nevi are markers 5 Other Occupational Skin
for risk, not precursor lesions. Cancers
• Geographic location: Higher incidence in
whites living near the equator. Actinic (solar) keratoses clinically are brownish
• Sun exposure: Cumulative sun exposure or reddish scaly areas, sometimes with a
probably does not influence risk, but intense, popular component or with inflammation, a
few millimeters in diameter, and a rough 6 Occupational Hazards

surface. They are located on sun-exposed
sites, typically the dorsal aspects of the hands, 6.1 Arsenic
the forearms, the face, and the scalp. They
may be associated with other stigmata of Arsenic occurs naturally in ores together with
sun-damaged skin, such as telangiectasia, irregu- zinc, lead, copper, and iron. In the past, it was
lar pigmentation, solar elastosis, or skin used for paints, pesticides, and as a medicine.
atrophy. Actinic keratoses are nowadays consid- Today, arsenic is only used in the semiconductor
ered as a squamous cell carcinoma in situ and microchip industry. Arsenic and inorganic
and belong therefore to NMSC (Röwert-Huber arsenic compounds are mainly absorbed via
et al. 2007). inhalation and ingestion. Several studies show
Tar keratoses are related to exposure to that the internal exposure to arsenic correlates
coal tar, pitch, shale oil, and products of the well with the external exposure. Therefore, der-
distillation of coal (Gawkrodger 2004). mal absorption under workplace conditions
They may appear some years after the period of does not seem to be relevant. Arsenic and inor-
exposure. Clinically, they are brown-colored, ganic arsenic compounds are distributed rapidly
flat-topped, round, or oval small plaques a in all organs. Accumulation is observed particu-
few millimeters in diameter, with a tendency to larly in the liver, kidneys, and lungs. Long-term
be clustered. Their surface may be smooth exposure to arsenic in humans causes fever,
or warty. They tend to be seen on the dorsal sleep disorders, weight loss, swelling of the
aspects of the hands, the forearms, and around liver, dark discoloration of the skin, sensory and
the face. motor neuropathy, and encephalopathy with
Arsenical keratoses are typically seen as symptoms such as headaches, poor concentration,
punctate keratoses on the palms of the hands and deficits in the learning of new information, diffi-
soles of the feet in subjects exposed to arsenic culties in remembering, mental confusion, anxi-
and are not seen with any other condition. They ety, and depression. Long-term exposure to
are usually multiple and may progress to squa- arsenic can also cause peripheral vascular
mous cell carcinoma. Intraepidermal carcinoma effects such as acrocyanosis, Raynaud’s disease,
or multiple basal cell carcinomas may be associ- and tissue necrosis on the extremities (blackfoot
ated (Gawkrodger 2004). disease) . Long-term exposure to dust containing
Keratoacanthoma is a rapidly growing dome- arsenic causes irritation of the conjunctiva and
shaped nodule up to 2 cm in diameter, with a mucous membranes of the nose and throat. The
central keratinous plug, that is usually found in pustular or follicular skin reactions observed after
sun-exposed areas such as the face, dorsa contact with inorganic arsenic compounds are
of hands, and the forearms (Gawkrodger 2004). usually attributed to irritative effects and not to
Histologically, they resemble squamous cell car- sensitizing effects of the arsenic compounds.
cinomas, but spontaneous resolution may occur. Arsenic and inorganic arsenic compounds are
It is associated with sunlight and tar exposure carcinogenic in humans. The target organs of the
(Letzel and Drexler 1998). carcinogenic effects after inhalation are the lungs
Intraepidermal carcinoma (Bowen’s disease) and after ingestion the bladder, kidneys,
is in situ squamous cell carcinoma. It occurs as lungs, and skin (Greim 2005).
scaly red plaques up to several centimeters in The premalignat skin tumors are punctuate
size, located on the sun-exposed sites of the keratoses on the palms of the hand and soles
lower legs, face, or arms (Gawkrodger 2004). of the feet in subjects exposed to arsenic. They
Progression to invasive carcinoma may cannot be observed under other conditions
occur. It is typically associated with arsenic and are therefore pathognomonic for chronic
ingestion. arsenic exposure. They are usually multiple
and may progress to squamous cell carcinoma Often, there are other signs of a so-called tar or
(Gawkrodger 2004). Besides the squamous cell pitch skin disease (e.g., folliculitis, acne, diffuse
carcinomas which can also occur on each position brownish pigmentation, and hyperkeratosis).
on the skin besides palms and soles, superficial The tumors can also occur without these signs.
basaliomas are often associated with a chronic The skin tumors are localized, in particular, in
arsenic exposure. the exposed areas including the nose, periorbital
region, and ears and on the backs of the hands
and forearms. The location seems to deviate from
6.2 Polycyclic Aromatic that of the light-induced tumors (more often
Hydrocarbons (PAHs) lower lip than upper lip, more often nasal vesti-
bule than bridge) (Letzel and Drexler 1998).
In 1773, Sir Percivall Pott was the first to describe
the occurrence of occupational causes of
cancers. He observed the frequent occurrence of 6.3 Ionizing Radiation
squamous cell carcinomas of the scrotum in
young chimney sweeps and identified soot as Ionizing radiation consists of particles (alpha
the causal agent. Soot is a pyrolysis product of particles, beta particles, neutrons) or electromagnetic
organic materials which contain, among numerous waves (gamma rays with wavelengths less than
other substances, polycyclic aromatic hydrocarbons 0.01 nm, which are less than the diameter of an
(PAHs). The extremely complex mixtures atom, and X-rays with wavelengths from 0.01 to
which have been examined to date contain, simul- 10 nm). Alpha particles are absorbed completely in
taneously and in widely differing proportions, car- the stratum corneum and do not cause a damage in
cinogenic components and substances which the skin. Under high acute radiation exposure (1 Sv
promote cancer development. Many of the PAHs, and above), the development of acute radiation der-
which occur regularly in pyrolysis products, are matitis is expected with redness, itching, and infil-
carcinogenic in animal studies. They exist at partic- tration of the skin. Higher doses may cause bleeding
ularly high levels in brown coal tars (soft coal tars), into the skin, blisters, and necrosis. The final stage
coal tars (black coal tars), coal tar pitches, coal tar can be a chronic dermatitis with radio atrophy of
oils, and coke oven emissions (DFG 2010). the skin, increasing sclerosis, keratinization disor-
The carcinogenic effect after occupational ders, pigmentary changes, and dryness developing
exposure to these mixtures of aromatic com- due to loss of sebaceous glands, hair loss,
pounds has been demonstrated in epidemiological and telangiectasia.
studies. Therefore, they are classified into the Ionizing radiation can cause malignant dis-
category of the human cancerogens. eases of the skin, especially squamous cell and
In the organism, PAHs are enzymatically basal cell carcinomas and less often sarcomas.
converted into carcinogenic metabolites. The Actinic keratoses caused by X-rays are carcino-
enzymes required for this activation are mono- mas in situ and were often observed in the
oxygenases (CYP 1A1, 1A2, 1B1) and are found past at the hands of surgeons and radiologists.
in the hair follicles of the skin. Therefore, the initial Today, in compliance with the radiation limits,
cancers (“tar warts”) develop – in contrast to solar however, no higher incidence of radiation-
keratosis – in the deeper layers of the epidermis. induced diseases is observed in occupationally to
PAHs can cause basal cell carcinomas and ionizing radiation-exposed persons. The radiation
squamous cell carcinomas. Direct skin contact exposure from accidents such as Chernobyl
seems to be a prerequisite. The latency of the or Fukushima, in contrast, is much higher and
initial exposure to PAHs to an onset of skin tumors suitable to cause both stochastic damages (cancer)
may be relevant for years to decades. Skin cancer and deterministic damages (inflammation to
can occur even after termination of exposure. necrosis) on the skin.
6.4 UV Radiation (Ridley et al. 2009). Several complex DNA

repair systems are needed to prevent the harmful
The spectrum of ultraviolet (UV) light comprises effects of these premutagenic adducts (Lear et al.
wavelengths of 100–400 nm and is therefore 2000).
below the range of visible light (400–780 nm). UVA radiation, which penetrates deeper into
Depending on its wavelength, UV radiation is the skin, reinforces the carcinogenic effects
divided into UVA (315–400 nm), UVB of UVB rays and causes aging and immunosup-
(280–315 nm), and UVC (100–280 nm), pression. In this way, both UVB and UVA are
although on the Earth, human beings are exposed involved in the development of skin cancer.
only to UVA and UVB. Natural solar UV radia- The relationship between UV radiation and
tion on this planet consists of 95% UVA and skin cancer has been well demonstrated at various
5% UVB. levels by epidemiology, clinical distribution
UV radiation is the most important cause of of the tumors, molecular biology, and plausible
skin aging and skin cancer. It causes chronic mechanisms. However, some aspects in the devel-
cutaneous photodamage (Saladi and Persaud opment of the disease and in the counter-
2005). The carcinogenic effects of UV radiation regulatory mechanisms, the interaction of
on the skin and eyes are well documented various photobiological processes, and the sec-
both experimentally and epidemiologically ondary biochemical effects after irradiation are
(Saladi and Persaud 2005). UV radiation acts still unclear.
as a carcinogen both directly, by inducing cell Light wskin complexion (especially light skin
damage (DNA mutations), and indirectly, and blond-red hair), freckling, and tendency
by inducing immunosuppression (suppression of to burn, not tan, after sun exposure, are constitu-
T lymphocytes). tional variables which affect the risk of skin
There is good evidence that UVB radiation acts cancer. People from Southern European ethnic
directly through specific changes in oncogenes origin are at a significantly lower risk than those
and p53 tumor suppressor genes, which are from English, Celtic, and Scandinavian origin.
responsible for the initiation and progression of Those who migrate early in their life from such
skin cancer. UV radiation, and in particular UVB, regions to lower latitudes increase their exposure
leads to the formation of pyrimidine dimers in levels to sunlight and show a higher risk of
deoxyribonucleic acid (DNA) and ribonucleic developing skin cancer. It can be further stated
acid (RNA). This gives rise to mutations in that the timing and character of sun exposure
keratinocytes and hence to neoplastic transforma- may affect differently the risk of different skin
tion. Particularly, significant mutations affect the cancers. Cutaneous melanoma and basal cell car-
telomerase gene and the p53 tumor suppressor cinoma are most significantly linked to early
gene. These mutations are important steps toward exposure to ultraviolet light. Intermittent sun
neoplastic transformation. exposure and sunburn history are more important
UVB radiation causes direct damage to DNA than cumulative dose in predicting adult risk for
and RNA by inducing covalent bond formation these tumors. Basal cell carcinoma and melanoma
between adjacent pyrimidines, leading to gener- tumors appear to have a rapidly accelerating rela-
ation of mutagenic photoproducts such as tive risk with relatively low exposures, followed
cyclopyrimidine dimers (TT) and pyrimidine- by a broad plateau. Among sensitive individuals,
pyrimidine (6–4) adducts (Rünger 2007). UVA sun avoidance behavior in adulthood may not
is less mutagenic than is UVB and causes indi- markedly reduce risk for these tumors. On the
rect DNA damage via a photooxidative stress- contrary, squamous cell carcinoma is associated
mediated mechanism, resulting in formation of with total lifetime sun exposure. It has also been
reactive oxygen species, which interact with demonstrated that intermittent and chronic sun
lipids, proteins, and DNA to generate intermedi- exposure is a risk factor for basal cell carcinoma
ates that combine with DNA to form adducts (Walther et al. 2004).
Outdoor workers such as farmers, welders, for preventive measures for individuals with
watermen, police officers, physical education high levels of work-related UV-light exposure.
teachers, pilots, and cabin attendants have an It is reasonable to assume that outdoor workers
increased risk of skin cancer (Ramirez et al. with a long history of work-related UV exposure
2005). There is scientific and epidemiological are at increased risk of developing BCC; however,
evidence to recognize squamous cell carcinoma it has not yet been demonstrated epidemiologically
induced by occupational UV-light exposure as an as clearly as for cutaneous SCC. Bauer et al. (2011)
occupational disease since a doubling of risk due summarized the actually available evidence of the
to occupational UV radiation can be demonstrated epidemiologic literature and could also clearly
(Diepgen and Drexler 2004). Two published sys- show a significant risk increase for occupationally
tematic reviews demonstrate the increased risk UV-exposed workers to develop BCCs compared
of nonmelanoma skin cancer in outdoor workers to non-exposed workers. In this systematic review
(Schmitt et al. 2011; Bauer et al. 2011). and meta-analysis, 24 relevant epidemiologic stud-
Schmitt et al. 2011 demonstrated in a systematic ies (5 cohort studies, 19 case-control studies) were
review and meta-analysis that occupational identified. Twenty-three studies reported sufficient
UV-light exposure increases the risk for the devel- data to be included in the meta-analysis. The pooled
opment of cutaneous squamous cell carcinoma. OR for the association between outdoor work and
The authors performed a systematic electronic lit- BCC risk was 1.43 (95% CI: 1.23–1.66;
erature search in PubMed (until May 2010) p = 0.0001). Studies adjusting for sex ( p < 0.0001)
supplemented by handsearch identified 18 relevant and individual nonoccupational UV exposure
studies that were included in the review. Eighteen ( p = 0.014) showed a significant stronger associa-
studies (6 cohort studies, 12 case-control studies) tion of occupational UV exposure and BCC risk.
met the eligibility criteria and were included in the Taking into account that the majority of the studies
systematic review. Sixteen studies (89%) found an published to date lack precision in the assignment
increased risk of SCC in individuals with occupa- of workers to indoor and outdoor tasks as well as
tional UV-light exposure compared to individuals concerning UV-exposure measurements and
without occupational UV-light exposure, reaching adjustment for major confounders, it is most likely
statistical significance in 12 studies. Two studies that the real risk is largely underestimated. In addi-
found no association between occupational tion, meta-regression revealed a significant inverse
UV-light exposure and SCC occurrence. The relationship between occupational UV-light expo-
pooled OR (95% CI) was 1.77 (1.40–2.22) and sure and BCC risk with latitude ( p = 0.015).
did not differ significantly between cohort studies This systematic review indicates that outdoor
(OR; 95% CI: 1.68; 1.08–2.63) and case-control workers are at significantly increased risk for
studies (OR; 95% CI: 1.77; 1.37–2.30). Meta- BCC. This study is important to inform occupa-
regression analyses suggested an increasing tional safety representatives, stimulate the imple-
strength of the association between occupational mentation of prevention strategies, and encourage
UV-light exposure and SCC risk with decreasing further research in this important field.
latitude. In addition, the authors identified several It has been estimated by the IARC that outdoor
reasons why the observed increase in the risk for workers had the two to three times higher UV
cutaneous SCC among individuals with work- radiation dose than indoor workers (IARC 1992).
related UV-light exposure compared to indoor In subjects older than 20 years, the UV radiation
workers is an underestimation of the true associa- (UVR) exposure is not related to age but to occu-
tion. This systematic appraisal of the epidemiologic pation, outdoor sports activities, or being a sun
literature and meta-analysis clearly indicates that worshipper (Thieden et al. 2004). Thieden et al.
occupational UV-light exposure is a substantial (2004) developed a personal electronic UVR
and robust risk factor for the development of cuta- dosimeter in a wristwatch and measured continu-
neous SCC. These findings are of significant public ously time-related UVR doses in standard
health impact as they highlight the need erythemal dose (SED). They demonstrated that
the median estimated yearly UVR dose was 1. The presence of a scar.
132 SEDs for indoor workers but 224 SEDs for 2. The tumor has developed within the bound-
gardeners. Knuschke et al. (2007) also found sig- aries of the scar.
nificantly increased UVR doses in different outdoor 3. The absence of a preexisting tumor of the
workers compared to indoor workers. It was esti- same type.
mated that the average annual UVR exposure of the 4. Any tumor cells must correspond to the cells
general population is 130 SED per year in Germany of the primary tumor in the scar (this item
(Knuschke et al. 2008). In a recent study from is only relevant for metastasis).
Denmark, the solar ultraviolet radiation exposure 5. An adequate time interval between the scar
of 457 workers in the Danish summer season was and the development of the neoplasm.
measured (Grandahl et al. 2018): presented as
semiannual standard erythemal dose (SED) on
working days, respectively, at leisure, the results 7 Occupational Skin Cancer
are for mainly outdoor workers 214.2 SED and According to German Low
64.8 SED, equal-parts-outdoor-and-indoor workers
131.4 SED and 64.8 SED, and indoor workers 55.8 In Germany, occupational skin cancer may be
SED and 57.6 SED. caused by occupational exposure to certain car-
In Canada, an estimated 2,846 (5.3%) of the cinogens, and currently, the following occupa-
53,696 newly diagnosed cases of basal cell car- tional disease numbers (BK numbers) may be
cinoma (BCC) and 1,710 (9.2%) of the 18,549 applied (Diepgen JDDG 2016).
newly diagnosed cases of squamous cell carci-
noma (SCC) in 2011 were attributable to occu-
pational solar radiation exposure (Mofidi et al. 7.1 BK No. 1108: Diseases Caused
2018). by Arsenic or Its Compounds
In conclusion, there is enough scientific evi-
dence that outdoor workers have an increased risk According to Diepgen et al. (2016), it is noted:
to develop a work-related occupational non- “Arsenic and its compounds may cause basal
melanoma skin cancer due to natural UVR expo- cell carcinoma and squamous cell carcinoma,
sure during working hours. In contrast to natural including Bowen’s disease and Bowen’s carci-
UVR exposure, epidemiological studies are noma. Pathognomonic manifestations include
still missing to demonstrate an increased risk of palmoplantar keratoses, which, however, are not
occupational skin cancer due to occupational necessarily present in all cases. Exposure mainly
exposure to artificial UVR. occurs through the respiratory tract, but may
also take place via the gastrointestinal tract
and, under special conditions, through the skin. Typ-
6.5 Malignant Skin Tumors in Scars ically, arsenic-induced lesions include multiple
superficial basal cell carcinomas that also occur at
Malignant skin tumors can develop within scars. non-UV-exposed sites. Squamous cell carcinomas
Thus, they can be caused indirectly by an indus- develop from precursors or on healthy skin.”
trial accident. Only burn scars and other tight
scars are premalignant conditions for squamous
cell carcinomas and basal cell carcinomas. 7.2 BK No. 2402: Diseases Caused
Squamous cell carcinomas occur more frequently by Ionizing Radiation
(Kowal-Verna and Criswell 2005; Dix 1960).
In order to postulate a causal context between In the newly revised Bamberg recommendations
the tumor and accidental scar, according to (Diepgen et al. 2016), it is noted: “Depending
Ewing (cited in Kowal-Verna and Criswell on the dose (see scientific argumentation for BK
2005), the following conditions must be met: No. 2402), exposure to ionizing radiation
may induce malignant skin diseases, primarily according to BK 5103 plus another 2,453 cases
squamous cell carcinoma, less commonly basal of the agricultural BG. Occupational skin cancer
cell carcinoma, and rarely fibrosarcoma and due to BK 5103 ranks number 3 of all notified
angiosarcoma.” occupational diseases (after noise).
Based on current scientific knowledge, it is
safe to assume that additional occupational UV
7.3 BK No. 5102: Skin Cancer or exposure of 40% at the site of tumor development
Skin Alterations Showing results in at least a twofold risk for cutaneous
a Cancerous Tendency squamous cell carcinoma and therefore suggests
Caused by Soot, Raw Paraffin, predominantly occupational causation (Drexler
Tar, Anthracene, Pitch, or et al. 2012; Diepgen et al. 2014). With respect
Similar Substances to the notification and recognition of skin cancer
as BK 5103, it is crucial that the clinical
One of the oldest occupational diseases in criteria of this new occupational disease are met
Germany, it was included in the ordinance on (Table 3).
occupational diseases in 1925. In the newly Recent measurements of the Institute for
revised Bamberg recommendations (Diepgen Occupational Safety and Health (IFA) of the
et al. 2016), it is noted: “According to current German Statutory Accident Insurance (DGUV)
knowledge, substances in the context of BK have in some cases yielded significantly higher
No. 5102 may cause squamous cell carcinoma, UV exposures. A so-called job-exposure matrix
carcinoma in situ, as well as basal cell carcinoma. for UV exposure is therefore currently being
Direct skin contact plays a crucial role. developed (Wittlich et al. 2016).
The latency period from initial exposure to the
occurrence of skin tumors may be years or even
decades long. At the onset of skin cancer, there 8 Prevention
are frequently also other signs of what is
referred to as “tar- or pitch-induced skin disease” 8.1 Primary Prevention
(e.g., folliculitis, acne, diffuse brownish pigmen-
tation, hyperkeratosis). However, cancer lesions Risk assessment is the systematic identification
may also occur without these symptoms. Tar warts and evaluation of relevant risks of workers with
represent carcinomas in situ. Tumors are primarily the aim of necessary measures for safety and
located in the head region (e.g., nose, periorbital health at work. It is based on an assessment of
region, ears) as well as on the back of the hands the hazard. Hazardous substances are labeled by
and forearms. many organizations regarding their potential
effects (carcinogen, absorbed through the skin,
sensitizing, irritating, etc.). To remove differences
7.4 BK No. 5103: Squamous Cell in the existing international systems of classifica-
Carcinoma or Multiple Actinic tion and labeling, a Globally Harmonized
Keratoses of the Skin Caused System of Classification and Labeling of
by Natural UV Irradiation Chemicals (GHS) was developed. The exposure
is important too, which makes an assessment of
This occupational disease was newly added to the activities associated with the inhalation
the occupational disease list on January 1, 2015. (breathing), the dermal uptake (through skin con-
In 2016, out of 75,491 notified occupational tact), and the physical-chemical hazards neces-
diseases (BK notification) of the commercial sary. If occupational exposure limits (OELs) are
occupational insurance associations (BGs) and available, it must be ensured that these values are
of the accident insurance institutions of the not exceeded. In many situations (skin absorption,
public sector, 6,101 cases have been notified long half-life time of the hazards, etc.), the
Table 3 Criteria for occupational skin cancer pursuant to BK 5103 (squamous cell carcinoma or multiple actinic
keratoses of the skin caused by natural UV irradiation) according to Diepgen 2016
Criterion Description
Location of skin tumors Has to be in areas of the body occupationally exposed to UV
radiation (note protective measures such as wearing a hard hat
in the case of scalp tumors)
Clinical diagnosis confirmed Squamous cell carcinoma (histologically confirmed) or at least
six individual actinic keratoses diagnosed on clinical grounds
within 12 months (histological confirmation of one AK is
recommended) or field cancerization of at least 4 cm2.
Non-genital Bowen’s disease is equivalent to AK; Bowen’s
carcinoma is equivalent to squamous cell carcinoma
Signs of chronic UV damage of the skin at which Chronic UV damage of the skin is not necessarily a
locations prerequisite for the recognition as BK
However, the intensity and distribution of UV damage in terms
of occupationally and recreationally exposed skin areas are
important clues as regards causation
Skin phototype according to Fitzpatrick Plays no essential role with respect to the recognition as BK
but should always be provided as part of the BK notification.
Equally modified by nonoccupational and occupational UV
exposure, the skin phototype is a major risk factor for skin
cancer. It may also affect the age of initial disease onset
Nonoccupational risk factors Other nonoccupational risk factors, if any, should be taken into
account, including immunosuppression, drugs that may affect
light sensitivity, phototherapy, defects in pigmentation,
impaired DNA repair mechanisms, and others
Additional occupational UV exposure of at least 40% An estimate is sufficient to file a BK report. Quantitative
determination of occupational UV exposure is carried out
(by specific calculation) by the Prevention Services Division
of the competent accident insurance
Information on differences from the general Calculations done by the Prevention Services Division are
population with respect to vacations and leisure based on the average recreational UV exposure of the general
activities population (130 SEDs (standard erythemal dose) annually).
Marked deviations caused by vacations spent in unusual
places or unusual leisure activities should be documented
Note: In order for the causal relation to be recognized, particularly with regard to “exposure” and “disease” (causation in
terms of liability), “sufficient probability” is required. This means that – considering all circumstances – there is a
preponderance of circumstances that corroborate the causal relation, on which the medical expert/accident insurance/court
may then base their judgment (Diepgen et al. 2016)
concentration of a hazardous substance in work- aim of primary skin cancer prevention is therefore
place air is less significant. A biological monitor- to limit UVR exposure. Campaigns to prevent
ing is more suitable to assess the individual risk of skin cancer have incorporated numerous mes-
an exposed subject (Drexler et al. 2008). sages including the need to avoid sunburn and
generally reduce exposure to ultraviolet radiation
by staying out of the midday sun (between 11 a.m.
8.2 Occupational Skin Cancer and 3 p.m.), wearing protective clothing, seeking
Prevention Strategies shade, and applying sunscreen. These campaigns
for Outdoor Workers are also needed for outdoor workers and subjects
with an increased occupational UVR exposure.
Experts believe that 90% of nonmelanoma skin There are three measures which are successful
cancer and two-thirds of melanomas may be and of particular importance in the prevention of
attributed to excessive exposure to the sun. The nonmelanoma skin cancer in outdoor workers:
1. Changes in behavior regarding awareness of testing and labeling of UV-protective summer

health and disease resulting from exposure to clothes, and the sun-aware consumer can easily
natural UV radiation recognize garments that definitely provide suffi-
2. Protection from direct UV radiation by wearing cient UV protection.
suitable clothing In the year 2001, a study carried out by
3. Regular and correct use of appropriate Gambichler et al. (2001) had demonstrated that
sunscreens one-third of European textiles are unsuitable and
have a UPF of less than 15. Wet or damp clothing
In the first place, changes in behavior have to be reduces the protective effects by one-third.
aimed at avoiding direct exposure to natural UV light The regular use of appropriate photoprotective
between 11 o’clock in the morning and 3 o’clock in agents has been shown to protect against the
the afternoon, wearing suitable clothing when out- development of UV-induced skin cancers in
doors, applying sunscreen regularly, and keeping in experimental, clinical, and epidemiological stud-
the shade (Fry and Verne 2003). This applies not ies. Using a broad-spectrum sunscreen with a
only to exposure during leisure activities, at week- high sun protection factor (SPF) has been clearly
ends, or on holiday but also to occupational exposure shown to protect against UV-induced immuno-
to natural UV radiation. suppression (Roberts et al. 1995).
Suitable clothing must cover the arms and Several randomized clinical trials carried out in -
legs and should not have low-cut backs or neck- Australia have shown that consistent use of sun-
lines. Broad-brimmed hats should not only cover screens not only reduces the occurrence of new
the head and face but also protect the ears actinic keratoses (AKs) but also causes existing
and back of the neck. Materials used should be lesions to regress (Thompson et al. 1993; Darlington
sufficiently thick in weave and in dark colors; et al. 2003). Also in Texas, USA, a prospective
clothing should not be too tight-fitting. Materials 2-year study showed a reduction in actinic keratosis
that are to be worn in the sun for any length of by the regular use of sun protection agents (Naylor
time should have an UV protection factor (UPF) et al. 2004). Likewise, over an observation period of
greater than 40 (Gambichler et al. 2006). The 4.5 years, a prospective epidemiological study in
European Committee for Standardization (CEN) Queensland showed that the incidence of squamous
has developed a new standard on requirements cell carcinoma is significantly reduced by the daily
for test methods and labeling of sun-protective use of sunscreens (Green et al. 1999).
garments. This document has now been com- Regular use of a sunscreen is therefore part of
pleted and is published. The first part of the stan- the treatment of chronically photodamaged skin.
dard (EN 13758-1) deals with all details of test Particularly, in high-risk patients, the regular use
methods (e.g., spectrophotometric measurements) of an appropriate sunscreen of SPF 50+ has to be
for textile materials and part 2 (EN 13758-2) strongly recommended. In an open interventional
covers classification and marking of apparel tex- study, it was shown that daily use of a liposomal
tiles. UV-protective cloths for which compliance sunscreen with photostable broad-spectrum filters
with this standard is claimed must fulfill all strin- (Daylong actinica) significantly reduced the occur-
gent instructions of testing, classification, and rence of new actinic keratoses and squamous cell
marking, including a UV protection factor (UPF) carcinomas in organ recipients over a follow-up
larger than 40 (UPF 40+), average UVA transmis- period of 24 months (Ulrich et al. 2009). While
sion lower than 5%, and design requirements as nine invasive squamous cell carcinomas were
specified in part 2 of the standard. A pictogram, diagnosed in the control group of 60 transplant
which is marked with the number of the standard patients using freely selected sunscreens, not a
EN 13758-2 and the UPF of 40+, shall be attached single new squamous cell carcinoma appeared
to the garment if it is in compliance with the in the interventional group using a sunscreen
standard. Garment manufacturers and retailers of SPF 50+ every day. During the 24-month
may now follow these official guidelines for study, 42 of the 120 patients developed 82 new
actinic keratoses (all in the control group). In the In Australia, where skin cancer is of epidemic
sunscreen group, 102 actinic keratoses healed proportions, aggressive public health campaigns
spontaneously. have been underway since the 1980s. In addition
It is also important to use a photoprotective agent to identifying tumors at an early stage, Australia
with a high SPF, as sunscreens are often applied too managed an exciting educational program on
thinly. This means that the actual protective effect is photodamage prevention and sets standards for
very much lower than that stated on the packaging. a wide variety of sun-protective products to
The SPF is based on the application of 2 mg sun- include sunscreens, photoprotective apparel,
screen per cm2 skin. In fact, on average, only sunglasses, and occupational standards for sun
0.5 mg/cm2 (range: 0.39–0.79 mg/cm2) is applied exposure. There, attitudes have already shifted
(Neale et al. 2002; Autier et al. 2001). The sun positively toward avoiding exposure to the sun
protection factor does not show a linear correlation and away from desire for a tan.
with the insufficient amount of sunscreen applied The mainstay of sun protection is through
but rather an exponential one, so that a sunscreen of avoidance of deliberate sun tanning; use of
SPF 16 is reduced to SPF 2 if only 0.5 mg/cm2 is adequate protection measures such as wearing
applied (Wulf et al. 1997). This has also been dem- wide-brimmed hats, sunglasses, and protective
onstrated recently for sunscreens with high SPFs clothing; and avoidance of peak hours for UV
(Kim et al. 2010). The sufficient dosing of a sunlight. Sunscreens cannot be a substitute for
screen can be visualized under a Wood’s lamp by other protective means. However, sunscreen
adding to sunscreens fluorescent substances use is the most popular form of sun protection
(Antonov et al. 2017). and can significantly reduce the risk of develop-
A change in health awareness regarding expo- ing skin cancer (Green et al. 1999). However, the
sure to UV radiation, knowledge of the previously results of a study from the UK, France, Italy,
mentioned preventative measures, and observing Germany, and Spain showed that both the gen-
and regularly applying them are all important for eral public and the majority of outdoor workers
the high-risk group in particular. Appropriate pre- do not regularly apply sunscreens (MacKie
ventative health-care concepts need to be devel- 2004). Concern has also been raised that they
oped. Halpern and Kopp (2005) found significant may directly or indirectly increase the risk of
differences in awareness of skin cancer and sun malignancy, primarily because of poor applica-
protection habits between normal people in tion and increased exposure to the sun. The
Australia, the USA, and Europe. In Australia, thickness of application has been shown to be
where the incidence of skin cancer is very high, less than half that officially tested, and
more than 80% of survey responders expressed key-exposed sites are often missed completely
concerns about the dangers of sun exposure and (Johnson et al. 2001).
skin cancer, while the figures were only 30% in For future public health policy, it is important
Germany and 34% in France. to increase skin cancer awareness among outdoor
Another important public health message is that workers, together with safe sun practices, such as
patients should promptly seek medical (dermatolog- application of sunscreen, wearing protective
ical) attention when they notice a suspicious or clothing, and avoiding the sun during times
changing skin lesion. The detection of skin cancer of peak solar intensity. In Germany, more than
at an early stage when it is most likely to be cured by 40% of apprentices in outdoor occupations
simple outpatient excision is classified as secondary (n = 245) did not receive any sun protection
prevention. UVR-induced skin cancerogenesis is a measures by their employer, and 34.5% of the
multistep process that provides an excellent chance students got sunburned during work (Ruppert
for effective prevention strategies to reduce the inci- et al. 2016). Working in the shade was a protective
dence, morbidity, and mortality of skin cancer and factor for occupational sunburn but was merely
its precursor lesions. Therefore, outdoor workers available for 23.7% of the outdoor workers
should be screened for skin cancer regularly. (Ruppert et al. 2016).
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Other Occupational Skin Diseases
10
Elke Weisshaar and Thomas L. Diepgen
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
2 Erysipeloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
3 Query Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4 Tinea Pedis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
5 Vitiligo-Like Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
6 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
7 Borreliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Borreliosis · Occupational dermatology ·
Psoriasis · Skin infections • Erysipeloid is an acute infection due to
Erysipelothrix rhusiopathiae, a gram-positive
bacillus. It may present as a localized cutaneous
form, a generalized cutaneous form with wide-
spread erythematous-edematous lesions and
symptoms such as fever, lymphadenitis, and
arthralgia. Healing normally occurs
spontaneously in 2 weeks with desquama-
tion or suppuration. Diagnosis is mainly clinical.
E. Weisshaar (*) Recommended treatment centers on anti-
Department of Clinical Social Medicine, Occupational and biotics with, e.g., penicillin. Prevention includes
Environmental Dermatology, University of Heidelberg,
Heidelberg, Germany
good sanitation, reduction of trauma, systematic
e-mail: elke.weisshaar@med.uni-heidelberg.de slaughtering of infected animals, and wearing of
T. L. Diepgen
protective gloves.
Department of Social Medicine, Occupational and • Query (Q) fever is a worldwide zoonosis
Environmental Dermatology, University Heidelberg, caused by Coxiella burnetii, a gram-negative
Heidelberg, Germany bacterium. Farm animals and pets are the main
e-mail: thomas.diepgen@med.uni-heidelberg.de

https://doi.org/10.1007/978-3-319-68617-2_11
98 E. Weisshaar and T. L. Diepgen
reservoir of human infections. Epidemiologi- 2 Erysipeloid

cal studies indicate Q fever as a public health
problem in many countries. Therapy centers Erysipeloid is an acute infection due to
on doxycycline. Query fever infections Erysipelothrix rhusiopathiae, a gram-positive, non-
resolve in most cases. Prevention includes sporulating, nonmotile bacillus. Infections are
protection measures such as protective cloth- worldwide in distribution (Reboli and Farrar
ing, tick control strategies, good hygiene prac- 1989). It was also named in the past Rosenbach’s
tice, and systematic slaughtering of infected disease and pseudoerysipelas (Veraldi et al. 2009).
animals. E. rhusiopathiae colonizes a wide variety of ani-
• Tinea pedis is caused by dermatophytes and mals worldwide, including mammals, birds, foal,
usually leads to an infection of the feet or toes. fish, and shellfish. Human infection is contracted
Living in an institution, especially when by direct contact from an animal or environmental
washing facilities are shared, is likely to source, most commonly from carcasses. This is the
increase the chances of infection. All profes- reason why the occupations mainly affected by the
sions demanding the wearing of shoes that disease are slaughtermen, butchers, abattoir
may occlude the skin are more frequently workers, meat-processing workers, cooks, fisher-
affected by tinea pedis. Diagnosis is made clin- men, farmers, veterinarians, leatherworkers, and
ically and by fungal culture. Mild interdigital housewives (Brooke and Riley 1999; Reboli and
tinea pedis can be treated topically with broad- Farrar 1989; Wang et al. 2010). Scratches or pricks
spectrum antifungal. Prevention includes treat- are the usual mode of incubation. Although
ment of onychomycosis if present, treatment of E. rhusiopathiae is killed by moist heat at 55 C
associated diseases such as vesicular eczema for 15 min, it is resistant to environmental influ-
and hyperhidrosis, and adequate hygiene of ences such as salting, pickling, and smoking
the feet. (Reboli and Farrar 1989) and can survive for
• Vitiligo-like skin lesions may occur in the rub- periods as long as several months (Brooke and
ber industry when thiols and quinones are used Riley 1999; Veraldi et al. 2009).
as additives. Treatment comprises identifying Reporting to health authorities of infection due
the underlying etiology and prevention of skin to E. rhusiopathiae is not required, so it is difficult
contact with the causing agent. to report incidence and prevalence of erysipeloid.
• Psoriasis of the hands may present as keratotic The risk of human infection with E. rhusiopathiae
patches on the palms, usually not displaying the is closely related to the opportunity for exposure
classical features of psoriatic lesions elsewhere to the organism (Reboli and Farrar 1989). Most
on the body. In the work environment, skin human cases are related to occupational exposure
trauma and mechanical irritation of the hands (Brooke and Riley 1999; Reboli and Farrar
are aggravating factors of psoriasis. No specific 1989). Technological changes in industries that use
occupation predominates. It is estimated that animal products have probably resulted in reduced
occupational contact psoriasis probably accounts contact between E. rhusiopathiae and humans
for 1.2% of all occupational dermatoses. (Reboli and Farrar 1989). Human-to-human infec-
• Borreliosis is the most common tick- tion has not been documented. Older studies
transmitted disease in the Northern Hemi- showed that an average of 20–40% of healthy
sphere caused by spirochetes of the Borrelia swine, and in some herds up to 98%, harbor
burgdorferi species. Diagnosis is made by E. rhusiopathiae in the lymphoid tissue of the ali-
clinical findings, a history of tick bites (up to mentary tract, particularly in the tonsils (Brooke and
50% of patients do not remember the tick Riley 1999). Infections in humans and animals
bite), and laboratory testings. Prevention of appear to have a seasonal incidence with most
tick bites and borreliosis comprises a combi- cases occurring in the summer months (Brooke
nation of primary prevention, early diagnosis, and Riley 1999). It is not clear if this is related to
and treatment. the biological activity of the temperature or to
10 Other Occupational Skin Diseases 99
increased contact between people and sources of working with dairy products, and laboratory per-
infections during these months. sonnel. Infection occurs aerogenic by contami-
Erysipeloid may present as a localized cut- nated dust or by direct contact with animals
aneous form, a generalized cutaneous form including their excretions. Person-to-person
with widespread erythematous-edematous lesions, transmission is rare; sexual transmission of Q
fever, lymphadenitis, arthralgia and myalgia, and a fever in animals has been demonstrated
rare septicemic form (Veraldi et al. 2009; Wang (Angelakis and Raoult 2010). There are several
et al. 2010). Generalized skin infection and septice- studies in which young age seems to be protec-
mia are seen sometimes in severe cases, e.g., tive against Coxiella burnetii (Angelakis and
immunosuppressed persons (Veraldi et al. 2009). Raoult 2010). The prevalence of clinical cases
Complications are encephalitis, meningitis, endo- increases with age. Men are symptomatic more
carditis, peritonitis, renal failure, and sepsis. Clinical often than women despite comparable exposure
symptoms are usually obvious about 2 days after and seroprevalence (Angelakis and Raoult
inoculation. A hot, violaceous, and tender erythema 2010).
develops around the inoculation site and extends Epidemiological studies indicate Q fever as a
centrifugally but irregularly with a sharp and some- public health problem in many countries like the
times great border. This may also be vesicular. United Kingdom, the Netherlands, Germany,
Erysipeloid is a true cellulitis. The lesions are most France, and Canada (Angelakis and Raoult
frequently located on the fingers, hands, and fore- 2010; van der Hoek et al. 2010; Wallensten et al.
arms (Veraldi et al. 2009; Wang et al. 2010). Fever 2010). A recent systematic review describes Q
and mild generous symptoms such as arthralgia are fever in goats to be likely associated with an
present in 10% of cases. Healing normally occurs increased Q fever risk in community members
spontaneously in 2 weeks with desquamation or (O’Connor et al. 2017).
suppuration. Diagnosis is mainly clinical. Isolation Query fever presents with high fever, head-
of E. rhusiopathiae is difficult. Two PCR assays ache, weight loss, atypical pneumonia, and endo-
have been described for swine erysipelas, one of carditis. Granulomatous hepatitis, cardiac
which can be used in cases of human erysipeloid involvement, skin rash, and neurologic manifes-
(Veraldi et al. 2009; Wang et al. 2010). tation such as disorientation, encephalitis, menin-
Recommended treatment centers on antibiotics goencephalitis, and peripheral neuropathy may
with, e.g., penicillin, cephalosporins, tetracy- occur as a complication. Up to 50% of infections
clines, and erythromycin. Prevention includes are asymptomatic. Chronic Q fever infection may
several measures such as sound husbandry, good develop months to years after initial infection
sanitation, reduction of trauma, systematic manifesting as bacterial culture-negative endocar-
slaughtering of infected animals, and wearing of ditis (Angelakis and Raoult 2010). The diagnosis
protective gloves. is based on a significant increase in serum anti-
body titers.
Differential diagnosis includes all other causes
3 Query Fever of pneumonia. Therapy centers on antibiotics:
doxycycline 100 mg twice daily for 2–3 weeks.
Query fever is a worldwide zoonosis caused by In cases of endocarditis, doxycycline is combined
Coxiella burnetii, an obligate intracellular gram- with quinolone or rifampicin plus ciprofloxacin
negative bacterium (Angelakis and Raoult 2010). for up to several years (Angelakis and Raoult
The time of incubation is 2–4 weeks. Farm ani- 2010). Query fever infections resolve in most
mals and pets are the main reservoir of human cases. Lethality is 1–2%. Prevention includes pro-
infections. Query fever can be transmitted to tection measures such as dust masks, protective
humans by ticks, rodents, sheep, cattle, goats, clothing, tick control strategies, good hygiene
and other wildlife animals. Persons at risk are practice, and systematic slaughtering of infected
farmers, veterinarians, abattoir workers, persons animals.
4 Tinea Pedis diffuse maceration in the cleft marginated by a

collarette of continuous desquamation. In some
Tinea pedis is caused by dermatophytes and cases, there is a small painful fissure running
usually leads to an infection of the feet or along the line of the cleft. The entire area is
toes. Three anthropophilic species, Trichophyton ulcerative and macerated from microbial super-
rubrum, Trichophyton mentagrophytes, and Epi- infection. Itching is usually present. A squamous
dermophyton floccosum, are responsible for the hyperkeratotic variety may occur in Trichophyton
vast majority of cases. Tinea pedis is the most rubrum infections. This may occur chronically
common form of dermatophytosis in most coun- and partially resistant to treatment. Tinea pedis
tries. It is estimated that about 10% of the total may also affect the soles, heels, and sides of
population are infected. The German “Foot Check the feet (“moccasin foot”). Associated onycho-
Study” showed that the prevalence of tinea pedis mycosis is common. Tinea pedis is sometimes
and/or onychomycosis was 31.6% (Seebacher associated with plantar hyperhidrosis, plantar
et al. 2008). Many patients are asymptomatic. pompholyx, and vesicular eczema.
Living in an institution, especially when washing Diagnosis is made clinically and by fungal
facilities are shared, is likely to increase the culture. Mild interdigital tinea pedis can be treated
chances of infection. Prevalences as high as 18% topically with broad-spectrum antifungals. Severe
have been reported in some factories or sport or refractory tinea pedis can be treated with oral
institutes. However, tinea pedis may be equally antifungal, e.g., terbinafine 250 mg twice daily
well transmitted within the family bathroom. for 2 weeks and itraconazole 200 mg twice daily
Reinfection from the environment is usual, with for 1 week. Prevention includes treatment of ony-
the same or another species or with combined chomycosis if present, treatment of associated
species. Maceration of the toe clefts plays an diseases such as vesicular eczema and hyperhi-
important role. In adolescents and children, swim- drosis, adequate hygiene of the feet, and the use of
ming pools are the major source of infection. socks and shoes permeable to air.
Tinea pedis may more frequently occur in pro-
fessions with wet environment and wearing of
rubber boots. All professions demanding shoes 5 Vitiligo-Like Skin Diseases
that may occlude the skin are more frequently
affected by tinea pedis. Occupational groups Vitiligo-like skin lesions may occur in the rubber
such as miners, soldiers, employees of meat industry when thiols and quinones are used as
and dairy product factories, fishermen, employees additives. Chemical substances such as phenols
of chemistry works, forestry workers, farmers, and hydroquinone may also lead to vitiligo-like
zookeepers in aquariums, people working in skin changes. Phenols in disinfectants may also
swimming pools, and athletes are exposed to cause pseudovitiligo or vitiligo-like skin lesions
particularly high infection risk. The frequency of because they are more intensely released when
tinea pedis in these professions ranges from used occlusively, e.g., by wearing protective
13% to 73% (Seebacher et al. 2008). A retrospec- gloves. Differential diagnosis includesPlease
tive cohort study in Germany containing check if edit to sentence starting “Differential
723 patients taking part in a tertiary individual diagnosis includes. . .” is okay. vitiligo; vitiligo-
prevention program for occupational skin dis- like lesions and hypopigmentation by systemic
eases demonstrated 11.4% (n = 31) suffering medications, e.g., chloroquine, and new immu-
from fungal infections (Brans et al. 2015). notherapies like anti-programmed cell death
The most common form of tinea pedis is (PD)-1 antibodies used for metastatic cancers
located in the toe webs. The fourth interdigital and leukoderma caused by skin diseases, e.g.,
web is preferentially infected, but the other webs psoriasis and eczema; and autoimmune disease
can also be infected on one or both feet. The such as systemic sclerosis. Vitiligo-like lesions
clinical symptoms are characterized by whitish, were reported as a classical side effect
occurring in patients receiving PD therapies the disease. Consequently, in some settings

(Larsabal et al. 2017). psoriasis may be work-related. This can be
There are no epidemiological data about the assessed by considering the type, intensity,
frequency of vitiligo-like skin lesions. This may and site of occupational exposure, location of
be caused by the fact that affected persons have the skin lesions, and previous and actual dis-
single skin lesions only and besides cosmetic ease course in consideration of occupational
impairment, they are usually not presented to a exposure and exposure-free time periods.
physician. Skin trauma, mechanical affections, and con-
Vitiligo-like skin lesions often appear clini- tact allergy of the hands are aggravating fac-
cally different compared to vitiligo. They are tors of psoriasis (Mahler et al. 2014). However,
frequently located symmetrically, e.g., on the pustular psoriasis of the hands is considered
underarms when caused by increased release of as a separate entity. No specific occupation
phenols by gloves’ occlusion. Vitiligo-like skin predominates. Manufacturer and craftsmen are
lesions are usually not located in the typical mainly affected. Pressure of the hands in metal
body sites like the genital and anal area, face, workers, bus drivers with the pressure of the
and back of hands. They are usually located steering wheel, health-care workers, and other
where skin contact to the releasing substance professions with a high degree of mechanical
occurred. trauma and pressure of the hands are some exam-
Treatment comprises identifying the under- ples. Unilateral palmar lesions are usually
lying etiology and prevention of skin contact located on the dominant hand. Patients with pal-
with the causing agent. Repigmentation may mar lesions involved in regular manual work
occur spontaneously; local PUVA or other forms tend to show lesions restricted to areas exposed
of UV phototherapy may help to repigment the to pressure (Kumar et al. 2002).
affected skin site. It is estimated that occupational contact psori-
asis probably accounts for 1.2% of all occupa-
tional dermatoses (Moroni et al. 1988). Other
6 Psoriasis epidemiological data are not available. Palmar
psoriasis is only noted as part of larger studies
Psoriasis is a chronic proliferative inflammatory on psoriasis or palmoplantar psoriasis (Kumar
skin disease. The severity of this disease ranges et al. 2002).
from mild focal enrollment to generalized forms. Diagnosis can be obtained by clinically
Psoriasis of the hands may present as keratotic demonstrable psoriasis localized on the hands,
patches on the palms, usually not displaying the mainly palms without significant involvement
classical features of psoriatic lesions elsewhere elsewhere, or psoriasis affecting other sites of
on the body. The presence of psoriatic lesions the body except the hands with further develop-
elsewhere, e.g., at elbows, knees, and scalp, ment of lesions on the hands after engaging in a
often helps to establish the diagnosis. If these particular job.
skin locations are not affected, diagnosis may Therapy of psoriasis of the hands can be a
be difficult. The most frequent differential diag- challenge. Local PUVA therapy is very helpful
nosis is hand eczema. It is often difficult to dif- as well as topical antipsoriatics such as cal-
ferentiate palmar psoriasis from chronic eczema. cipotriol. Depending on the clinical picture,
Skin biopsies often show nonspecific changes of keratolytic topicals such as salicylic acid may
eczema rather than that of psoriasis, and the be necessary. Prevention comprises mainly the
histological findings often do not help to confirm identification of individuals with a propensity to
a diagnosis. develop occupational contact psoriasis during
A relation between the occupational activ- the course of work. This can be reached by pre-
ity as an essential cause and psoriasis may employment evaluation including psoriasis and
present as an induction or an aggravation of clinical examination of the skin with specific
emphasis on the scalp, elbows, knees, pitting of generally considered as first-line therapy
the nails, hyperkeratoses of the palms in winter using 200 mg daily. Ceftriaxone is
time, hyperkeratoses with persistent fissures on recommended when parenteral antibiotic
the heel, and dry perionychium and eponychium therapy is recommended, e.g., 2 g daily for
with rhagades. 3–4 weeks. Multiple trials have shown efficacy
for a 10-day course of oral doxycycline for
treatment of erythema migrans and for a
7 Borreliosis 14-day course for treatment of early neuro-
logic borreliosis in ambulatory patients
Borreliosis is the most common tick-transmitted (Sanchez et al. 2016).
disease in the Northern Hemisphere caused by spi- Prevention is very important including behav-
rochetes of the Borrelia burgdorferi species (Stanek ioral prevention such as wearing appropriate
and Strle 2003). The skin is the most frequently clothes (long-sleeved, white or light color), the
affected organ, mostly as erythema migrans and use of insect repellents, and careful (self) skin
also as borrelial lymphocytoma, both occurring inspection for ticks (Hayes and Piesman 2003).
days to weeks after the infectious tick bite and Educational prevention comprises disseminating
acrodermatitis chronica atrophicans occurring information via different media such as TV, news-
months to years later. Influenza-like or unspecific papers, and magazines, providing advice, changing
symptoms such as malaise, fatigue, fever, headache, attitudes, and behavior including practical
myalgia, and arthralgia may occur. approaches, e.g., prompt removal of the tick in
A Swedish study found that there is a 4% risk case of tick bites. A population-based, randomized
of being tick-bitten per 10 h spent outdoors and study showed that an educational intervention can
the risk of contracting borreliosis was 1/221 tick increase the proportion of people who check them-
bites (Stjernberg and Berglund 2002). In Ger- selves and use repellents (Malouin et al. 2003).
many, the state of Baden-Wuerttemberg was Prevention of tick bites and borreliosis comprises
tested for antibodies against Borrelia burgdorferi a combination of primary prevention, early diagno-
sensu lato revealing human seroprevalence rates sis, and treatment.
in forestry workers ranging from 18% to 52%
depending on the county of the state (Oehme
et al. 2002). Own data showed that children in References
forest kindergarten have a 2.8 higher risk for
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Websites, Online Databases, and
Sources of Information 11
Marc Rocholl, Swen Malte John, and Annika Wilke
Abstract Keywords
The internet can be a useful source of infor- Databases · Sources of information ·
mation for practitioners and experts involved Prevention · Internet · Protective equipment ·
in the field of occupational skin diseases (e.g., Protective gloves · Skin protection · Skin care ·
dermatologists, occupational physicians, and Hazardous substances · Information system ·
other healthcare workers). Various informa- Chemical resistance guide · Website ·
tion on occupational dermatoses, prevention Platform · Education
strategies, campaigns, protective equipment, The internet has become the most important
as well as contact allergens and hazardous media of our time, and the relevance of online
substances are provided by different national available information has significantly increased
and international institutions and authors. in recent years. Because of rapid changes in occu-
Several websites, platforms, and databases pational safety and health (e.g., in terms
exist that may be helpful when it comes to of exposure to chemicals at workplace and
the management and prevention of occupa- the development of new skin protective equip-
tional skin diseases and the identification of ment), web-based sources of information
an appropriate protective equipment (e.g., are essential. These do not only provide
protective gloves). This chapter shall give an information but may also help to get in contact
overview of some of these sources of with experts, research networks, professional
information. associations, and societies to gain up-to-date
knowledge. Therefore, the tables presented
here contain information about a number of
current websites and databases that deal with the
following domains of occupational skin diseases,
occupational safety and health, and related topics:
M. Rocholl (*) · A. Wilke
Institute for Health Research and Education, Department
• Table 1: Hazardous substances
of Dermatology, Environmental Medicine and Health
Theory, University of Osnabrück, Osnabrück, Germany • Table 2: Personal protective equipment (PPE),
e-mail: mrocholl@uni-osnabrueck.de; including gloves
awilke@uni-osnabrueck.de • Table 3: Education, information platforms, and
S. M. John campaigns
Department of Dermatology, Environmental Medicine and • Table 4: Allergens and allergy testing
Health Theory, University of Osnabrück, Osnabrück,
• Table 5: Research networks, professional asso-
Germany
e-mail: johnderm@uni-osnabrueck.de ciations, and societies

https://doi.org/10.1007/978-3-319-68617-2_114
106 M. Rocholl et al.
Table 1 Online databases and websites concerning hazardous substances (listed in alphabetical order)
Description Institution or author Weblinks and comments
GESTIS Institute for Occupational Safety and http://www.dguv.de/ifa/index-
(Gefahrstoffinformationssystem/ Health (IFA) of the German Social 2.jsp (English)
Information system on hazardous Accident Insurance (DGUV) http://www.dguv.de/ifa
substances): (German)
Substance database that provides Databases on hazardous
information about safe handling of substances (GESTIS):
hazardous substances (e.g., to identify Webcodea: e20570 (English)
appropriate personal protective Webcode: d3380 (German)
equipment such as protective gloves) Substance manager tool to
identify and reduce inhalative
hazards (registration is
required):
Webcode: e540215 (English)
Webcode: d117179 (German)
GISBAU (Gefahrstoff- German Social Accident Insurance: http://www.bgbau.de/gisbau
Informationssystem der BG Bau): Institution for the Building Trade (German)
Comprehensive information system for (BG BAU)
hazardous substances including various
databases (e.g., regarding protective
gloves, allergens in protective gloves,
personal protective equipment) focusing
the building trade
GISCHEM German Social Accident Insurance: http://www.gischem.de
(Gefahrstoffinformationssystem Institution for the Raw Materials and (German)
Chemikalien): Chemical Industry (BG RCI) and
Specific information system for Institution for Woodworking and
hazardous substances in chemical and Metalworking Industries (BGHM)
metalworking industries (e.g., to
identify appropriate personal protective
equipment such as gloves)
GISCODES: German Social Accident Insurance: http://www.bgbau.de/gisbau/
Product groups of hazardous substances Institution for the Building Trade giscodes (German)
and information about personal (BG BAU)
protective equipment
Isi (Informationssystem für Institute for Occupational Safety and http://www.dguv.de/ifa/index-
Sicherheitsdatenblätter/information Health (IFA) of the German Social 2.jsp (English)
system for safety data sheets): Accident Insurance (DGUV) http://www.dguv.de/ifa
Database that provides access to safety (German)
data sheets for various chemicals and Information system for safety
products data sheets (ISi):
Access with personal user-ID
and password or via guest login
Occupational Health Guidelines for Centers for Disease Control and https://www.cdc.gov/
Chemical Hazards: Prevention (CDC): National Institute for (English)
Websites provide occupational Health Occupational Safety and Health NIOSH:
Guidelines for Chemical Hazards with (NIOSH) https://www.cdc.gov/niosh/
information on exposure limits, physical index.htm (English)
properties, and health hazards Occupational Health
Guidelines for Chemical
Hazards:
https://www.cdc.gov/niosh/
docs/81-123/ (English)
NIOSHTIC-2 Publications
Search:
https://www2a.cdc.gov/
(continued)
11 Websites, Online Databases, and Sources of Information 107
Table 1 (continued)
nioshtic-2/advsearch2.asp
(English)
Stoffenmanager 7: Dutch Ministry of Social Affairs and https://stoffenmanager.nl/
Substance manager tool to identify and Employment (German, English, Dutch,
evaluate inhalative hazardous Polish, Finish, Swedish)
substances Registration is required
WINGIS ONLINE: German Social Accident Insurance: http://www.wingis-online.de
Information system for hazardous Institution for the Building Trade (German)
substances (e.g., to identify appropriate (BG BAU)
personal protective equipment such as
protective gloves)
a
Long hyperlinks and internet paths may change over time, are not user-friendly, and hamper cross-linking of information
and dissemination. Therefore, some websites (e.g., the German Social Accident Insurance) use webcodes to code online
available information, brochures, and databases. To get access to this different information, the specific webcode needs to
be entered in the search box.
Table 2 Online databases and websites concerning personal protective equipment [PPE] (listed in alphabetical order)
CDC and NIOSH (Centers for Disease Centers for Disease Control and https://www.cdc.gov/
Control and Prevention and the National Prevention (CDC): National Institute for (English)
Institute of Occupational Safety and Occupational Safety and Health NIOSH:
Health): (NIOSH) https://www.cdc.gov/niosh/
Recommendations for chemical index.htm (English)
protective clothing (e.g., glove materials Recommendations for
for chemicals) are provided Chemical Protective Clothing
Database:
https://www.cdc.gov/niosh/
ncpc/ (English)
GISBAU (Gefahrstoff- German Social Accident Insurance: http://www.bgbau.de
Informationssystem): Institution for the Building Trade (German)
Allergens in protective gloves (provided (BG BAU) GISBAU database:
by various glove manufactures) http://www.bgbau.de/gisbau/
service/allergene (German)
List of allergens in specific
gloves (assorted by
manufacturer):
http://www.bgbau.de/gisbau/
service/allergene/
allergeneliste-nach-
hersteller-1 (German)
ICSC (International Chemical Safety Centers for Disease Control and International Chemical Safety
Cards): Prevention (CDC): National Institute for Cards:
ICSCs include a brief summary on Occupational Safety and Health https://www.cdc.gov/niosh/
essential safety information regarding (NIOSH) ipcs/ (English)
chemicals for workers in factories,
agriculture, construction, and other
workplaces
IFA (Institut für Arbeitsschutz der Institute for Occupational Safety and http://www.dguv.de/ifa/
Deutschen Gesetzlichen Health (IFA) of the German Social index-2.jsp (English)
Unfallversicherung/Institute for Accident Insurance (DGUV) http://www.dguv.de/ifa
Occupational Safety and Health of the (German)
German Social Accident Insurance): Practical solutions: Personal
(continued)
Table 2 (continued)
The website provides information about Protective Equipment (PPE):
personal protective equipment and Webcode: e959138 (English)
selection of appropriate protective gloves Webcode: d959138 (German)
for chemical exposures (e.g., selection Which glove is suitable?:
guide for materials, pictograms, DIN Webcode: e109389 (English)
standards) Webcode: d106742 (German)
Why should chemical gloves
be used?:
Webcode: e109388 (English)
Information brochure on allergens in German Social Accident Insurance http://publikationen.dguv.de/
protective gloves (DGUV) dguv/pdf/10002/i-8584.pdf
(German)
WINGIS ONLINE: German Social Accident Insurance: http://wingisonline.de/
Database of protective gloves for various Institution for the Building Trade handschuhdb (German)
exposures in building industries (e.g., (BG BAU)
epoxy resins, paints, cleaners)
Table 3 Online databases, information platforms, and websites concerning education, campaigns, and general informa-
tion on skin protection and occupational health and safety (listed in alphabetical order)
BASIS (Branchen- und Arbeits- German Social Accident Insurance: http://www.basis-bgetem.de/
Schutz-Informations-System): Institution for the Energy, Textile, (German)
Industrial and occupational safety Electrical, and Media Product Sectors
and health information system: (BG ETEM)
E-Learning module on hand and skin
protection: modules on dental
technology, printing and paper
processing, textile industry, and
footwear
Beruflicher-Hautschutz.de: crowd-owning-GmbH https://beruflicher-hautschutz.de/
Community-based platform with (German)
information about occupational skin
diseases and prevention (e.g., skin
protection plans for specific
occupations, media) as well as direct
linkage to further internet sources
BeSWIC (Belgian Safe Work BeSWIC (Belgian Safe Work http://www.beswic.be/nl (Dutch)
Information Center): Information Center) http://www.beswic.be/fr (French)
Platform to share knowledge on
occupational safety and health
CISDOC bibliographic database: International Labour Organization www.ilo.org/cisdoc (English,
Database with different types of (ILO) French, Spanish)
documents (e.g., laws and Direct access to database:
regulations, chemical safety data http://www.ilo.org/dyn/cisdoc2/
sheets, training materials) cismain.search
CosIng: European Commission http://ec.europa.eu/growth/tools-
Database for information regarding databases/cosing/ (English)
cosmetic ingredients and substances
DGUV (Deutsche Gesetzliche German Social Accident Insurance http://www.dguv.de/en/ (English)
Unfallversicherung/German Social (DGUV) http://www.dguv.de (German)
Accident Insurance): Healthy Skin Campaign:
(continued)
Table 3 (continued)
Website of the “Healthy Skin Webcode: e566126 (English)
Campaign” Webcode: d69810 (German)
DGUV (Deutsche Gesetzliche German Social Accident Insurance http://www.dguv.de/en/ (English)
Unfallversicherung/German Social (DGUV) http://www.dguv.de (German)
Accident Insurance): Skin hazards and skin protection –
Website with information regarding prevention strategies:
skin protection and skin hazards Webcode: e565791 (English)
Educational website – E-learning – Swiss Accident Insurance Fund http://www.2mains.ch/ (English,
for school teachers, trainers, and (SUVA) French, German, Italian)
occupational physicians (e.g.,
including teaching and information
material regarding normal and
disordered skin, risk factors, and
protective gloves)
E-Learning platform for German Social Accident Insurance: https://bgw.uv-lernportal.de
occupational physicians and Institution for the Health and Welfare (German)
healthcare professionals (e.g., Services (BGW) (Registration is required)
occupational skin diseases and skin
protection, the usage of protective
gloves)
ENETOSH (European Network The network is coordinated by the www.enetosh.net (English)
Education and Training in Institute for Work and Health (IAG)
Occupational Safety and Health): of the German Social Accident
Platform to share knowledge on the Insurance (DGUV)
topics education and training in
occupational safety and health
EPOS (European Initiative for the Department of Dermatology, http://www.eadv2010.info (English)
Prevention of Occupational Skin Environmental Medicine, and Health
Diseases): Theory, University of Osnabrück
Platform to connect experts,
scientists, and physicians and to
promote the EADV campaign
“healthy skin@work”
EU-OSHA (European Agency for European Agency for Safety and https://osha.europa.eu/en (English
Safety and Health at Work): Health at Work (EU-OSHA) and many more)
Agency that provides information on Online interactive Risk Assessment
occupational safety and health (OiRA):
https://osha.europa.eu/en/tools-and-
publications/oira (English and many
more)
Factsheet 40 – skin sensitizer:
https://osha.europa.eu/en/tools-and-
publications/publications/factsheets/
40/view (English and many more)
Database on occupational safety and Federal Institute of Occupational http://www.bmas.de/DE/Themen/
health research Safety and Health (BAuA), German Arbeitsschutz/
(Forschungsdatenbank Arbeitsschutz) Social Accident Insurance (DGUV), Forschungsdatenbank/
of the Federal Institute for Commission for Occupational Health forschungsdatenbank.html (English,
Occupational Safety and Health and Safety and Standardization German)
(BAuA), the German Social Accident (KAN)
Insurance (DGUV), and the
Commission for Occupational Health
and Safety and Standardization (KAN)
(continued)
Table 3 (continued)
Information about the causes and Health and Safety Executive (HSE), http://www.hse.gov.uk/skin/
pathogenesis of occupational skin Great Britain (English)
diseases and skin protection (e.g., the
correct use and disposal of protective
gloves)
Information brochure on skin German Social Accident Insurance: https://www.bgetem.de (German)
protection including explicit Institution for the Energy, Textile, Short tips for skin protection:
recommendations regarding Electrical, and Media Products Webcode: 16670267 (German)
protective gloves, skin protection Sectors (BG ETEM)
advices, regeneration creams, and
skin cleansers for different
workplaces and exposures
INSHT (Instituto Nacional de Instituto Nacional de Seguridad e http://www.insht.es (Spanish)
Seguridad e Higiene en el Trabajo/ Higiene en el Trabajo
National Institute for Safety and
Health at Work):
Website with various information
concerning occupational safety and
health
interAKTIV: German Social Accident Insurance: https://www.bgetem.de (German)
E-Learning platform on occupational Institution for the Energy, Textile, Webcode: 12460943 (German)
safety and health, module on skin Electrical, and Media Products
protection Sectors (BG ETEM)
Learning and Health: German Social Accident Insurance https://www.dguv-lug.de (German)
Platform that provides educational (DGUV) Webcode: lug829356 (German)
materials about occupational safety
and health (e.g., skin protection,
information material for different
occupations, media)
Mach mit – Haut fit: German Social Accident Insurance: http://machmit-hautfit.de/11126/
E-Learning module about Institution for the Foodstuffs and 47447 (German)
occupational skin diseases and Catering Industry (BGN)
prevention in the food- processing
and catering industry (e.g., skin
protection, protective gloves,
appropriate skin care, and hygiene in
the meat-processing industry
including exemplary skin protection
plans, products for specific sectors,
and a skin check)
NCvB (Netherlands Center for Netherlands Center for Occupational http://www.occupationaldiseases.nl
Occupational Diseases): Diseases (English, Dutch)
Website that provides information on
registration and reporting of
occupational diseases. The NCvB
combines different organizations
(e.g., government institutions and
policy makers) and provides data on
occupational diseases
NIOSHTIC-2 Publication Search: Centers for Disease Control and https://www2a.cdc.gov/nioshtic-2/
Database of occupational safety and Prevention (CDC): National Institute advsearch2.asp (English)
health publications for Occupational Safety and Health
(NIOSH)
OSH Wiki European Agency for Safety and https://oshwiki.eu (English)
Online encyclopedia following the Health at Work (EU-OSHA)
(continued)
Table 3 (continued)
wiki concept to create and share
knowledge in terms of occupational
safety and health (OSH)
Online encyclopedia of Prof. Dr. med. Peter Altmeyer and http://www.enzyklopaedie-
dermatology, allergology, and Dr. Volker Paech (authors) dermatologie.de (German)
environmental medicine Provider: Springer-Verlag GmbH,
Heidelberga
Platform with information and Cooperation between the Department http://www.dermis.net/ (English,
photographs of skin diseases of Clinical Social Medicine French, Spain, Turkish, German,
including various information (University of Heidelberg) and the Japanese, Portuguese)
modules (e.g., on eczema, on skin Department of Dermatology Information module on eczema:
cancer) (University of Erlangen) http://eczema.dermis.net/ (English,
German, Turkish)
Information module on skin cancer:
http://skincancer.dermis.net/
(English)
Information module on medical skin
care:
http://skincare.dermis.net/ (English,
German)
Platform to raise awareness Swedish National Institute of Public http://www.workhealthy.se/
regarding occupational skin diseases Health: Centre for Occupational and (Swedish)
including a career guide for pupils Environmental Medicine http://www.workhealthy.se/en
who are in the process of career Translation into English funded by (English)
choice as well as for parents, career European Society of Contact
advisors, or school healthcare Dermatitis (ESCD)
professionals
SafeHair: Department of Dermatology, http://www.safehair.eu (English,
Website of the EU-funded projects Environmental Medicine and Health German, Dutch, Danish, French,
“SafeHair 1.0 and 2.0” (Common Theory, Osnabrück University Slovenian, Maltese)
Health and Safety Development in
Professional Hairdressing in Europe)
that contains information on skin
protection in the hairdressing trade
and a virtual toolbox with materials
designed for different target groups
(e.g., apprentices, employees, salon
owners, and teachers)
StanDerm: Department of Dermatology, http://www.standerm.eu (English)
Website of Cost Action TD1206 Environmental Medicine, and Health
Theory, University of Osnabrück
TRGS 401 (Technische Regel für Federal Institute for Occupational https://www.baua.de/DE/Angebote/
Gefahrstoffe/Technical Rules for Safety and Health (BAuA), Germany Rechtstexte-und-Technische-
Hazardous Substances): Regeln/Regelwerk/TRGS/TRGS-
Risks resulting from skin contact – 401.html (German, English)
identification, assessment, and
measures
Website that provides basic Austrian Workers’ Compensation https://www.auva.at/gesunde-haut
information (e.g., brochures) on Board (AUVA) (German)
occupational skin diseases and skin
protection for different occupations
Website with information about the German Social Accident Insurance: https://ww.bghm.de (German)
anatomy of the skin, occupational Institution for the Woodworking and Information about skin protection:
skin diseases, and skin protection Metalworking Industries (BGHM) Webcode: 227 (German)
(e.g., the usage of protective gloves, Topics:
(continued)
Table 3 (continued)
examples for skin protection plans, Skin hazard
and manufacturers of skin protection Skin protection products
creams) Skin cleansing and skin care
Protective gloves
Movie: skin protection in metal
working factories
Webcode: 2305 (German)
Website with information sheets on German Social Accident Insurance: https://www.bghw.de/ (German)
skin protection in different Institution for the Trade and Logistics Compendium occupational safety:
occupations (e.g., florist or Industry (BGHW) https://bghw.vur.jedermann.de//
warehousing and logistics) and legal bghw/ (German)
basics (Use search function: Hautschutz)
Website with information about the German Social Accident Insurance: https://www.bgrci.de/ (German)
anatomy of the skin, skin protection, Institution for the Raw Materials and Hand and skin protection:
the use of protective gloves, and skin Chemical Industry (BG RCI) Webcode: #PMZY (German)
hazards including a short E-Learning module:
E-Learning module http://wbt-haut.bgrci.jedermann.de/
index.html (German)
Website about occupational skin German Social Accident Insurance: https://www.bgw-online.de
diseases and prevention in the health Institution for the Health and Welfare (German)
and welfare service (e.g., skin Services (BGW) (Section: Gesund im Betrieb >
protection plans for specific Hautschutz – gesunde Haut
occupations, publications, behalten)
information material for hairdressers,
and geriatric nurses, media, and
starter sets)
Website of the WHO that contains World Health Organization (WHO) http://www.who.int/gpsc/tools/Five_
information on hand hygiene moments/en/ (English, Spanish,
French)
Website that provides basic Campaign Healthy Hairdresser http://www.healthyhairdresser.nl/
information on occupational skin (Dutch)
diseases and skin protection in the
hairdressing trade (e.g., use of
protective gloves, photographic hand
eczema self-test)
a
The website is supported by a commercial company
Table 4 Online databases and websites concerning allergens and allergy testing (listed in alphabetical order)
CABA (Contact Allergen Bank Australia): Occupational Dermatology http://www.occderm.asn.au/ (English)
Basic information about occupational skin Research and Education Contact Allergen Bank Australia
diseases for patients and healthcare Centre (ODREC) (CABA):
professionals with emphasis on patch http://www.occderm.asn.au/contact-
testing instructions and the Contact allergen-bank-australia/ (English)
Allergen Bank Australia
DKG (Deutsche Kontaktallergie-Gruppe/ German Contact Dermatitis http://dkg.ivdk.org/ (German)
German Contact Dermatitis Research Research Group (DKG)
Group):
Information about contact allergens for
physicians and healthcare professionals
with recommendations on patch testing
ESSCA-DC (European Surveillance European Surveillance System http://www.essca-dc.org/ (English)
System on Contact Allergies – Data on Contact Allergies – Data
Centre): Centre (ESSCA-DC)
Monitoring and analyzing data on contact
allergies (e.g., for quality control and
international comparisons, time trend
analyses, subgroup analyses)
EU-OSHA (European Agency for Safety European Agency for Safety https://osha.europa.eu/en (English and
and Health at Work): and Health at Work many more)
Agency that provides information, (e.g., (EU-OSHA) Factsheet 40 – skin sensitizer:
tools, publications, statistics, campaigns, https://osha.europa.eu/en/tools-and-
legislation) on occupational safety and publications/publications/factsheets/
health 40/view (English and many more)
GISBAU (Gefahrstoff- German Social Accident http://www.bgbau.de (German)
Informationssystem): Insurance: Institution for the GISBAU database:
Allergens in protective gloves (provided Building Trade http://www.bgbau.de/gisbau/service/
by various glove manufactures) (BG BAU) allergene (German)
List of allergens in specific gloves
(assorted by manufacturer):
http://www.bgbau.de/gisbau/service/
allergene/allergeneliste-nach-
hersteller-1 (German)
Information about allergy testing for Austrian Society of http://www.allergologie.at/ (German)
physicians Dermatology and Venereology
(ÖGDV): Allergy Working
Group
Information brochure on allergens in German Social Accident http://publikationen.dguv.de/dguv/
protective gloves Insurance (DGUV) pdf/10002/i-8584.pdf (German)
IVDK (Informationsverbund Information Network of http://www.ivdk.org/en/ (English)
Dermatologischer Kliniken/Information Departments of Dermatology http://www.ivdk.org/de/ (German)
Network of Departments of Dermatology): (IVDK)
Monitors and scientifically evaluates
developments of contact allergies
Platform with basic information about European Society of Contact https://www.escd.org/ (English)
(occupational) contact dermatitis and patch Dermatitis (ESCD)
testing for physicians and researcher
Videncenter for allergi: Danish Allergy Center: http://www.videncenterforallergi.dk/
Website with information about allergy Allergy Research Center (English, Danish)
testing and allergic contact dermatitis
Table 5 National and international research networks, website of the European Academy of Dermatology and
professional associations, and societies (listed in alphabet- Venerology: https://eadv.org/links)
ical order) (Some of the links listed here are taken from the
Research network, association, or society Weblink
Austrian Society of Dermatology and Venereology (ÖGDV) http://www.oegdv.at
American Academy of Dermatology (AAD) https://www.aad.org
American Contact Dermatitis Society (ACDS) https://www.contactderm.org
Arbeitsgemeinschaft für Berufs- und Umweltdermatologie (ABD) http://www.abd.dermis.net
British Association of Dermatologists (BAD) http://www.bad.org.uk
British Society for Cutaneous Allergy (BSCA) http://www.cutaneousallergy.org
British Contact Dermatitis Group (BCDG) http://www.bcds.org.uk
Bulgarian Dermatological Society http://www.bg-derm.org
Cyprus Society of Dermatology and Venereology http://www.cyderm.org/index.php/el
Czech Dermatovenereology Society http://www.derm.cz
Danish Dermatological Society http://www.dds.nu
Deutsche Gesellschaft für Allergologie und Klinische http://www.dgaki.de
Immunologie (DGAKI)
Dutch Society for Dermatology and Venereology http://www.huidarts.info
Estonian Society for Dermatovenereologists http://www.ensas.ee/avaleht
European Academy of Dermatology and Venerology (EADV) https://www.eadv.org
European Environmental and Contact Dermatitis Research Group http://www.orgs.dermis.net/eecdrg
(EECDRG)
European Dermato-Epidemiology Network (EDEN) http://eden.dermis.net
European Society for Dermatological Research (ESDR) http://www.esdr.org
European Academy of Allergy and Clinical Immunology http://www.eaaci.org
(EAACI)
Finnish Dermatological Society http://www.sily.fi
German Society of Dermatology (DDG) http://www.derma.de
Hellenic Society of Dermatology and Venereology http://www.edae.gr
Hungarian Dermatological Society http://www.derma.hu
International Commission on Occupational Health (ICOH) http://www.icohweb.org
International Social Security Association (ISSA) http://socialprotection.org
Irish Association of Dermatologists (IAD) http://www.irishdermatologists.ie
Lithuanian Association of Dermatovenereologists http://www.ldvd.lt
Maltese Society of Dermatology and Venereology http://www.madv.org.mt
Norwegian Society of Dermatology and Venereology http://www.legeforeningen.no/Fagmed/Norsk-
forening-for-dermatologi-og-venerologi
Polish Dermatological Society http://www.ptderm.pl
Portuguese Society of Dermatology and Venereology http://www.spdv.com.pt
Romanian Society of Dermatology http://www.dermanet.be
Royal Belgian Society for Dermatology and Venereology http://www.srd.ro
Russian Society of Dermatovenereologists http://www.rodv.ru
Serbian Association of Dermatologists http://www.udvs.org
Slovakian Dermatovenerological Society http://www.sds-sk.sk
Slovenian Society of Dermatology and Venereology http://www.zsd.si
Società Italiana di Dermatologia medica, chirurgia, estetica e delle http://www.sidemast.org
Malattie Sessualmente Trasmesse (SIDeMaST)
Société Française de Dermatologie http://www.sfdermato.org
(continued)
Table 5 (continued)
Research network, association, or society Weblink
Spanish Academy of Dermatology and Venereology http://www.aedv.es
Swedish Society for Dermatology and Venereology http://www.ssdv.se
Swiss Society for Dermatology and Venereology http://www.derma.ch
Turkish Society of Dermatology http://www.turkdermatoloji.org.tr
Even though the tables do not claim to be The material safety data sheets of hazardous
exhaustive, they may provide helpful information substances provide further information about
for the daily practice (e.g., the choice and usage of the choice of appropriate protective equipment
appropriate protective equipment) and give an (e.g., gloves). Data regarding allergens in
overview of a variety of different institutions and protective gloves and the permeation of
authors that aim at raising awareness regarding specific substances can be directly obtained
occupational skin diseases. This overview does from the glove manufacturers. It needs to be
not exclusively present sources of information for considered that the choice of appropriate protec-
physicians (e.g., dermatologists or occupational tive equipment strongly depends on the individ-
physicians) but as well for occupational health ual workplace, work processes, and complex
and safety officers, healthcare professionals, exposures and thus requires a specific risk
teachers, career advisors, exposed workers in assessment.
“high-risk professions,” consumers, and patients. The authors of the listed websites are respon-
Obviously, it has to be checked whether the infor- sible for the content in view of actuality, quality,
mation given is current. and correctness.
Part II
Occupational Skin Diseases: Clinical
Contact Dermatitis due to Irritation
12
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3 Clinical Types of Irritant Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
3.1 Acute ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
3.2 Acute Delayed ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.3 Irritant Reaction ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.4 Cumulative (Chronic) ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3.5 Traumiterative ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.6 Exsiccation Eczematid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.7 Traumatic ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.8 Pustular and Acneiform ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.9 Nonerythematous ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
3.10 Subjective ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
3.11 Other Forms of ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4 Irritation or Allergy? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
5 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
6 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
7 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
9 Treatment and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
10 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
D. Antonov · P. Elsner (*)

Department of Dermatology, University Hospital Jena,
Jena, Germany
e-mail: elsner@derma-jena.de
S. Schliemann
e-mail: schliemann@derma-jena.de

https://doi.org/10.1007/978-3-319-68617-2_12
120 D. Antonov et al.
Keywords appealing problem of allergic sensitization

Irritant contact dermatitis has changed dramatically. In Germany, skin dis-
eases are the second most frequent occupational
disease following musculoskeletal disorders.
1 Core Messages Occupational skin disease is usually among the
top five occupational diseases in many countries
• Irritant contact dermatitis (ICD) denotes (Keegel et al. 2009). Most occupational derma-
inflammation of the skin which results from a toses are cases of contact dermatitis. Of the two
contact with external agent and does not varieties of contact dermatitis, irritant and aller-
require prior sensitization of the immune gic, a higher prevalence of ICD is predominantly
system. reported; only in few sources a higher frequency
• Irritant contact dermatitis is the most frequent of ACD is to be found (Keegel et al. 2009).
cause for occupational contact dermatitis. Epidemiologic studies on hand eczema from var-
• The clinical features are quite diverse and ious countries show that irritation is the most
there are ten clinical types described: frequent cause and in many further cases is a
acute, acute delayed, irritant reaction, cumula- contributing factor to allergy or atopy (Lofgren
tive, traumiterative, exsiccation eczematid, and Warshaw 2006; Thyssen et al. 2010a; Nich-
traumatic, pustular and acneiform, non- olson 2011).
erythematous, and subjective. In contrast to ACD, ICD is defined as being
• Distinction from allergic contact dermatitis the result of a primarily unspecific damage to the
(ACD) usually relies on time course (quicker skin, i.e., it does not require prior sensitization
onset in irritation), subjective symptoms (itch of the immune system. ICD is not a clinical
in ACD vs burning or pain in ICD), and mor- entity but rather a spectrum of diseases. The
phology (spread outside the contact area, clinical aspect of ICD is determined by the
more infiltration and vesiculation in ACD). dose–effect relationship (Patil and Maibach
However, distinction may be clinically very 1994). The morphology of acute ICD shows
difficult or impossible; histology, pathogene- erythema; edema; and vesicles that may coa-
sis, and therapy are also very similar. lesce, bullae, and ooze (Figs. 1 and 2). Necrosis
• Atopic skin predisposition is the best and ulceration are seen with corrosive materials
established risk factor for irritant contact (Fig. 3). The clinical features of chronic ICD
dermatitis; respiratory manifestations of include redness, lichenification, excoriations,
atopy are less predictive than skin scaling, and hyperkeratosis (Figs. 4 and 5). Any
manifestations. skin site may be affected. However, most fre-
• Prevention, early recognition, and therapy are quently affected by ICD are the hands, as they
decisive in averting chronic and persistent are the human “tools” that interact with the
forms.
2 Introduction
Irritant contact dermatitis (ICD), defined as

inflammation of the skin resulting from exposure
to an exogenous agent (Chew and Maibach 2006)
which does not require prior sensitization of
the immune system, is a leading cause of occu-
pational disease in dermatology and causes eco-
nomic damage to workers, companies, and social
security systems worldwide. The perception of
ICD as more trivial than the more intellectually Fig. 1 Chemical burn caused by tear gas in a policeman
12 Contact Dermatitis due to Irritation 121
Fig. 2 Jellyfish reaction in a lifeguard Fig. 4 Housewives’ eczema due to chronic wet work
Fig. 5 Fingertip eczema due to physical trauma in a cellist
3 Clinical Types of Irritant

Contact Dermatitis
Irritants produce a wide range of clinical fea-

tures. Cutaneous responses depend on the type
Fig. 3 Caustic reaction caused by cement
of irritant (detergent, acid, alkali, oil, organic
solvent, oxidant, reducing agent, water –
environment most and have intensive contact to Table 1), the concentration at which the irritant
irritants. Spilling of fluids may irritate the fore- comes into contact with the skin, the type of
arms or other body sites, especially when fluids exposure, and the individual response. Clinical
soak through work clothes. manifestations of the ICD syndromes are also
Table 1 Common irritants and their modes of action Table 2 Factors influencing the irritancy potential
(Elsner 1994) (Wilkinson and Willis 1998)
Substances Mechanisms of toxicity Exogenous Endogenous Cofactors
Detergents Solubilization and/or disorganization of Chemical characteristics Individual Mechanical
the barrier lipids and the natural susceptibility
moisturizing factor in the stratum Molecular structure Atopy Thermal
corneum (SC); protein denaturation; pH Race/skin Climatic
membrane toxicity color/
Acids Protein denaturation, cytotoxicity phototype
Alkali Barrier-lipid denaturation, cytotoxicity pKa Age
through cell swelling Hydrophobicity (log of Hormonal
Oils Disorganization of barrier lipids the partition coefficient)
Organic Solubilization of barrier lipids; Inherent toxicity Barrier
solvents membrane toxicity; retrograde function
inflammation through release of Concentration/dose Repair
mediators from the dermis capacity
Oxidants Cytotoxicity Penetration Eczema
Reducing Keratolysis characteristics elsewhere
agents Vehicle Other skin
Water If barrier is disrupted, cytotoxicity disease
through swelling of viable epidermal Solubility Other
cells unknown
Duration of contact Cite of
Type of contact exposure
modified by external factors such as environmen-

tal factors (mechanical pressure, temperature,
Table 3 Subtypes of ICD and their prognosis. (Based on
and humidity (Fluhr et al. 2005)) and pre- Chew and Maibach 2006; Frosch and John 2006)
disposing characteristics of the individual (age,
Types of ICD Prognosis
sex, ethnic origin, preexisting skin disease,
Acute Good
atopic skin diathesis, and anatomic region Acute delayed Good
exposed) (Pinnagoda et al. 1989; Wilkinson and Irritant reaction Good
Willis 1998). Cumulative Variable
For example, elderly people are not only Traumiterative Variable
affected more often by contact dermatitis because Exsiccation eczematid Variable
of their reduced epidermal barrier, but they also Traumatic Variable
show more severe symptoms (Patil and Maibach Pustular and acneiform Variable
1994; Ghadially et al. 1995; Zhai et al. 2012; Nonerythematous Variable
Prakash and Davis 2010). Environmental influ- Subjective Excellent
ences, such as cold and low ambient humidity,
are important factors decreasing the water content
of the stratum corneum (Mozzanica 1992). Cold 3.1 Acute ICD
alone can also reduce the plasticity of the horny
layer and lead to cracking. Occlusion increases the Acute ICD develops when the skin is exposed to a
water content of the stratum corneum with conse- strong irritant or caustic chemical. Usually this
quent enhanced percutaneous absorption of water happens as an accident at work or in special emer-
soluble substances. A list of the factors which gency situations. The irritant reaction reaches its
influence the irritant potential of the irritants is peak quickly and then starts to heal; this is called
presented in Table 2. the decrescendo phenomenon. Because the lag
Several different types of ICD have been time is short (usually minutes to hours after expo-
described (Table 3). sure) and the association between exposure and
skin symptoms is usually clear, the diagnosis is Table 4 Chemicals inducing delayed acute irritation
easy in most cases. It may become difficult when (Lammintausta and Maibach 1990)
the patient was unaware of an exposure. Acute Anthralin
ACD has to be considered as differential diagno- Calcipotriol
sis, which is caused by a delayed sensitization Benzalkonium chloride
reaction, and requires 24–48 h after allergen con- Tretinoin
tact for symptoms to appear; this type of contact Bis(2-chloroethyl)sulfide
dermatitis is characterized by the crescendo phe- Hexanediol and butanediol diacrylates
Dichloro(2-chlorovynil)arsene
nomenon (i.e., a transient increase of signs and
Epichlorohydrin
symptoms despite removal of the allergen). The
Ethylene oxide
clinical appearance of acute ICD is highly vari-
Hydrofluoric acid
able, and it may even be indistinguishable from
Hydroxypropylacrylate
the allergic type. There are numerous reports in Podophylline
the literature of even experienced dermatologists Propane sulfone
being misled into an initial assumption of ACD
which later, after a careful workup, turned out to
be “only irritation” (Frosch and John 2011). Fur- irritation may be more common than generally
thermore, the combination of allergic and irritant thought. Clinically, acute delayed ICD resembles
dermatitis is frequent, e.g., “black-spot poison ivy acute ICD. The visible inflammation is not seen
dermatitis” (Hurwitz et al. 1984), as an acute ICD until 8–24 h or more after exposure (Malten et al.
superimposed upon an ACD. 1979). Irritant patch-test reactions to benzalkonium
Symptoms of acute irritant dermatitis are burning, chloride may be papular and increase in intensity
stinging, and soreness of the skin. Signs are ery- with time, thus imitating ACD and the crescendo
thema, edema, bullae, and possibly necrosis. These phenomenon. On the normal skin surrounding pso-
lesions are restricted to the area where the irritant or riatic plaques, dithranol causes redness and edema,
toxicant damaged the tissue. Borders are mostly which may become very severe on the legs because
sharply demarcated, and the asymmetrical pattern of venous stasis. Irritation due to tretinoin develops
of the lesions hints at an exogenous cause (Figs. 1, after a few days and is characterized by mild to
2, and 3). The prognosis of this type is good (Elsner fiery redness followed by desquamation or large
1994). The most frequent potent irritants leading to flakes of stratum corneum. The symptoms are
acute ICD are acids and alkaline solutions (Eichmann burning rather than itching which is a helpful indi-
and Amgwerd 1992). A typical accident situation is cator to distinguish from ACD. The skin becomes
chemical burning in construction workers (Skogstad sensitive to touch and to water (Frosch and John
and Levy 1994) when alkaline concrete fluid soaks 2006). Patch testing helps differentiate acute
through garments or spills into work boots. delayed ICD from ACD (Chew and Maibach
Chemical burns by fluoric acid are the most 2006).
dangerous of all injuries caused by acids and need
special treatment. But even substances thought to
be less toxic, such as N-methyl-2-pyrrolidone, 3.3 Irritant Reaction ICD
may cause acute ICD (Malten et al. 1979).
Irritant reaction ICD is a type of subclinical irritant
dermatitis in individuals exposed to wet work, such
3.2 Acute Delayed ICD as hairdressers or metal workers, in their first
months of training. This diagnosis is made if the
Acute delayed ICD is characteristic for certain clinical picture is monomorphic rather than poly-
irritants, such as benzalkonium chloride, anthralin, morphic and characterized by the predominance of
calcipotriol, tretinoin, and others (Table 4) that one of the following signs: scaling, redness, vesi-
elicit a retarded inflammatory response. Delayed cles, pustules, and erosions (Frosch and John 2011).
On the hands it often begins under rings and sensitive skin are characterized by a decreased
then may spread over the fingers to the hands and threshold or an increased restoration time leading
the forearms. It usually affects the dorsum of the to earlier development of clinical irritant dermati-
hands and fingers, but irritants can also cause tis. The “manifestation threshold” is not a fixed
eczema of the palmar sides of the fingers and the value for an individual, but it may decrease with
hands. the disease. This explains why in patients with
This distribution occurs in caters, and, cumulative ICD even a limited irritant exposure
described as dyshidrotic eczema, it has been may perpetuate the condition. Cumulative ICD is
reported in metal workers with an ICD from linked to exposure to weak irritants, rather than
cooling lubricants (Cronin 1995). Frequently, potent irritants. It develops slowly, after repeated
this condition heals spontaneously, resulting in subthreshold irritations over a period ranging from
hardening of the skin; sometimes it progresses to days to weeks or even years (Chew and Maibach
cumulative irritant dermatitis. 2006). Very often, this exposure occurs not only at
work but also in private life. Because the link
between exposure and disease is often not obvious
3.4 Cumulative (Chronic) ICD to the patient, diagnosis may be delayed consider-
ably. This is one of the reasons for the rather
According to Malten (Fig. 6) cumulative ICD is a doubtful prognosis of this disease (Belsito 2005).
consequence of multiple subthreshold damages to Cumulative and chronic ICD are synonymous,
the skin if the time between the insults is too short because the same phenomenon is deemed to take
for complete restoration of skin barrier function place in chronic ICD, i.e., new insults occur
(Malten 1981). It may be the result of too frequent before the restoration of the skin is completed.
repetition of one impairing factor (see Sect. 3.5), Such insults may occur not only through the expo-
but is more commonly the result of a variety sure to irritants which can cause acute ICD by
of stimuli, each beginning to be active before themselves. Repeated exposure to many weak
recovery from the foregoing stimuli has been com- irritants, which would otherwise be well tolerated
pleted. Clinical symptoms will develop only when by a healthy skin, could prolong the condition
the damage exceeds a certain “manifestation into chronic ICD. For the diagnosis of chronic
threshold,” which is individually determined. ICD to be made, the disease duration should
The development of visible changes in irritant der- exceed the proposed arbitrary limit of 6 weeks
matitis has also been compared to being only the (Chew and Maibach 2006). Symptoms of chronic
“tip of the iceberg” of functional derangement irritant dermatitis are itching and pain due to
(Freeman and Maibach 1988). Persons with cracking of the hyperkeratotic skin. Signs include
Fig. 6 Model of the pathogenesis of chronic irritant con- (b) When the same irritants follow each other closely or
tact dermatitis, according to Malten. (a) Subliminal irri- when the manifestation threshold is reduced, irritant der-
tants do not lead to clinical irritant dermatitis if exposures matitis develops. (Based on Malten 1981)
are far enough apart for restoration of skin barrier function.
dryness, erythema, and vesicles but mainly The most common location is the hands. In a
lichenification, hyperkeratosis, and chapping. In fully developed case, redness, infiltration, and scal-
contrast to acute irritant dermatitis, the lesions are ing with fissuring are seen all over the affected areas.
less sharply demarcated. Xerotic dermatitis is the
most frequent type of cumulative toxic dermatitis
(Eichmann and Amgwerd 1992). 3.8 Pustular and Acneiform ICD
Pustular and acneiform ICD is a result of exposure

3.5 Traumiterative ICD to certain irritants, such as croton oil, mineral oils,
tars, greases, naphthalenes, chlorinated aromatic
In contrast to cumulative ICD resulting from a too hydrocarbons (“chlor acne”), fluorinated com-
early repetition of exposures differing in type, pounds (Steciuk et al. 1997), and others. This
traumiterative ICD is a result of too early repetition syndrome must always be considered in condi-
of just one type of load (Malten and den Arend tions in which acneiform lesions develop outside
1985). Nevertheless, these two types are very sim- the typical acne age. Those most affected are
ilar clinically and are often combined in one group. patients with seborrhoea, macroporous skin con-
ditions, and prior acne vulgaris, as well as atopics.
The pustules are sterile and transient; however,
3.6 Exsiccation Eczematid subcorneal pustular eruption may also be a man-
ifestation of allergy (ACD). An example is the
Other terms frequently used for this condition are allergy to trichlorethylene, which has to be con-
asteatotic eczema and eczema cracquelé (Chew sidered as a differential diagnosis in patients with
and Maibach 2006; Thong and Maibach 2008). appropriate history (Goh 1995).
Exsiccation eczematid is a special variant of ICD Pustular and vesicular reactions are typical for
that is seen mainly in elderly individuals with the acute irritant dermatitis caused by the contact
a history of frequent showering and bathing with- with the hemolymph of crushed bodies or some-
out remoisturizing their skin. Patients suffer times with the whole bodies of certain bugs. While
from intensive itching and sensation of “skin in Paederus dermatitis, the subtype caused by the
tightness,” and their skin appears dry, cracked, bugs from the Paederus family, the lesions are
and with ichthyosiform scaling. Mostly the legs, inflamed, linear “whiplash-” or burn-shaped; the
the backs of the hands, and the arms are affected. lesions induced by the vesiculant from other insects,
The condition mainly occurs during the winter cantheridin, are vesicles and bullae on uninflamed
months, when humidity is low. skin (Zargari et al. 2003). Outbreaks in factories or
deployed military personnel are reported (Dursteler
and Nyquist 2004; Huang et al. 2009).
3.7 Traumatic ICD
Traumatic ICD may develop after acute skin 3.9 Nonerythematous ICD
trauma, such as burns, lacerations, and acute
ICD. Patients should also be asked whether they Nonerythematous ICD may be defined as a
have cleansed the skin with strong soaps or deter- subclinical form of ICD with early stages of skin
gents. The syndrome is characterized by delayed irritation characterized only by changes in the
healing and eczematous lesions, such as ery- stratum corneum barrier function (detectable
thema, papules, vesicles, and scaling (Chew and by bioengineering methods) without a clinical cor-
Maibach 2006). This eczematous condition per- relate, i.e., not exceeding the “manifestation thresh-
sists for a considerable time period, with a mini- old” or not reaching the “tip of the iceberg,” as
mum of 6 weeks (Frosch 1995). In the later stages, discussed in the Cumulative ICD section (van der
it may resemble nummular dermatitis (Chew and Valk et al. 1985; Berardesca and Maibach 1988;
Maibach 2006). Lammintausta et al. 1988).
3.10 Subjective ICD Mainly sensitive exposed skin is affected, such

as the face and especially the periorbital region
Subjective or sensory ICD is characterized by (Dooms-Goossens et al. 1986; Patiwael et al.
the lack of clinical signs, but individuals complain 2005; Lachapelle 2006; Tan et al. 2014). Which
of a subjective sensation of stinging, burning, areas are affected and the morphology of the
smarting, or even pain after contact with certain lesions are related to the physical form of
chemicals, such as lactic acid, which is also the irritant: dust or fibers, where a mechanical
a model irritant for this type of invisible cutan- friction is important, or sprays, vapors and gases
eous irritation. This reaction may be reliably (Lachapelle 2006). Most reports concern occupa-
reproduced in a double-blinded exposure test. tional exposure (Santos and Goossens 2007). Air-
The property of the chemical agents to elicit borne ICD caused by industrial dust adhered
such sensations depends on their concentration to the clothing may mimic textile dermatitis,
and vehicle. Neural pathways are considered with lesions most prominent in sites with close
to be responsible (Lee et al. 2009). Frosch (Frosch skin–garment contact, such as the axilla, the glu-
and John 2011) distinguishes between immediate- teal region, or the thighs (Hafner et al. 1995).
type stinging, caused by chemicals such as chlo- More detailed information is given in ▶ Chap.
roform and methanol (1:1) or 95% ethanol, and 17, “Airborne Contact Dermatitis” of this book.
delayed-type stinging. The delayed type is mostly The aspects of pigmented contact dermatitis
caused by sunscreen agents, insect repellants and are reviewed in ▶ Chap. 27, “Pigment Disorders.”
several dermatological therapeutic agents and Pigmentary changes may arise on the sites of
vehicles that are used in cosmetics and topical irritation dermatitis as a postinflammatory hyper-
medicaments (Frosch and John 2011; Frosch and pigmentation. Melanodermatitis toxica is viewed
Kligman 1977). With some irritants, for example, to be a phototoxic dermatitis due to tars, pitch, or
chloroform and methanol (1:1) or some caustic oil products. The phototoxic reactions are
chemicals, the sensations of burning, stinging, etc. reviewed in ▶ Chap. 15, “Phototoxic Dermatitis.”
can be viewed as an early warning signal and Other less common related conditions, in the
an initial phase of irritation, because the continued sense that they are caused by contact with external
exposure would invariably produce damaging substances and irritants, but have morphology
effects (Frosch and John 2011). Substances other than eczema/dermatitis, are also the subject
which produce non-immunologic contact urti- of separate chapters in this book – granulomatous
caria, like cinnamic aldehyde, also produce only reactions (▶ Chap. 28, “Noneczematous Occupa-
sensorial irritation, when applied at concentra- tional Contact Reactions”) and non-immunologic
tions too low to induce a detectable reaction. The contact urticaria (▶ Chap. 21, “Frictional Trauma/
sensory irritant properties do not correspond with Mechanic Skin Diseases”).
the actual corrosive or irritant characteristics. For
example, undiluted kerosene and others may
induce severe irritation without any accompany- 4 Irritation or Allergy?
ing sensation (Frosch and John 2011).
The distinction between irritant and allergic con-
tact dermatitis has become increasingly blurred.
3.11 Other Forms of ICD Despite their different pathogenesis, ACD and
ICD, especially of the chronic type, show a
Airborne ICD is not separated as a distinct type, remarkable similarity with respect to clinical
because it develops through similar mechanisms appearance, histology, and immunohistology
as the other types listed above. What sets it apart (Tan et al. 2014). It is apparent that some of the
is the fact that the irritants are dispersed and car- same inflammatory immune mechanisms are
ried by the air before they come into contact with important both in ACD and ICD (Brasch et al.
uncovered skin (Chew and Maibach 2006). 1992; Dika et al. 2004; Lee et al. 2013). The
epidermal and dermal cell activity that produces et al. 2004; Spiekstra et al. 2005; Angelova-
the cascade of inflammation appears to be similar Fischer 2016).
and applicable to both irritants and allergens. The cytokine IL-1α is available as a preformed
However, although inflammatory and immuno- pool in the keratinocytes and is quickly secreted
logical mediators may be activated, in contrast to upon keratinocyte damage or activation (Kupper
ACD, no memory T-cell function is involved. 1990; Wood et al. 1996). The release of IL-1α has
Many comparative studies suggest these two enti- been called the “main switch” in the activation
ties are more alike than they are not (Dika et al. of the inflammatory cascade in the skin (Welss
2004). Histologically, irritant contact dermatitis et al. 2004), but there is evidence that it is not the
reactions show much greater pleomorphism than only primary inflammatory mediator (Corsini and
those elicited by allergens. Various alterations of Galli 2000). TNFα is another early cytokine,
epidermal cells can be observed according to the which is not shown to be readily stored in the
nature and concentration of the irritant applied, keratinocytes but is secreted by them upon activa-
the type and duration of exposure, and the indi- tion. IL-1α, IL-1β, and TNFα are considered “pri-
vidual reactivity of the skin. Frequently, even mary” cytokines, as they can trigger inflammation
therapy is similar. Additionally, the concept that independently, without additional stimuli (Kupper
irritants are thought to cause symptoms and signs 1990; Welss et al. 2004). The release of IL1α
within minutes to hours whereas allergens take and TNFα can be viewed as a primary general
days has been disqualified for one of the most “alarm signal” which is a common phase in the
widely studied irritants. Occlusion of sodium response to various stimuli, including irritants and
lauryl sulfate (SLS) for 24 h resulted in clearly allergens (Spiekstra et al. 2005). The secretion of
more signs of inflammation at 48 h, a time course other cytokines follows, such as IL-6, IL-8,
more characteristic of allergic reactions (Rietschel GM-SCF, and other cyto- and chemokines which
1997; Dika et al. 2004). Some allergens such as recruit inflammatory cells to the injured skin
benzalkonium chloride possess irritant properties (Corsini and Galli 2000). Such cytokines are
as well (Wolf et al. 2013). considered “secondary,” because although they
modulate the inflammation, they could not trigger
it alone (Kupper 1990; Corsini and Galli 2000).
5 Pathogenesis Adhesion molecules including ICAM-1 are
upregulated on endothelial cells and fibroblasts
The various irritants may cause damage through in the skin, and further secondary chemokines,
different mechanisms, which depend on the such as CXCL 8, CCL 20, GM-CSF, IFN
nature and the dose of the irritant (Elsner 1994; gamma, are released (Lee et al. 2013). Other path-
Fluhr et al. 2008). Some may, for example, dis- ways are also shown to be activated, for example,
rupt the organization of the lipids in SC, swell or the arachidonic acid cascade in experimental
denaturate proteins, cause damage to the models with surfactants (Welss et al. 2004) and
keratinocytes or penetrate and reach the dermis, other irritants (Thong and Maibach 2008). A role
and release inflammatory mediators there for the oxidative stress with formation of reactive
(Table 1). Whatever their exact mechanisms oxygen species has also been described in the
may be, they elicit irritation either by disrupting pathogenesis of allergic and irritant contact der-
the epidermal barrier (Angelova-Fischer 2016), matitis (Nakai et al. 2012). The similarity between
by causing an epidermal cellular damage, or a allergic and irritant contact dermatitis in terms of
combination of both (Berardesca and Distante involved inflammatory cytokines has been noted,
1994; Welss et al. 2004). Inflammatory response especially in the early phases (Lee et al. 2013;
follows through the secretion of cytokines and Gittler et al. 2013). In allergic contact dermatitis,
chemokines by the keratinocytes. There are iden- the antigen-specific T cells take over to increase
tical stages in this process among various irri- the inflammatory response in the later phases in
tants and allergens (Hoefakker et al. 1995; Dika contrast to ICD. Some cytokines including
CXCL9, CXCL10, and CXCL11 are specifically induces skin irritation, unlike other irritants
upregulated in allergic contact dermatitis but not (Holliday et al. 1997; Corsini and Galli 2000;
in irritant contact dermatitis (Lee et al. 2013). The Thong and Maibach 2008). Another example is
similarities and the differences on the molecular the difference in the epidermal cytokines, induced
level among the irritant contact, allergic contact, in the initial steps of irritation with SLS compared
and atopic dermatitis have been recently reviewed to nonanoic acid (NAA) (Grangsjo et al. 1996).
(Gittler et al. 2013). When these model irritants were applied at con-
The irritation causes the keratinocytes to centrations which cause a similar cellular injury at
secrete anti-inflammatory and modulatory cyto- 24 h, NAA provoked a more consistent expression
kines as well, like IL-1 receptor antagonist of IL-6 mRNA, while only SLS led to a GM-CSF
(ILRA) and IL-10 (de Jongh et al. 2006, 2007). mRNA expression (Grangsjo et al. 1996). The
The main function of the ILRA is to balance same irritants were also compared in a study
the inflammatory properties of IL-1 (Arend and using gene expression analysis with microarray
Guthridge 2000). The ILRA to IL-1α ratio is what chips at early and late time points (Clemmensen
directs the inflammatory response (de Jongh et al. et al. 2010). This technology allowed the compar-
2007). This ratio is decreased after a single irrita- ison of the expression of 47,000 transcripts
tion with sodium lauryl sulfate (SLS) and is between the two irritants and to discern the com-
increased after repeated SLS applications which mon and the distinct pathways activated at early
model the cumulative ICD (de Jongh et al. 2006, (acute irritation) and late stages and after cumula-
2007). The studies on cutaneous cytokines show tive irritation. A complex picture was revealed
dissimilar cytokine levels in the acute versus where most of the early activated genes are
cumulative irritation with SLS, implying different quickly turned off. The two irritants exhibited
pathogenesis of the acute and cumulative ICD very different expression profiles, while at the
(de Jongh et al. 2006, 2007). These studies also same time commonly expressed transcripts were
reveal great interpersonal variability in the cyto- identified which could be potential biomarkers
kine responses to the standardized single and repet- for cumulative skin irritation (Clemmensen et al.
itive irritation with SLS, as well as variability in the 2010). Besides elucidating the pathways involved
baseline cytokine levels (de Jongh et al. 2006). It in the pathogenesis of the irritation, this technol-
has been suggested that the uneven personal sus- ogy may have diagnostic uses. Discrimination
ceptibility to acute and chronic irritation might be between irritant or allergic dermatitis and even
due to different levels of certain cytokines in the the identification of the causative irritants could
skin (de Jongh et al. 2006). Correlation between be possible, if their specific transcription profiles
higher baseline ILRA and IL-8 levels and stronger are known (Wong et al. 2004). RNA could
irritation responses to SLS has been reported be sampled for this purpose with minimally inva-
(de Jongh et al. 2006). An association is reported sive tape-stripping procedures (Wong et al. 2004).
between genetic polymorphisms in the TNFα and The expression patterns after irritation with
IL-1α genes and the susceptibility to chronic hand other irritants have also been investigated on
eczema (de Jongh et al. 2008a). These findings various models, such as on rats, cultured human
may have implications for identifying individuals keratinocytes, human skin equivalents, and
with a higher risk of developing chronic dermatitis human volunteers (Fletcher et al. 2001; Rogers
(de Jongh et al. 2008a). et al. 2003; Borlon et al. 2007; McDougal et al.
The differences in the irritation responses, 2007; Clemmensen et al. 2010).
evoked by the diverse irritants, are thought to The cytokines secreted during irritation not
be due to the varying properties of these irritants only orchestrate the inflammation response, but
to activate inflammatory and cytokine path- they also trigger the keratinocyte proliferation and
ways (Corsini and Galli 2000). For example, the lipid synthesis and secretion, needed for
benzalkonium chloride does not induce a detect- the epidermal barrier restoration (Feingold et al.
able production of TNFα at a concentration which 2007). Such function is demonstrated for IL-1,
TNFα, and IL-6 in mice experiments (Proksch definitions, and degrees of industrialization
et al. 2008). It is therefore considered that the (Keegel et al. 2009). The general opinion is that
chronic increase in these cytokines could be many cases of OCD remain undetected,
responsible for the hyperproliferation of the epi- undiagnosed, or unreported. The incidence of
dermis seen in chronic dermatitis (Proksch et al. reported OCD is similar in countries with a com-
2008). Additional mechanisms, activated when pulsory reporting systems and comparable rates of
the stratum corneum barrier is disrupted and/or industrialization, such as Germany, Denmark, and
the epidermis is damaged, include the changes in Finland, and is in the range of 5–8 cases per
the gradients of the calcium and other ions, the 10,000 workers per year (Keegel et al. 2009).
change in the pH gradient, the serine protease/ The voluntary systems of reporting, like the
proteinase-activated receptor-2 (PAR-2) pathway, EPIDERM in the UK and a similar one in the
and the nitric oxide (NO) pathway (Feingold et al. Netherlands, rely on the voluntary submission of
2007). While some of these accelerate the barrier data from various physicians – dermatologist,
repair, like the cytokines and the ion gradients, general practitioners, and occupational physi-
others downregulate it (PAR-2 and NO path- cians. Their estimated incidence rates per 10,000
ways). The function of the interrelated positive workers are more variable – 15 in the Netherlands,
and negative signals is considered to finely tune 1.3 in the UK, and 2.2 in Australia. Studies based
the barrier homeostasis (Feingold et al. 2007). on self-reporting (mailed questionnaires or inter-
views) have the highest rates of OCD (Keegel
et al. 2009). The National Health Interview Sur-
6 Epidemiology vey in the USA which included randomly selected
households estimated a 1-year-period prevalence
While population-based epidemiological studies of 170 cases per 10,000 workers of occupational
on the frequency of ICD are rare, there is agree- skin disease in 1988 (Lushniak 2003). An inter-
ment that irritant dermatitis is more frequent than esting fact is the statistically significant decrease
ACD, although ACD tends to have more severe in the incidence of OCD, reported in Bavaria for
consequences for the patient. Coenraads and Smit the period 1990–1999 (Dickel et al. 2001). This
reviewed international prevalence studies for decrease seems to be a consequence of preventive
eczema due to all causes conducted with general public health initiatives and legislative measures
populations in five countries (England, the Neth- for the occupational groups at highest risk (Dickel
erlands, Norway, Sweden, and the USA). They et al. 2001).
showed point prevalence rates of 1.7–6.3% and The perception that irritant dermatitis is more
1- to 3-year-period prevalence rates of 6.2–10.6% frequent than ACD in the occupational setting is
(Coenraads and Smit 1995). supported by data from Singapore. Of 557 patients
Contact dermatitis (all types) represents with occupational dermatoses, 55.7% (310) had
90–95% of all cases with occupational skin dis- ICD, 38.6% (215) had ACD, and 5.7% (32) had
ease in the Western countries (Keegel et al. 2009). noncontact dermatitis (Goh 1987). However, the
The hands are usually involved (Dickel et al. incidence rates of ICD and ACD in a population-
2001), but in studies on hand eczema which are based study in North Bavaria showed different
population-based, the effects of the occupation predominance of ICD or ACD in the different
may be diluted within the other types of eczema occupational groups (Diepgen et al. 1995). Since
and, therefore, less evident (Thyssen et al. 2010a). cases of irritant dermatitis tend to be less severe
A recent review found that the rates of ICD are and chronic than those of ACD, the latter may
higher than ACD in most studies on occupational outnumber the former in specialized occupational
contact dermatitis (OCD) (Keegel et al. 2009). dermatology clinics (Kanerva et al. 1988). More
The reviewed epidemiology data were strongly information on the epidemiology of ICD and
influenced by the method of information gather- OCD are given in ▶ Chap. 8, “Surveillance in
ing in each country, reporting systems, Occupational Contact Dermatitis.”
7 Risk Factors Genetic factors other than atopy may contrib-

ute to the susceptibility to hand eczema (all types),
A number of individual factors for irritant derma- according to twin studies (Bryld et al. 2003;
titis have been identified. Although occupational Lerbaek et al. 2007). Patch testing of twins with
irritant hand dermatitis is more frequent in women three model irritants in the past suggests that for
(Meding 2000), no sex difference of irritant reac- some irritants, there might be a genetic predispo-
tivity could be established experimentally (Hogan sition for the higher susceptibility (Holst and
et al. 1990; Thyssen et al. 2010a). It is suspected Moller 1975).
that the increased exposure to irritants at home Filaggrin mutations could be additional genetic
accounts for the higher prevalence in women factors. The insufficient or absent function of
(Meding 2000). This is supported by the observa- filaggrin leads to xerosis and impairment of the
tion that caring for children under the age of stratum corneum barrier function and is a known
4 years and the lack of dish washing machine predisposing factor for atopic dermatitis (de Jongh
significantly increased the risk of contracting et al. 2008b). Filaggrin loss-of-function mutations
hand eczema in a population of female hospital were linked to an increased risk of occupational
workers (Nilsson 1986). Irritant reactivity chronic irritant contact dermatitis, but it is still
declines with increasing age. This is true not unclear if it is a risk factor independent from
only for acute but also for cumulative irritant atopy (de Jongh et al. 2008b). Another study
dermatitis (Suter-Widmer and Elsner 1996). In found an association between filaggrin mutations
population studies on hand eczema, there was a and a particular type of chronic hand eczema,
trend of declining frequency with age (Thyssen a combined form of allergic and irritant contact
et al. 2010a). The self-reported rates of hand dermatitis (Molin et al. 2009). Genes involved in
eczema were the highest for women in their the skin barrier function, inflammatory response,
twenties. The prevalence among men was less and biotransformation of xenobiotics determine the
age-dependent, but there was also a declining individual susceptibility for occupational contact
trend with age (Thyssen et al. 2010a). Atopy is dermatitis (Kezic et al. 2009). More on the genetic
probably the best established risk factor for irritant predictors is given in ▶ Chap. 110, “Genetic Iden-
hand dermatitis (Meding and Swanbeck 1990; tification of Individuals with Increased Risk of
Diepgen 2003; Nicholson 2011). It has to be Developing Occupational Skin Diseases.”
stressed, however, that respiratory manifestations Prediction of the individual susceptibility to
of atopy seem to be less predictive of irritant irritation by means of bioengineering testing
reactivity compared with a skin manifestation. In with model irritants, such as DMSO (dimethyl
a study with metal worker trainees, it was the sulfoxide) and sodium hydroxide, has been
personal history of flexural eczema in the past, attempted, but the correlations were weak and no
rather than the total atopic score, which indicated single test was found to be sufficient by itself
an increased risk of occupational contact dermati- (Bangha et al. 1996). A combination of tests
tis (Berndt et al. 2000). On the level of the indi- showed better results (Berndt et al. 1999). It is
vidual, there remains considerable uncertainty in generally considered that, with a few exceptions,
the prediction of irritant reactivity. As was shown the higher sensitivity to a given irritant does
in a Swedish study, about 25% of the atopics in not predict sensitivity to other irritants (Marriott
extreme risk occupations, such as ladies’ hair- et al. 2005), perhaps due to the high inter-
dressers and nursing assistants, did not develop personal variability in the sensitivity to irritants
hand eczema (Rystedt 1985). Because of the coex- (Robinson 2001). Further details are provided in
istence and overlapping between atopy and the ▶ Chap. 106, “Prediction of Skin Irritation by
various types of contact dermatitis, an extensive Noninvasive Bioengineering Methods.”
diagnostic program has been recommended in all The influence of lifestyle factors has been
cases of chronic dermatitis (Spiewak 2012; investigated in hand eczema in the general popu-
Diepgen et al. 2009a). lation (Thyssen et al. 2010a). No association with
alcohol consumption was consistently found, and allergic contact dermatitis remains challeng-
while for smoking there are controversies and ing, especially in the chronic state. The two con-
some studies have reported such an association ditions may often coexist (Ale and Maibacht
(Thyssen et al. 2010b). 2010). Irritant dermatitis may be diagnosed if
The incidence of ICD correlates with irritant patch tests remain negative, if there is an exposure
exposure of the workers in a given profession to irritants, and if the disease develops and
(Goldner 1994). Some high-risk occupations heals, depending on the frequency and intensity
are caterers (Wood and Greig 1997), construc- of the irritant exposure. However, many allergens
tion workers (Avnstorp 1996), hospital workers, are also good irritants and may confuse the inter-
nurses (Kassis et al. 1984), cleaners, kitchen pretation of patch testing (Moshell 1997). The
workers, hairdressers (Diepgen and Coenraads interplay of ICD with ACD and atopy to produce
1999; Dickel et al. 2001), and metal workers the clinical picture of hand eczema was demon-
(Elsner et al. 1995; Wigger-Alberti et al. 1997). strated in a study which gathered data from ten
Recently, apart from chemical irritants, European patch-test clinics and proposed a rele-
additional important risk factors for the develop- vant classification of the subdiagnoses of hand
ment of occupational hand dermatitis in eczema (Diepgen et al. 2009b). ICD was the sub-
metal worker trainees have been examined: diagnosis of 21.5% of patients, ICD + ACD in
atopic disposition, mechanical irritation, and 15.2%, and ICD + atopic hand eczema in 7.8%
insufficient amount of skin regeneration time (Diepgen et al. 2009b).
(Berndt et al. 2000). Generally, occupations Since cumulative ICD may become chronic
involving “wet work” are especially prone to in a later stage, the relation between exposure
irritant dermatitis. The various occupational and disease tends to weaken. Histologic examina-
groups were classified into “exceedingly high tion of a biopsy cannot differentiate between
risk” and “high risk” according to the yearly chronic irritant and allergic or atopic dermatitis.
incidence of occupational skin disease (all However, chronic ICD differs morphologically
types), reported to the compulsory system in from acute ICD (Willis 1996). Immunohistologic
Germany (Dickel et al. 2001). Some occupations staining has not shown any significant differ-
in the exceedingly high group were hairdressers ences in the inflammatory infiltrate of chronic
and barbers, bakers, florists, health-care irritant and allergic dermatitis (Brasch et al.
workers, machinists, metal-surface processors, 1992). Detection of antigen-specific T cells in
and others. The high-risk group included cooks, the skin and/or in the blood, particularly by
painters, metal processors, mechanics, house- enzyme-linked immunospot assay (ELISPOT),
keepers and cleaners, and others (Dickel et al. has been proposed as a new tool enabling the
2001). More detailed lists of specific occupa- immunobiological diagnosis of allergic contact
tional hazards are given in the chapters with job dermatitis (Nosbaum et al. 2009). Whereas
descriptions. a biopsy may be helpful to exclude palmar psori-
asis, psoriasis can usually be excluded or con-
firmed on clinical grounds that consider sharply
8 Diagnosis demarcated hyperkeratotic or pustular lesions in
contrast to the fuzzy borders of eczema while
ICD has to be diagnosed by excluding other searching for other features such as nail and
causes of contact and endogenous dermatitis. scalp involvement.
While this is more easily done on the basis of Visual evaluation of skin erythema and
signs and symptoms for acute ICD, it is usually surface changes is still widely used to assess
more difficult for cumulative irritant dermatitis. irritant reactions. However, various noninvasive
ACD, which tends to show spreading papules and techniques have been developed that permit
vesicles, is the most important diagnosis to be objective evaluation of skin changes compared
excluded. The differentiation between irritant to a visual assessment (Fluhr et al. 2001). The
bioengineering techniques such as measuring concerns, and the availability of newer therapies
transepidermal water loss as an indicator of (Warner and Cruz Jr 2008). Bacterial superinfec-
epidermal barrier function are well suited to tion may be a complication of contact dermatitis;
detect minute epidermal barrier impairment it is treated with topical or systemic antibiotics.
earlier than clinical examinations and to assess Potential irritants not only in the workplace
the grade of dermatitis quantitatively. However, but also in the home environment, such as
they are not useful in making a safe differential irritant cleansing products, must be identified
diagnosis between ACD and ICD. They and whenever possible eliminated (Diepgen
rather offer the possibility to evaluate inflamma- et al. 2009a).
tion parameters such as redness, scaling, and The treatment modalities for contact dermatitis
infiltration objectively and to quantify these influence the barrier function repair. While both
reactions. topical and systemic corticosteroids and retinoids
such as alitretinoin have negative effects, the top-
ical calcineurine inhibitors allow normal recovery,
9 Treatment and Prognosis and UV-phototherapy upregulates the barrier
function of the skin. A key component of the
Avoiding the irritant(s) remains the basis of therapy of ICD is the basic topical therapy with
treating occupational ICD. This is achieved emollients (see ▶ Chap. 97, “Emollients: Effects,
through technical measures (exchange of working Evidence, and Side Effects”). It has been shown to
substances, encapsulation of irritating fluids), promote the healing of dermatitis and the restora-
individual skin protection (gloves, protective tion of the skin barrier. Besides the use of protec-
suits, protective creams), and, if necessary, sick tive (barrier) creams and emollients, many other
leave until the epidermal barrier has completely anti-irritant agents are being investigated as pos-
regenerated. The epidermal barrier recovery may sible therapy for irritant contact dermatitis (Zhai
be a lengthy process, especially in cumulative and Maibach 2012).
irritant dermatitis. For example, a study on tertiary Prognosis for acute ICD is good if irritant
individual prevention foresees a period of 6 weeks contact is avoided. Cumulative irritant dermatitis,
(3 weeks inpatient treatment, followed by addi- however, has a doubtful prognosis. The prognoses
tional 3 weeks off-work) for patients with chronic of occupational and nonoccupational contact der-
occupational contact dermatitis in order to pro- matitis, ICD, and ACD are often compared in
mote recovery (Skudlik et al. 2009). review articles. The conflicting conclusions may
The use of topical corticosteroids in the suc- be due to the improved response to therapy over
cessful treatment of ACD has been questioned time (Belsito 2005) or to the fact that the various
in irritant dermatitis (van der Valk and Maibach subtypes of ICD have different prognoses, for
1989). They may be effective in chronic, hyper- example, cumulative ICD has a worse prognosis
keratotic irritant dermatitis, but their prolonged than ACD or acute ICD (Belsito 2005). According
use may lead to epidermal atrophy and conse- to Cahill et al., the prognosis is more likely to be
quently increased irritant sensitivity (see also poor for occupational ACD than for ICD in gen-
▶ Chap. 95, “Topical and Systemic Corticoste- eral (Cahill et al. 2004), although other opinions
roids”). Other therapeutic options recommended are also published. The prognoses of ICD and
by the published guidelines include topical tars, ACD were reported to be similar by Hogan et al.
calcineurine inhibitors, phototherapy (UVB or (1990). According to Goh, most studies appear to
PUVA), and retinoids (Diepgen et al. 2009a; indicate that patients with ICD have a poorer
English et al. 2009). In difficult cases of chronic prognosis than those with ACD (Goh 1997).
irritant hand dermatitis, radiation therapy may be A reason could be that in allergic dermatitis, a
indicated but it is ever less frequently used or even specific causative allergen can be identified and
obsolete in some countries due to the need for avoided and the specific cause of ICD is often
licensed equipment and personnel, the safety unknown.
A well-known factor that causes a poor and the benefit of skin care (Itschner et al. 1996).
prognosis of ICD is the existence of atopic der- Considering this finding, it seems urgent to inten-
matitis (Hogan et al. 1990). It contributes to the sify health and safety education in high-risk
poor prognosis through a higher susceptibility workplaces.
to irritation and probably a slower healing The general scheme of prevention in public
(Chew and Maibach 2003). It is considered health divides it into primary, secondary, and ter-
that atopic workers more frequently continue to tiary prevention, and this classification is trans-
suffer from persistent hand dermatitis even after ferred to OCD as well. Primary prevention tries to
changing the job (Belsito 2005). The term “per- prevent the development of disease in the healthy
sistent post-occupational dermatitis (PPOD),” individual. Secondary prevention is targeted at the
with pertinent criteria, has been proposed for the diseased individual trying to inhibit a relapse of
cases where the dermatitis has the tendency to contact dermatitis. In tertiary prevention (rehabil-
persist, even when all conceivable triggering itation), a chronically diseased patient is treated
causes have been removed (Wall and Gebauer and reintegrated into the working environment
1991; Sajjachareonpong et al. 2004). For exam- (Wigger-Alberti and Elsner 1997).
ple, metal workers with cutting fluid dermatitis A Cochrane systematic review found no suffi-
took up to several years to recover despite job cient evidence for the effectiveness of most of
change and avoidance of irritants (Elsner et al. the interventions used in the primary prevention
1995). This stresses the importance of early inter- of occupational irritant hand dermatitis (Bauer
vention in irritant dermatitis before it reaches the et al. 2010).
chronic stage. Prevention of ICD requires an integrated
The influence of job change on the prognosis approach that considers both the exposure and the
of occupational contact dermatitis (all types) has exposed individual. The responsibility for primary
been assessed in various studies over decades prevention rests mainly with manufacturers and
(Hogan et al. 1990; Cahill et al. 2004; Belsito producers of chemicals and products, government
2005). These studies revealed that a job change agencies, consumer organizations, industrial physi-
did not affect the course of the disease; the cians and nurses, and safety engineers. A multi-
workers with OCD who change jobs often have dimensional approach with eight basic elements
reasons other than dermatitis and that the social of prevention planning has been proposed by
prognosis without a job change might be better Mathias (1990): recognition of potential cutaneous
despite ongoing OCD (Hogan et al. 1990; Cahill irritants and allergens, engineering controls or
et al. 2004; Belsito 2005). More information on chemical substitution to prevent skin exposure,
the prognosis of ICD is given in ▶ Chap. 103, personal protection with appropriate clothing or
“Prognosis of Irritant Contact Dermatitis.” protective creams, personal and environmental
hygiene, regulation of potential allergens and irri-
tants within the workplace, educational efforts to
10 Prevention promote awareness of potential allergens and irri-
tants, motivational techniques to promote safe
Considering the high incidence of ICD at the work conditions and practices, and preemployment
workplace, preventive measures play an impor- and periodic health screening.
tant role. In order to increase the awareness of this In the prevention of exposure, the main ele-
health risk and to achieve an optimal compliance ments are technical measures, i.e., avoidance
with the protective measures, employees should of the irritant through its removal from the work-
be adequately instructed already at the start of place or through technical shielding by the
their training. It was shown in a study on the risk use of potent irritants in closed systems or
behavior that metal working apprentices were automation, irritant replacement or removal
very poorly informed about skin diseases, the (Lachapelle 1995), and personal protection of
potential risk of hand eczema at the workplace the workers (Wigger-Alberti and Elsner 1998).
On the individual’s side, screening for predispo- Cahill J, Keegel T et al (2004) The prognosis of occupa-
sition to irritant dermatitis and counseling of sen- tional contact dermatitis in 2004. Contact Dermatitis
51(5–6):219–226
sitive individuals may be appropriate preventive Chew AL, Maibach HI (2003) Occupational issues of
measures. More on the prevention of occupational irritant contact dermatitis. Int Arch Occup Environ
dermatoses is given in the dedicated section in Health 76(5):339–346
this book. Chew A-L, Maibach HI (2006) Ten genotypes of irritant
contact dermatitis. In: Chew A-L, Maibach HI (eds)
Irritant dermatitis. Springer, Berlin, pp 5–9
Clemmensen A, Andersen KE et al (2010) Genome-wide
expression analysis of human in vivo irritated epider-
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Chemical Skin Burns
13
Audris Chiang, Magnus Bruze, Sigfrid Fregert, and
Birgitta Gruvberger
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
4 Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
5 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
6 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
7 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
8 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
9 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Sigfrid Fregert: deceased.

A. Chiang (*)
Department of Dermatology, University of California
Medical School, San Francisco, CA, USA
e-mail: audrischiang@berkeley.edu
M. Bruze
Department of Occupational and Environmental
Dermatology, Skåne University Hospital, Malmö,
Lund University, Malmö, Sweden
e-mail: magnus.bruze@med.lu.se
S. Fregert
Malmö, Sweden
B. Gruvberger
Department of Occupational and Environmental
Dermatology, Skåne University Hospital Malmö, Lund
University, Malmö, Sweden
e-mail: birgitta.gruvberger@med.lu.se

https://doi.org/10.1007/978-3-319-68617-2_13
140 A. Chiang et al.
10 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Keywords including a fatal outcome, depending on exposure

Calcium gluconate gel · Chemical skin burns · conditions and the incriminating agent. For these
Eczematous dermatitis · Hypopigmentation · reasons it is important for the physician to have
Neutralizing solutions knowledge of corrosive chemicals as well as of
chemical burns with regard to their clinical man-
ifestations, specific medical treatments, and pre-
1 Core Messages
ventive measures.
• Chemical skin burns are common in industry
but can also occur in non-work-related
environments. 3 Definition
• Chemical burns from household products may
not be noticeable, but oftentimes the cause of a A caustic burn (chemical burn) is an acute, severe
burn is obvious and medical treatment is not irritant reaction by which the cells have been dam-
sought. aged to a point where there is no return to viability;
• Usually chemical burn damage is minimal, but in other words, a necrosis develops (Stewart 1985;
some chemical burns have risk of complica- Sykes et al. 1986; Cartotto et al. 1996). One single
tions and long-term disabilities. skin exposure to certain chemicals can result in a
• The severity of a burn can be diminished if chemical burn. These chemicals react with intra-
treated properly and promptly. and intercellular components in the skin. However,
• It is important for physicians to understand corro- the action of toxic (irritant) chemicals varies, caus-
sive chemicals as well as chemical burns in regard ing partly different irritant reactions morphologi-
to their clinical manifestations, mechanism, med- cally. They can damage the horny layer, cell
ical treatment, and preventive measures. membranes, lysosomes, mast cells, leukocytes,
DNA synthesis, blood vessels, enzyme systems,
and metabolism. The corrosive action of chemicals
2 Introduction depends on their chemical properties, concentra-
tion, pH, alkalinity, acidity, temperature, lipid/
Chemical skin burns are particularly common in water solubility, interaction with other substances,
industry, but they also occur in non-work-related and duration and type (e.g., occlusion) of skin
environments. Occupationally induced chemical contact. It also depends on the body region, previ-
burns are frequently noticed when visiting and ous skin damage, and possibly on individual resis-
examining workers at their work sites. Corrosive tance capacity.
chemicals used in hobbies are an increasing cause Many substances cause chemical burns only
of skin burns. Disinfectants and cleansers are when they are applied under occlusion from, for
examples of household products which can example, gloves, boots, shoes, clothes, caps, face
cause chemical burns. However, in most cases, masks, adhesive plasters, and rings. Skin folds may
the cause of a chemical burn is obvious to the be formed and act occlusively in certain body
affected persons, and damage is minimal and regions, e.g., under breasts and in the axillae.
heals without medical care, so medical attention Many products, which under ordinary skin expo-
is not sought. Sometimes the chemical burns are sure conditions cause weak irritant reactions or
severe and extensive, with the risk of complica- irritant contact dermatitis, can under occlusion
tions and long-term disability. In the acute stage, cause chemical burns, e.g., detergents, emulsifiers,
there is a varying risk of systemic effects, solvents, plants, woods, topical medicaments,
13 Chemical Skin Burns 141
toiletries, insecticides, pesticides, preservatives, acid-base reaction, redox reaction, chelation,

cleansers, polishes, plastic monomers, and portland addition, substitution, and solvation. Depending
cement. Wet cement can usually be handled with- on the type of elementary reaction, different
out causing a chemical burn, but when present types of entities are exchanged: electrons for
under occluding clothes for some hours, it can redox reactions, ions for acid-base and chelating
cause severe skin damage, e.g., on knees. White reactions, and atoms or molecules for additions
spirit causes only slight dryness at open application and substitutions.
but causes blisters under occlusion. Acid-base and redox reactions modify the bal-
There are different mechanisms for reactions ances of chemical reactivity.
between skin components and agents causing For acid-base reactions, protons are exchanged
chemical and thermal burns. Chemical agents until reaching an equilibrium pH. Given the con-
cause progressive damage until either no more centration and pK of a substance, it is possible to
chemical remains unreacted in the tissue or the predict the resulting degree of irritability. Above a
agent is inactivated by treatment, while thermal certain threshold concentration and pK lower than
damaging effects cease shortly after removal of 4 or above 10, a burn will develop from the
the heat source. aggressor substance. Levels of cellular structures
The most commonly reported chemicals that are successively destroyed from the surface down-
can cause chemical burns are listed in Table 1. ward until exhaustion of the aggressor molecules.
Acids and alkalis have been grouped separately, An acid with a given energy level pK consumes
as the corrosive effect within the respective group all bases of weaker energy level (with a bigger
is exerted through the same mechanism. These pK) beginning with the weakest base. The transfer
groups contain both strong and weak acids and of H + ions modifies the H +/OH balance of the
alkalis, respectively. The other compounds are chemical environment, thus changing the acidity/
listed together although their corrosive effects basicity of the environment, possibly resulting in
are mediated through different mechanisms. irritation or corrosion.
Most of these compounds are neutral. However, For redox reactions, the oxidizing agent oxi-
some are weak acids or alkalis but are considered dizes reducing agents with weaker potentials than
to be corrosive due to properties other than acidity its own, accepting electrons to complete its orbitals
or alkalinity, respectively. and thus become stable. For example, chlorine
bleaches can cause skin burns. This is because
they contain the strong oxidizer hypochlorite, and
4 Mechanism the by-products of the oxidation reaction are cor-
rosive. Redox reactions, similar to acid-base reac-
A chemical burn occurs when two chemical enti- tions, can generate lesions to tissues.
ties, one acting as the donor and the other as the Addition and substitution reactions modify
acceptor, interact with each other. The strength of biological molecules, for example, by disin-
the aggressor affects the weakness of its biochem- tegrating the 3D configuration of proteins or by
ical target until it consumes it completely, and then coagulation of proteins.
the aggressor continues to attack species of subse- Chelation and solvation cause the disappear-
quently higher energy levels until exhausting its ance of an active entity. For example, the F ion
own concentration. from hydrofluoric acid chelates calcium and mag-
Chemical agents can have corrosive effects nesium ions, changing physiological balance by
on tissues by damaging cytoplasmic membranes, disrupting biochemical metabolisms until cell
by denaturing or coagulating proteins, or by che- death and, consequently, tissue necrosis occurs.
lating trace elements essential to cellular Burgher provides significant detail for
function. eye burns (Burgher et al. 2011); the principles
Six types of elementary reactions delineate delineated above probably relate equally to
the possible mechanisms of a chemical burn: the skin.
Table 1 Agents causing chemical burns. The chemicals features strong corrosive substances and also less irritating
listed are the most common reported to cause chemical compounds that require special conditions, for example,
burns in industries, hobbies, and households. The list occlusion, to cause chemical burns
Acids Alkalis Miscellaneous
Acetic acid Amines Acetyl chloride
Acrylic acid Ammonia Acrolein
Benzoic acid Barium hydroxide Acrylonitrile
Boric acid Calcium carbonate Alkali ethoxides
Bromoacetic acid Calcium hydroxide Alkali methoxides
Chloroacetic acids Calcium oxide Allyl diiodine
Chlorosulfuric acid Hydrazine Aluminum bromide
Fluorophosphoric acid Lithium hydroxide Aluminum chloride
Fluorosilicic acid Potassium hydroxide Aluminum trichloride
Fluorosulfonic acid Sodium carbonate Ammonium difluoride
Formic acid Sodium hydroxide Ammonium persulfate
Fumaric acid Sodium metasilicate Ammonium sulfide
Hydrobromic acid Antimony trioxide
Hydrochloric acid Aromatic hydrocarbons
Hydrofluoric acid Arsenic oxides
Lactic acid Benzene
Nitric acid Benzoyl chloride
Perchloric acid Benzoyl chlorodimethylhydantoin
Peroxyacetic acid Benzoyl chloroformate
Phosphonic acids Borax
Phosphoric acids Boron tribromide
Phthalic acids Bromine
Picric acid Bromotrifluoride
Propionic acid Calcium carbide
Salicylic acid Cantharides
Sulfonic acids Carbon disulfide
Sulfuric acid Carbon tetrachloride
Tartaric acid Chlorhexidine gluconate
Toluenesulfonic acid Chlorobenzene
Trifluoroacetic acid Chlorinated acetophenones (tear gas)chlorinated solvents
Chloroform
Chlorocresols
Chlorophenols
Chromates
Chromium oxychloride
Chromium trioxide
Cresote
Cresolic compounds
Croton aldehyde
Dichloroacetyl chloride
Dichromates
Dimethyl acetamide
Dimethyl formamide
Dimethyl sulfoxide (DMSO)
Dioxane
Dipentene
Dithranol
Epichlorohydrine
Epoxy reactive diluents
Ethylene oxide
Ferric chloride hexahydrate
Fluorides
Fluorine
Fluorosilicate
(continued)
Table 1 (continued)
Formaldehyde
Gasoline
Gentian violet
Glutaraldehyde
Halogenated solvents
Hexylresorcinol
Iodine
Isocyanates
Kerosene fuel
Limonene
Lithium
Lithium chloride
Mercury compounds
Methylchloroisothiazolinone
Methylenedichloride
Methylisothiazolinone
Morpholine
Perchloroethylene
Peroxides
Benzoyl
Cumene
Cyclohexanone
Hydrogen
Methylethylketone
Potassium
Phenolic compounds
Phosphorus
Phosphorus bromides
Phosphorus chlorides
Phosphorus oxychloride
Phosphorus oxides
Piperazine
Potassium
Potassium cyanide
Potassium difluoride
Potassium hypochlorite
Potassium permanganate
Povidone iodine
Propionic oxide
Propylene oxide
Quarternary ammonium compounds
Reactive diluents
Sodium
Sodium borohydride
Sodium difluoride
Sodium hypochlorite
Sodium sulfite
Sodium thiosulfate
Styrene
Sulfur dichloride
Sulfur dioxide
Sulfur mustard
Thioglycollates
Thionyl chloride
Tributyltin oxide
Trichloroethylene
(continued)
Table 1 (continued)
Turpentine
Vinyl pyridine
White spirit
Zinc chloride
reactions which first appear several hours, or

5 Diagnosis
even a day, after the exposure.
Strong acids coagulate skin proteins, and fur-
It is usually easy to arrive at a diagnosis of chem-
ther penetration is decreased by the barrier
ical skin burn, as the symptoms are easily recog-
formed. Some common toxic chemicals affect
nized and the exposure to a corrosive agent
the skin in a special way (Kuniyuki and Oonishi
obvious. However, sometimes the exposure is
1997). Principally, all strong acids give the same
concealed, at least initially. For example, hospital
symptoms and major features, including ery-
personnel may be exposed to ethylene oxide,
thema, blisters, and necrosis. Some acids discolor
which may remain in gowns and straps after ster-
the skin, e.g., producing a yellow color from nitric
ilization (Biro et al. 1974), and cleaners may
acid. Sulfuric acid, as an example, dehydrates the
occasionally be exposed to a corrosive agent con-
skin by creating excessive heat in the tissue, pro-
taminating nonhazardous objects in a laboratory.
ducing coagulation necrotic eschars with throm-
Corrosive substances under occlusion may also, at
bus formation in the lesion’s microvasculature
least initially, confuse and delay the diagnosis.
(Flammiger and Maibach 2006). The action of
Occasionally, a chemical burn can mimic other
hydrofluoric acid in the skin differs from other
dermatoses, e.g., ethylene oxide can mimic bul-
strong acids (Vance 1990; Kirkpatrick et al.
lous impetigo.
1995). It causes liquefaction necrosis, and the
penetration may continue for days. When an area
above 1% of the total body surface is affected,
systemic effects can arise. In the skin, this acid
6 Clinical Features causes much stronger pains than other acids.
Diluted hydrofluoric acid can cause pain starting
Not only the skin but also the eyes, lips, mouth, several hours or even a day after the exposure. For
esophagus, nose septum, glottis, and lungs can example, when bricklayers use this acid at a con-
be directly affected. As a result of resorption, centration of 10–30% for rinsing brick walls, it
toxic chemicals can damage the blood, bone may penetrate into their nail beds and, thereby,
marrow, liver, kidneys, nerves, brain, and other cause severe pain after several hours. The strong
organs. The most common locations of chemical pain is due to the capacity of fluorine ions to bind
burns on the skin are the hands and face/neck, calcium in the tissue, which affects the nervous
but the whole body can be affected. The expo- system. Hydrofluoric acid can penetrate to the
sure usually occurs by accident. However, occa- bone and cause decalcification there. Also, fluo-
sionally, a chemical burn is the result of rides and fluorosilicic acid can give the same types
malingering. The major symptoms are burning of symptoms.
and smarting. Morphologically, chemical burns Alkalis often cause more severe damage than
are characterized by erythema, blisters, erosions, acids, except hydrofluoric acid (Gelmetti and
ulcers, and necrosis with surrounding erythema. Cecca 1992; Winemaker et al. 1992; Beausang
Usually, the symptoms develop immediately or and Herbert 1994). The necrotic skin first
in close connection to exposure, but certain appears dark brown and then changes to black.
chemicals, such as phenols, weak hydrofluoric Later, skin becomes hard, dry, and cracked. Gen-
acid, and sulfur mustard gas, can give delayed erally, no blisters appear in the skin. Alkalis split
proteins and lipids, and there is a saponification Ethylene oxide gas used for sterilization of
of the released fatty acids. The emulsifying surgical instruments, textile, and plastic material
effect of the soap formed facilitates further pen- can remain in these objects for several days if not
etration of the alkali into deeper layer of the skin. ventilated well enough (Biro et al. 1974; Fisher
Chemical burns from alkaline chemicals are 1990). Thus, when hospital personnel handle such
more painful than from acids, except from objects, there is possible exposure to ethylene
hydrofluoric acid. Because of its alkalinity, oxide, which is not obvious, and the symptoms,
cement mixed with water can cause acute ulcer- including erythema, edema, and large bullae, may
ative damage (Stoermer and Wolz 1983; therefore be misdiagnosed as another skin disease.
McGeown 1984; Lane and Hogan 1985; Fisher Accidental skin exposure to chemicals under high
1986; Onuba and Essiet 1986; Tosti et al. 1989; pressure, for example, hydraulic oil, can result in
Adams 1990; Morley et al. 1996). Severe skin deep penetration into the skin, where a chemical
damage has involved the lower limbs, often after burn with necrosis can develop.
kneeling on wet concrete or when it gets inside
boots or shoes. Sometimes, necrotic skin appears
8–12 h after exposure. Rarely, hands can also be 7 Treatment
affected, particularly when the insides of gloves
have been contaminated. The alkalinity can also Repair cannot proceed until the responsible agent
vary considerably between batches from the is inactivated by chemical reaction with tissues,
same cement factory. neutralized, or removed. As long as the chemical
Phenolic compounds such as phenol, cresol, is present, tissue destruction will continue, so skin
chlorocresol, and unhardened phenolic resins pen- decontamination is important (Flammiger and
etrate the skin easily and can damage peripheral Maibach 2006). Rinsing with water is the first-
nerves, resulting in insensibility. Sometimes, aid treatment; preferably, tepid running tap water
peripheral nerves can be affected without visible should be used. Irrigation should not be done at
damage to the skin. After exposure to phenolic high pressure, as the corrosive agent may be
compounds, the local blood vessels become splashed onto other parts of the body or on the
constricted, which can contribute to the develop- persons treating the burn. It is important that the
ment of the necrosis. Shock and renal damage can treatment starts immediately after exposure and
appear after absorption of phenolic compounds that copious volumes of water be supplied, some-
(Lin and Yang 1992; Horch et al. 1994; Shibata times for hours. Occasionally, chemical burns are
et al. 1994). caused by corrosive substances insoluble in water;
Sulfur mustard, 2,20 -dichlorodiethyl sulfide, therefore, a solution of water and soap should
is a chemical warfare agent (Newman-Taylor frequently be used instead. However, sometimes
and Morris 1991; Smith and Dunn 1991; Ruhl specific antidotes for certain types of chemical
et al. 1994). It has been dumped into the sea, and burns are required. Clothes, watches, rings,
fishermen have been injured when leaking con- shoes, etc. can be contaminated with the corrosive
tainers get in their nets. The chemical is a vis- agent, so they should be removed.
cous liquid below and a gas above 14 C. On the Theoretically, neutralizing solutions should be
skin, the liquid causes blisters and necrosis an alternative treatment to water after exposure to
10–12 h after skin exposure. The gas attacks acids and alkalis (Dunn et al. 1992; Yano et al.
mainly the eyes and the respiratory organs. 1994; Erdmann et al. 1996). However, neutraliza-
Sometimes the skin is also affected by direct tion of the corrosive agent with weak acids/bases
contact with the gas, and the chemical burn is not recommended for two reasons: (1) irrigation
then clinically appears 3–6 h after exposure; should not be delayed while waiting for a specific
initial redness is followed by blisters and antidote – immediate irrigation provides the best
ulcers. Tear gas can give a bullous dermatitis removal of the agent, and (2) neutralization of the
(Zekri et al. 1995). corrosive agent may produce an exothermic
reaction, and the heat can cause further damage powder. The powder is mixed with 20 ml of a
(Sawhney and Kaushish 1989). water-soluble lubricant to create a slurry. This
Heat is generated when strong sulfuric and calcium preparation is applied repeatedly to the
phosphoric acids are exposed to water; hence, a skin until the pain has disappeared. Necrotic
thermal burn can add to the chemical burn. Even tissue should be excised, blisters debrided, and
so, an experimental study by Davidson found the underlying tissue treated with the calcium
less skin injury when the agent, sulfuric acid, preparation. Nails should be removed if
was removed by dilution with water when com- the acid penetrates to the nail bed and matrix
pared to treatment with neutralizers (Davidson and causes severe pain there. If there is no effect
1927). Thus to prevent a burn, it is important that of the topical treatment within 2 h, 10% calcium
copious volumes of running water be applied. gluconate (0.5 ml/cm2) should be injected
However, water is contraindicated in into and under the lesions. No anesthetics
extinguishing burning metal fragments of should be given, since the disappearance of
sodium, potassium, and lithium, because a pain is a sign of successful treatment. Without
chemical burn can be caused by hydroxides treatment, the burn can increase in depth for
formed when water is added to hot metals. several weeks.
These metals spontaneously ignite when Superficial chemical burns from chromic acid
exposed to water. To extinguish the burning with an area greater than 1% of the total body
metal, sand can be used. The burn should then surface imply a high risk of systemic damage to
be covered with cooking or mineral oil to isolate many organs, including erythrocytes (Terrill and
the metal from water. Metal pieces should be Gowar 1990). Therefore, immediate irrigation of
mechanically removed. Embedded pieces should the burn with copious volumes of water is neces-
be removed surgically. First, though, the area sary. Thereafter, and within 2 h after the exposure,
should be irrigated with water to prevent an all burnt tissue must be excised. To remove circu-
alkali burn from the hydroxides already formed lating chromium, peritoneal dialysis has to be
from the metal and water naturally present in carried out during the first 24 h. Solid particles
the skin. of lime, cement, and phosphorus, for example,
Skin exposed to hydrofluoric acid should be tend to fix to the skin and should be mechanically
carefully irrigated with copious volumes of run- removed before or during irrigation.
ning tap water as soon as possible. The results of Phosphorus, above all white phosphorus, is
a study by Bromberg et al. on the effect of a 1 h oxidized by air and can ignite spontaneously,
water irrigation on hydrochloric acid burns in thus causing thermal burns (Kaufman et al.
mice showed that less severe burns were noted 1988; Eldad and Simon 1991; Eldad et al. 1992;
when treatment began immediately, and severity Eldad et al. 1995). In water, oxidized phosphorus
of burns worsened with greater delay in treat- is transformed into phosphoric acid, which can
ment, even with 5 s intervals (Bromberg et al. cause a chemical burn; therefore, it is important
1965). After water irrigation, the target site then to remove particles mechanically before washing
should be treated with calcium gluconate gel with soap and water. The skin is then washed with
(2.5%) by massaging into the burned skin for at 1% copper(II) sulfate in water, which reacts with
least 30 min (“K-Y Jelly,” Johnson and Johnson phosphorus to form black copper phosphite,
Products, Inc., New Brunswick, NJ, USA) which makes any remaining phosphorous visible
(Anderson and Anderson 1988; Chick and and thus easily removable. Wet dressings of cop-
Borah 1990; Seyb et al. 1995; Dunn et al. per sulfate should never be applied to wounds
1996). The calcium gluconate gel can also be because of the risk of systemic copper poisoning.
made by mixing 3.5 g calcium gluconate with To minimize the copper absorption, a water solu-
150 g of a water-soluble lubricant. A variation of tion of 5% sodium bicarbonate and 3% copper
this treatment is suggested – ten 10 g tablets of sulfate suspended in 1% hydroxyethyl cellulose
calcium carbonate (648 mg) crushed to a fine can be used for irrigation instead of the 1% copper
sulfate solution. However, it should be stressed blood-vessel compression. The best method for
that copper is a potentially toxic substance, which treating the black, adherent necrotic tissue caused
can cause systemic effects. Copper sulfate must by cement and other toxic compounds is excision.
therefore be used only for a few minutes in order For example, the healing time of cement burns on
to visualize phosphorous, and, after mechanical knees can be diminished from 8–10 weeks to
removal of the phosphide, it is important to irri- 3 weeks if the necrotic tissue is excised.
gate the skin with water. Several chemicals can also produce systemic
Skin contaminated with bromine or iodine effects without severe skin injury, e.g., phenolic
should be washed frequently with soap and compounds, hydrofluoric acid, chromic acid, sulfur
water and treated with 5% sodium thiosulfate, mustard, and gasoline (Andersen 1990; Chan et al.
which reacts with bromine and iodine, forming 1995). When the chemical burn is not minimal,
ions less hazardous to the skin (White and Joseet there is risk of systemic damage, and an analysis
1990; Corazza et al. 1997). including hematological screening and liver and
Skin contaminated with phenolic compounds kidney function should be made both at the first
can initially be washed with soap and water and examination and then later in the course of treat-
treated as early as possible with undiluted poly- ment, depending on the intensity and extension of
ethylene glycol 300 or 400, or with 10% ethanol, the chemical burn as well as on the results of the
which all dissolve phenolic compounds (Lin and laboratory investigations. These analyses are
Yang 1992; Horch et al. 1994; Shibata et al. 1994). performed mainly to enable precautions and mea-
Tissues with deep damage from phenolic com- sures necessary to prevent and diminish damage to
pounds should be excised immediately, as the internal organs, in addition to legal reasons.
compounds easily penetrate further with subse- Patients with severe and extensive skin dam-
quent damage of, for example, nerves. age and/or with systemic symptoms after expo-
Skin contaminated with sulfur mustard liquid sure to corrosive agents should be treated in
should be treated with a mixture of 75% calcium intensive care units. It should be noted that
hypochlorite and 25% magnesium sulfate for some hydrofluoric acid or chromic acid exposure affect-
minutes before washing with soap and water. Con- ing even 1% of the total body surface of a person
taminated objects should also be treated with this means risk of severe systemic effects. Hospitali-
mixture (Newman-Taylor and Morris 1991; Smith zation is also recommended for persons who have
and Dunn 1991; Ruhl et al. 1994). concurrent illnesses, implying that they are high-
Hot tar, pitch, and asphalt cause burns mainly risk patients, as well as for persons with chemical
due to the heat. They stick to the skin and should burns on the hands, feet, and perineum (Andersen
not be removed mechanically, as the skin can be 1990; Chan et al. 1995).
further damaged and thus increase the risk of
secondary infection. The material falls off spon-
taneously in due time. 8 Complications
Generally, an antibacterial cream should be given
to chemical skin burns to protect the surface and to Chemical skin burns can cause hyper- or hypo-
prevent secondary infection. If there is a significant pigmentation. Chemical burns involving deeper
element of inflammation in non-necrotic areas, a parts of the skin heal with scarring. Tumors of
mild topical corticosteroid preparation can be used. both malignant and benign types may rarely
Frequent examinations of primarily superficial and develop in scars. In the acute stage of chemical
limited burns are also advisable, as they can become burns from, for example, phenolic compounds
deeper in a few days. and hydrofluoric acid/fluorides, the sensory
Surgical treatments, such as excision, nerve system is frequently affected.
debridation of blisters, transplantation, and Many contact sensitizers also have irritant
removal of nails can be of great value. When a properties. Patch testing with such sensitizers at
limb is affected circumferentially, there is a risk of high concentrations can cause an irritant reaction
or a chemical burn, which seems to facilitate hoses or connections with snap couplings. A
active sensitization. However, only a few sensi- non-accidental but unintended exposure may
tizers can cause chemical burns without occlu- occur due to material sterilized with ethylene
sion, e.g., formaldehyde, chromic acid, amines, oxide; thus, the material should be well ventilated
chloroacetophenone, some plastic monomers, and not used until a week after the sterilization
and methylisothiazolinones. Even one single con- procedure. For these reasons, it is important to
tact with these chemicals can both cause a chem- prevent chemical burns via careful planning and
ical burn and induce sensitization, with supervision of the working environment.
subsequent possible development of allergic con-
tact dermatitis (Bruze et al. 1990; Kanerva et al.
1994). Therefore, when a potential sensitizer has 10 Summary
caused a chemical burn, the patient should be
patch tested with the sensitizer after healing of Thousands of chemicals and products can cause
the burn, independent of any subsequent develop- chemical skin burns, some only under special
ment of eczema. circumstances, for example, occlusion. Most
Another type of eczematous dermatitis that can chemical burns are due to accidents, and the
follow after a chemical burn is “post-traumatic majority are occupationally induced, but chemi-
eczema” (Mathias 1988). It can present as discoid cal burns also frequently occur in households
eczema and is a poorly understood complication and while engaged in hobbies. Clinically, a
of skin injuries (Wilkinson 1979). It can appear chemical burn is characterized by erythema, blis-
after either physical or chemical skin injuries, ters, and necrotic skin. Some corrosive
including chemical burns, and is always unrelated chemicals, such as phenolic compounds, sulfur
to infection and topical treatment. mustard, chromic acid, hydrofluoric acid, and
gasoline, may cause systemic effects that require
hospitalization. Other chemical burns, particu-
9 Prevention larly those affecting hands, feet, and perineum,
may also require hospitalization. To prevent and
Employees should be informed of the risks of expo- diminish the damage after exposure to corrosive
sure to corrosive agents and be well trained to agents, it is important to administer immediate
handle the chemicals as well as to act when they treatment. Irrigation with copious volumes of
have been exposed. Showers for rapid irrigation water is a universal remedy, except for treatment
with water should be easily accessible. A 1% copper of burning metal fragments of sodium, potas-
sulfate solution, polyethylene glycol 300 or 400, 5% sium, and lithium. First-aid treatment after expo-
sodium thiosulfate solution, and a proper calcium sure to water-insoluble corrosive agents consists
preparation should be present in the first-aid kit. A of washing with soap and water. Sometimes spe-
calcium preparation for topical treatment should cific antidotes are needed, as for chemical burns
also be present near employees’ work site where from hydrofluoric acid, phenolic compounds,
hydrofluoric acid or fluorides are used. Workers at phosphorous, iodine, bromine, and sulfur mus-
risk should wear proper protective equipment, tard (Table 2). Surgical intervention may be
which may include eye glasses, face masks, gloves, required for certain chemical burns. A few cor-
boots, and safety dresses. rosive compounds are potential sensitizers, and
In industries in which corrosive chemicals are one single exposure to such a compound may
handled, certain procedures frequently lead to cause a chemical burn and induce sensitization
accidents, resulting in exposure to the chemicals. with subsequent allergic contact dermatitis. To
Such procedures include the repairing as well prevent chemical burns, it is important to use as
as charging and discharging of procedure few corrosive agents as possible and, when
vessels, during which chemicals can be spilt and unavoidable, to use the weakest ones possible,
splashed. Accidents can be caused by breakage of particularly in households and while engaged in
Table 2 Treatment for chemical skin burns caused by Corazza M, Bulciolu G, Spisani L et al (1997) Chemical
some specific chemicals burns following irritant contact with povidone-iodine.
Contact Dermatitis 36:115–116
Chemical Treatment
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mustard liquid and 25% magnesium sulfate
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Mechanisms of Allergic Contact
Dermatitis 14
Thomas Rustemeyer, Ingrid M. W. van Hoogstraten,
B. Mary E. von Blomberg, and
Rik J. Scheper
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3 Binding of Contact Allergens to Skin Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4 Hapten-Induced Activation of Allergen-Presenting Cells . . . . . . . . . . . . . . . . . . . . . 156
5 Recognition of Allergen-Modified Langerhans’ Cells by Specific T Cells . . . 159
6 Proliferation and Differentiation of Specific T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
7 Systemic Propagation of the Specific T-Cell Progeny . . . . . . . . . . . . . . . . . . . . . . . . . . 164
8 The Effector Phase of Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
9 Flare-Up and Retest Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
10 Hyporeactivity: Tolerance and Desensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
11 Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Keywords process · Langerhans cells · Prehaptens ·

Activation-induced cell death · Bandrowski’s Prohaptens · Tetrachlorosalicylanilide
base · Effector memory T cells · Imprinting
1 Core Messages
T. Rustemeyer (*) • Allergenicity depends on several factors deter-

Department of Dermatology and Allergology, VU mined by the very physicochemical nature of
University Medical Center, Amsterdam, The Netherlands
e-mail: t.rustemeyer@vumc.nl the molecules themselves, i.e., their capacity to
penetrate the horny layer, lipophilicity, and
I. M. W. van Hoogstraten · B. M. E. von Blomberg ·
R. J. Scheper chemical reactivity. The sensitizing property of
Department Pathology, VU University Medical Center, the majority of contact allergens could be pre-
Amsterdam, The Netherlands dicted from these characteristics (Patlewicz et al.
e-mail: I.vanHoogstraten@vumc.n; 2004; Gerberick et al. 2008). Two other factors,
BME.vonBlomberg@vumc.nl; RJ.Scheper@vumc.nl

https://doi.org/10.1007/978-3-319-68617-2_14
152 T. Rustemeyer et al.
however, further contribute to the allergenicity • The respective contributions of similar subsets of
of chemicals, viz. their pro-inflammatory activ- allergen-specific CD8+ T cells are still unknown,
ity and capacity to induce maturation of but distinct effector roles of allergen-specific Tc1
LC. These issues will be dealt with in more and Tc2 have been postulated.
detail in the following sections. • Priming via the skin results in CLA positive T
• Along with their migration and settling within cells, which upon inflammatory stimuli prefer-
the draining lymph nodes, haptenized LC fur- entially enter the skin; on the other hand, gut
ther mature, as characterized by their increased homing T cells have been primed and gener-
expression of costimulatory and antigen- ated along mucosal surfaces. Upon priming, T
presentation molecules (Cumberbatch et al. cells loose much of their capacity to recirculate
1997; Heufler et al. 1988). In addition, they via the lymph nodes, but gain the capacity to
adopt a strongly veiled, interdigitating appear- enter the tissues. In particular recently acti-
ance, thus maximizing the chances of produc- vated T cells will enter skin inflammatory
tive encounters with naive T lymphocytes sites. ACD reactions are primarily infiltrated
and recognition of altered self (Steinman by CD4 and/or CD8 pro-inflammatory cells,
et al. 1995; Furue et al. 1996; Schuler and later reactions may be dominated by Th2 cells
Steinman 1985). and regulatory T cells. Skin infiltation by T
• The intricate structure of lymph node para- cells is fine-tuned by sets of adhesion mole-
cortical areas, the differential expression of cules and chemokine receptors, whose expres-
chemokines and their receptors, the character- sion is not rigid, but can be modulated by
istic membrane ruffling of IDC, and the pre- micro-environmental factors.
dominant circulation of naïve T lymphocytes • After antigenic activation the progeny of
through these lymph node areas provide opti- primed T cells is released via the efferent
mal conditions for T-cell-receptor binding, i.e., lymphatics into the bloodstream. Circulating
the first signal for induction of T-cell activation allergen-specific cells can be challenged
(Banchereau and Steinman 1998). Intimate in vitro to provide diagnostic parameters for
DC–T-cell contacts are further strengthened contact hypersensitivity. At least for water-
by secondary signals, provided by sets of cel- soluble allergens, like metal salts, the degree
lular adhesion molecules, and growth- of allergen-specific proliferation and cytokine
promoting cytokines (reviewed in Hommel production, in particular type-2 cytokines,
(2004), Cella et al. (1997)). correlate with clinical allergy. For routine
• In healthy individuals, primary skin contacts application of a broad spectrum of allergens,
with contact allergens lead to differentiation culture conditions still need to be improved.
and expansion of allergen-specific effector T For mechanistic in vitro studies in ACD, how-
cells displaying Th1, Th2, and/or Th17 cyto- ever, with selected sets of relatively nontoxic
kine profiles. The same allergens, if encoun- allergens, peripheral blood provides an excel-
tered along mucosal surfaces, favor the lent source of lymphocytes and antigen-
development of allergen-specific Th2 and presenting cells.
Th17 effector cells, and/or Th3 and Tr1 • ACD reactions can be mediated by classical
allergen-specific regulatory T cells. Whereas effector cells, i.e., allergen-specific CD4+
the first two subsets may assist or replace Th1 type-1 T cells which, upon triggering by
cells in pro-inflammatory effector functions, allergen-presenting cells, produce IFN-γ to
the latter two subsets are mainly known for activate nonspecific inflammatory cells like
downregulating immune responsiveness. For macrophages. However, CD8+ T cells, and
most, if not all allergens, along with prolonged other cytokines, including IL-4, IL-17, and
allergenic contacts, the role of Th2 cells as IL-22 can also play major roles in ACD. The
effector cells gradually increases given conspicuous difference with DTH reactions
reduced longevity of Th1 responses. induced by intradermal administration of
14 Mechanisms of Allergic Contact Dermatitis 153
protein antigens, i.e., the epidermal infiltrate, guinea pig models, next to clinical studies, have
can largely be attributed to hapten-induced greatly contributed to our present knowledge of
chemokine release by keratinocytes. ACD, both data sets provide the basis for this
chapter.
In ACD, a distinction should be made between
2 Introduction induction (also known as sensitization or primary)
and effector (also known as elicitation or second-
During the past few decades, the understanding of ary) phases (Saint-Mezard et al. 2003) (Fig. 1).
why, where, and when allergic contact dermatitis The induction phase includes the events following
(ACD) might develop has rapidly increased. Crit- a first contact with the allergen and is complete
ical discoveries include the identification of T when the individual is sensitized and capable of
cells as mediators of cell-mediated immunity, giving a positive ACD reaction. The effector
their thymic origin and recirculation patterns, phase begins upon elicitation (challenge) and
and the molecular basis of their specificity to just results in clinical manifestation of ACD. The
one or few allergens out of the thousands of aller- entire process of the induction phase requires at
gens known (Janeway 2008). Progress has also least 4 days to several weeks, whereas the effector
resulted from the identification of genes that deter- phase reaction is fully developed within 1–4 days.
mine T-cell function, and the development of Main episodes in the induction phase (steps 1–5)
monoclonal antibodies that recognize their prod- and effector phase (step 6) are:
ucts. Moreover, the production of large amounts
of recombinant products, e.g., cytokines and 1. Binding of allergen to skin components. The
chemokines, and the breeding of mice with dis- allergen penetrating the skin readily associates
ruptions in distinct genes (knockout mice) or pro- with all kinds of skin components, including
vided with additional genes of interest (transgenic major histocompatibility complex (MHC) pro-
mice), have allowed in-depth analysis of skin- teins. These molecules, in humans encoded for
inflammatory processes, such as those taking by histocompatibility antigen (HLA) genes,
place in ACD. are abundantly present on epidermal antigen-
Although humoral antibody-mediated reac- presenting cells, called Langerhans cells
tions can be a factor, ACD depends primarily on (LC) (Lepoittevin 2006; Gerberick et al.
the activation of allergen-specific T cells 2008; Divkovic et al. 2005).
(Bergstresser 1989), and is regarded as a proto- 2. Hapten-induced activation of allergen-
type of delayed hypersensitivity, as classified by presenting cells. Allergen-carrying LC become
Turk (1975) and Gell and Coombs (type IV hyper- activated, mature, and travel via the afferent
sensitivity) (Gell et al. 1975). Evolutionarily, cell- lymphatics to the regional lymph nodes,
mediated immunity has developed in vertebrates where they settle as so-called interdigitating
to facilitate eradication of microorganisms and cells (IDC) in the paracortical T-cell areas.
toxins. Elicitation of ACD by usually nontoxic 3. Recognition of allergen-modified LC by spe-
doses of small molecular weight allergens indi- cific T cells. In nonsensitized individuals the
cates that the T-cell repertoire is often slightly frequency of T cells with certain specificities is
broader than one might wish. Thus, ACD can be usually far below 1 per million. Within the
considered to reflect an untoward side effect of a paracortical areas, conditions are optimal for
well-functioning immune system. allergen-carrying IDC to encounter naive
Subtle differences can be noted in macro- T cells that specifically recognize the
scopic appearance, time course, and histopathol- allergen–MHC molecule complexes. The den-
ogy of allergic contact reactions in various dritic morphology of these allergen-presenting
vertebrates, including rodents and man (Mestas cells strongly facilitates multiple cell contacts,
and Hughes 2004). Nevertheless, essentially all leading to binding and activation of allergen-
basic features are shared. Since both mouse and specific T cells.
sensitization elicitation
hapten
LC
epidermis
KC
migration &
dermis maturation inflammatory
cytokines
afferent
lymphatic
vessel
blood
circulation
draining
lymph thoracic duct
efferent
node lymphatic
vessels
Fig. 1 Immunological events in allergic contact dermatitis homing receptors, these cells can easily extravasate periph-
(ACD). During the induction phase (left), skin contact with eral tissues. Renewed allergen contact sparks off the effec-
a hapten triggers migration of epidermal Langerhans cells tor phase (right). Due to their lowered activation threshold,
(LC) via the afferent lymphatic vessels to the skin-draining hapten-specific effector T cells are triggered by various
lymph nodes. Haptenized LC home into the T cell-rich haptenized cells, including LC and keratinocytes (KC), to
paracortical areas. Here, conditions are optimal for encoun- produce proinflammatory cytokines and chemokines.
tering naïve T cells that specifically recognize Thereby, more inflammatory cells are recruited further
allergen–MHC molecule complexes. Hapten-specific T amplifying local inflammatory mediator release. This
cells now expand abundantly and generate effector and leads to a gradually developing eczematous reaction,
memory cells, which are released via the efferent lym- reaching a maximum within 18–48 h, after which reactivity
phatics into the circulation. With their newly acquired successively declines
4. Proliferation of specific T cells in draining of these cells display receptor molecules facil-
lymph nodes. Supported by interleukin (IL)-1, itating their migration into peripheral tissues.
released by the allergen-presenting cells, acti- In the absence of further allergen contacts, their
vated T cells start producing several growth frequency gradually decreases in subsequent
factors, including IL-2 (Hoyer et al. 2008). A weeks or months, but does not return to the
partly autocrine cascade follows since at the low levels found in naive individuals.
same time receptors for IL-2 are upregulated in 6. Effector phase. By renewed allergen contact,
these cells, resulting in vigorous blast forma- the effector phase is initiated, which depends
tion and proliferation within a few days. not only on the increased frequency of specific
5. Systemic propagation of the specific T-cell T cells, and their altered migratory capacities,
progeny. The expanded progeny is subse- but also on their low activation threshold.
quently released via the efferent lymphatics Thus, within the skin, allergen-presenting
into the blood flow and begins to recirculate. cells and specific T cells can meet, and lead to
Thus, the frequency of specific effector- plentiful local cytokine and chemokine release.
memory T cells in the blood may rise to as The release of these mediators, many of which
high as one in a thousand, whereas most have a pro-inflammatory action, causes the
arrival of more inflammatory cells, thus further molecules are too small to be antigenic them-
amplifying local mediator release. This leads to selves, contact sensitizers are generally referred
a gradually developing eczematous reaction to as haptens.
that reaches its maximum after 18–72 h and Upon penetration through the epidermal horny
then declines. layer, haptens readily conjugate to endogenous
epidermal and dermal molecules. Sensitizing
The following sections discuss these six main organic compounds may covalently bind to pro-
episodes of the ACD reaction in more detail. tein nucleophilic groups, such as thiol, amino, and
Furthermore, the chapter will discuss local hyper- hydroxyl groups, as is the case with poison
reactivity, such as flare-up and retest reactivity, oak/ivy allergens (reviewed in Roberts and
and hyporeactivity, i.e., upon desensitization or Lepoittevin 1998). Examples of contact allergens
tolerance induction. containing electrophilic components include alde-
hydes, ketones, amides, or polarized bonds. Metal
ions, e.g., nickel cations, instead form stable meta-
3 Binding of Contact Allergens l–protein chelate complexes by coordination bonds
to Skin Components (Budinger and Hertl 2000). The most reactive
nucleophilic side chains are those found in the
Chemical Nature of Contact Allergens. Most con- amino acids lysine, cysteine, and histidine
tact allergens are small, chemically reactive mol- (Gerberick et al. 2008). Of note, their degree of
ecules with a molecular weight less than 500 Da ionization and hence nucleophilicity is dependent
(Bos and Meinardi 2000) (Fig. 2). Since these on the pH of the microenvironment which is
hapten
lipophilic hydrophilic
horny
layer
LC
MHC-I
MHC-II
presentation to
CD8 ligand CD4 ligand
Fig. 2 Hapten presentation by epidermal Langerhans present on epidermal Langerhans cells (LC). Both MHC
cells. Allergen penetrating into the epidermis readily asso- class I and class II molecules may be altered directly or via
ciates with all kinds of skin components, including major intracellular hapten processing and, subsequently, be rec-
histocompatibility complex (MHC) proteins, abundantly ognized by allergen-specific CD8+ and CD4+ T cells
influenced by surrounding amino acids as well as e.g., by enzyme-induced metabolic conversion,

protein location within the epithelium (Divkovic are referred to as prohaptens. A classical pro-
et al. 2005). Predicting the chemicals that can func- hapten is p-phenylenediamine, which needs to
tion as haptens in allergic contact dermatitis as well be oxidized by N-acetyltransferases to a reactive
as identifying cutaneous proteins involved in metabolite which can form a trimer, known as
hapten–protein complexes is the subject of current Bandrowski’s base (Krasteva et al. 1993; Merk
intense investigations (Gerberick et al. 2008; et al. 2004). Reduced enzyme activity in certain
Mutschler et al. 2009; Lepoittevin 2006). individuals, related to genetic enzyme polymor-
Hapten Presentation by Langerhans cells phisms, explains the reduced risk of sensitization
(LC). Sensitization is critically dependent on to prohaptens that need enzymatic activation
direct association of haptens with epidermal (Schnuch et al. 1998; Karlberg et al. 2008;
LC-bound MHC molecules, or peptides present Blömeke et al. 2009).
in the groove of these molecules. Both MHC class
I and class II molecules may be altered this way,
and thus give rise to allergen-specific CD8+ and 4 Hapten-Induced Activation
CD4+ T cells, respectively. Distinct differences of Allergen-Presenting Cells
between allergens can, however, arise from differ-
ences in chemical reactivity and lipophilicity Physiology of Langerhans Cells. Although origi-
(Fig. 2), since association with MHC molecules nally thought to be neurons based on their staining
may also result from internalization of the hap- properties and cellular morphology (Langerhans
tens, followed by their intracellular processing as 1868), LC subsequently were surmised to func-
free hapten molecules or hapten–carrier com- tion as “professional” antigen-presenting cells
plexes. Lipophilic haptens can directly penetrate (Wilson and Villadangos 2004). They form a con-
into LC, conjugate with cytoplasmic proteins and tiguous network within the epidermis and repre-
be processed along the “endogenous” processing sent 2–5% of the total epidermal cell population
route, thus favoring association with MHC class I (Hoath and Leahy 2003). Their principal func-
molecules (Blauvelt et al. 2003). In contrast, tions are internalization, processing, transport,
hydrophilic allergens such as nickel ions may, and presentation of skin-encountered antigens
after conjugation with skin proteins, be processed (Breathnach 1988; Romani et al. 2003). As such,
along the “exogenous” route of antigen pro- LC play a pivotal role in the induction of cutane-
cessing and thus favor the generation of altered ous immune responses to infectious agents as well
MHC class II molecules. Thus, the chemical as to contact sensitizers (Kimber and Dearman
nature of the haptens can determine to what extent 2003; Inaba et al. 1986; Kimber and Cumberbatch
allergen-specific CD8+ and/or CD4+ T cells will 1992). Recent studies of LC indicate that this cell
be activated (Kimber et al. 2002; Liberato et al. type has direct epidermal innervations and can
1981; Kalish et al. 1994; Toebak et al. 2006). respond to a number of neurotransmitters
Pre- and Prohaptens. Whereas most contact (among them are calcitonin gene-related peptide,
allergens can form hapten–carrier complexes α-melanocyte stimulating hormone and substance P)
spontaneously, some need activation first. Contact (Luger 2002). Most of the experimental evidence
allergens requiring activation outside the body, to date indicates a suppressive effect of the neu-
e.g., by UV-light or oxygen, are called prehaptens rohormones and neuropeptides on Langerhans
(Naisbitt 2004; Lepoittevin 2006). The typical cell function and cutaneous inflammation, but it
photoallergen tetrachlorosalicylanilide is a proto- has become evident lately that the timing of expo-
type of this. Tetrachlorosalicylanilide, which sure to a stimulus is critical to the outcome of the
undergoes photochemical dechlorination with immune response (Romagnani 2006). Thus,
UV irradiation, ultimately provides photoadducts administration of a stress hormone or exposure
with skin proteins (Epling et al. 1988). Contact to a stressor before the LC encounters an allergen
allergens dependent on activation inside the body, may diminish the immune response toward that
substance, while a stressor may enhance immune (Iversen and Johansen 2008). IL-1β in concert
function when acting on a maturing LC or before with IL-18 stimulates release of tumor necrosis
reexposure to the allergen (Seiffert and Granstein factor (TNF)-α and granulocyte-macrophage col-
2006). LC originate from CD34+ bone marrow ony-stimulating factor (GM-CSF) from
progenitors, entering the epidermis via the blood keratinocytes (Iversen and Johansen 2008).
stream (Dieu et al. 1998). Their continuous pres- Together, these three cytokines facilitate migra-
ence in the epidermis is also assured by local tion of LC from the epidermis toward the lymph
proliferation (Stingl et al. 1978; Czernielewski nodes (Wang et al. 2003; Steinman et al. 1995).
and Demarchez 1987). They reside as relatively IL-1β and TNF-α downregulate membrane-bound
immature DC, characterized by a high capacity to E-cadherin expression and thus cause disentan-
gather antigens by macropinocytosis, whereas glement of LC from surrounding keratinocytes
their capacity to stimulate naïve T cells is still (Fig. 3) (Schwarzenberger and Udey 1996; Tang
underdeveloped at this stage (Streilein and et al. 1993; Jakob and Udey 1998). Simulta-
Grammer 1989). Their prominent dendritic mor- neously, adhesion molecules are upregulated pro-
phology and the presence of distinctive Birbeck moting LC migration by mediating interactions
granules were observed long ago (Langerhans with the extracellular matrix and dermal cells,
1868; Birbeck 1961; Braathen 1980). In the last such as CD54, α 6 integrin, and CD44 variants
decade, their pivotal function in the induction of (Ma et al. 1994; Rambukhana et al. 1995; Price
skin immune responses was explained by high et al. 1997; Weiss et al. 1997; Brand et al. 1999).
expression of molecules mediating antigen pre- Also, production of the epidermal basement mem-
sentation (e.g., MHC class I and II, CD1), as brane degrading enzyme metalloproteinase-9 is
well as of cellular adhesion and costimulatory upregulated in activated LC (Kobayashi 1997).
molecules (e.g., CD54, CD80, CD86, and cutane- Next, LC migration is directed by hapten-
ous lymphocyte antigen [CLA]) (Kimber et al. induced alterations in chemokine receptor levels
1998, 2002; Park et al. 1998). (Randolph 2001). Upon maturation, LC down-
Hapten-Induced LC Activation. Upon topical regulate expression of receptors for inflammatory
exposure to contact sensitizers, or other appropri- chemokines (e.g., CCR1, 2, 5, and 6), whereas
ate stimuli (e.g., trauma, irradiation), up to 40% of others (including CCR4, 7, and CXCR4) are
the local LC become activated (Weinlich et al. upregulated (Fig. 3) (reviewed by Sallusto
1998; Richters et al. 1994), leave the epidermis, (1998a), Zlotnik et al. (1999), Caux et al. (2000),
and migrate, via afferent lymphatic vessels, to the Sallusto et al. (1999)). Notably, CCR7 may guide
draining lymph nodes (Jakob et al. 2001) (Fig. 3). maturing LC into the draining lymphatics and the
This process of LC migration results from several lymph node paracortical areas, since two of its
factors, including contact allergen-induced pro- ligands (CCL19 and 21) are produced by both
duction of cytokines favoring LC survival lymphatic and high endothelial cells (Saeki et al.
(Ozawa et al. 1996; Wong et al. 1997; Aiba and 1999; Gunn et al. 1998). Importantly, the same
Tagami 1999) and loosening from surrounding receptor-ligand interactions cause naive T cells,
keratinocytes (Inaba et al. 1993; Jakob and Udey which also express CCR7, to accumulate within
1998; Schwarzenberger and Udey 1996). Thus, the paracortical areas (Kim and Broxmeyer 1999).
within 15 min after exposure to a contact sensi- Migratory responsiveness of both cell types to
tizer, production of IL-1β mRNA is induced (Enk CCR7 ligands is promoted by leukotriene C4,
1992; Enk et al. 1993). Along with this, caspase-1, released from these cells via the transmembrane
formerly known as interleukin-1-converting transporter molecule Abcc1 (previously called
enzyme, is activated and cleaves the active IL1 β MRP1) (Randolph 2001; Robbiani et al. 2000;
cytokine from the translated precursor-IL1β pro- Honig et al. 2003; van de Ven et al. 2009). Inter-
tein. Caspase-1 activates also IL-18 from its pre- estingly, Abcc1 belongs to the same superfamily
cursor form. These inflammatory processes are as the transporter associated with antigen-
now viewed at as making up the “inflammasome” processing TAP, known to mediate intracellular
hapten
a b
E-cadherin
KC KC
IL-1β
IL-18 IL-1α
LC LC TNF-α
GM-CSF
MHC-I / II
epidermis
basal membrane
dermis
afferent
lymphatic
vessel
c d
matrix metallo-
proteinases
dermal matrix
CCR7
fibroblast
CCL19, CCL21
endothelial
cells
afferent
lymphatic
vessel
Fig. 3 (a–d) Hapten-induced migration of Langerhans cytokines facilitate migration of LC from the epidermis
cells. (a) In a resting state, epidermal Langerhans cells toward the lymph nodes. (c) Emigration of LC starts with
(LC) reside in suprabasal cell layers, tightly bound to cytokine-induced disentanglement from surrounding
surrounding keratinocytes (KC), e.g., by E-cadherin. (b) keratinocytes (e.g., by downregulation of E-cadherin) and
Early after epidermal hapten exposure, LC produce IL-1β production of factors facilitating penetration of the
and IL-18, which induces the release of IL-1α, TNF-α and basal membrane (e.g., matrix metalloproteinases) and
GM-CSF from keratinocytes. Together, these three interactions with extracellular matrix and dermal cells
peptide transport in the “endogenous route” which Rustemeyer et al. 1999). Nevertheless, the prefer-
favors peptide association with MHC Class I mol- ential homing of naive T cells into the lymph node
ecules. Final positioning of the LC within the paracortical areas, and the large surface area of
paracortical T-cell areas may be due to another interdigitating cells, make allergen-specific T-cell
CCR7 ligand, EBI1-ligand chemokine (ELC, activation likely with only few dendritic cells
CCL19), produced by resident mature DC exposing adequate densities of haptenized MHC
(Sallusto 1998). molecules (Crivellato et al. 2004; Itano and
Jenkins 2003).
Activation of Hapten-Specific T Cells. As
5 Recognition of Allergen- outlined in “Binding of Contact Allergens to
Modified Langerhans’ Cells by Skin Components,” the chemical nature of the
Specific T Cells hapten determines its eventual cytoplasmic
routing in antigen-presenting cells (APC), and
Homing of Naive T Cells into Lymph Nodes. More thus whether presentation will be predominantly
than 90% of naive lymphocytes present within the in context of MHC class I or II molecules (Fig. 2).
paracortical T-cell areas have entered the lymph T cells, expressing CD8 or CD4 molecules can
nodes by high endothelial venules (HEV) (Haig recognize hapten-MHC class I or II complexes
et al. 1999). These cells are characterized not only showing stabilized MHC membrane expression
by CCR7 but also by the presence of a high (Griem et al. 1998; Moulon et al. 1995). Chances
molecular weight isoform of CD45 (CD45RA) of productive interactions with T cells are high
(Haig et al. 1999; Altin and Sloan 1997). Entering since each MHC-allergen complex can trigger a
the lymph nodes via HEV is established by the high number of T-cell receptor (TCR) molecules
lymphocyte adhesion molecule l-selectin (“serial triggering”) (Li et al. 2004). Moreover,
(CD62L), which allows rolling interaction along after contacting specific CD4+ T cells, hapten-
the vessel walls by binding to peripheral node presenting DC may reach a stable super-activated
addressins (PNAd), such as GlyCAM-1 or CD34 state, allowing for efficient activation of subse-
(Schon et al. 2003; von Andrian and Mrini 1998; quently encountered specific CD8+ T cells
Vestweber and Blanks 1999). Next, firm adhesion (Schoenberger et al. 1998). The actual T-cell acti-
is mediated by the interaction of CD11a/CD18 vation is executed by TCRξ-chain mediated signal
with endothelial CD54, resulting in subsequent transduction, followed by an intracellular cascade
endothelial transmigration. Extravasation and of biochemical events, including protein phos-
migration of naïve T cells to the paracortical phorylation, inositol phospholipid hydrolysis,
T-cell areas is supported by chemokines such as increase in cytosolic Ca2+ (Gascoigne and Zal
CCL18, 19, and 21 produced locally by HEV and 2004; Cantrell 1996), and activation of transcrip-
by hapten-loaded and resident DC (Robbiani et al. tion factors, ultimately leading to gene activation
2000; Adema et al. 1997; Ngo et al. 1998; Nagira (Fig. 4) (Kuo and Leiden 1999).
et al. 1997). In non-sensitized individuals, fre- For activation and proliferation, TCR trigger-
quencies of contact-allergen-specific T cells are ing (“signal 1”) is insufficient, but hapten-
very low, and estimates vary from 1 per 109 to presenting APC also provide the required
maximally 1 per 106 (Haig et al. 1999; costimulation (“signal 2”; Fig. 5) (Davis and van
Fig. 3 (continued) (e.g., integrins and integrin ligands). activated LC. Along their journey, haptenized LC further
(d) Once in the dermis, LC migration is directed toward the mature as characterized by their increased dendritic mor-
draining afferent lymphatic vessels, guided by local pro- phology and expression of costimulatory and antigen-
duction of chemokines (e.g., CCL19 and CCL21) acting on presentation molecules
newly expressed chemokine receptors, such as CCR7, on
resting signal 1
APC
MHC-II MHC-II
or CD40 or
CD40
MHC-I CD80/ MHC-I CD80/
CD86 CD86
CD4
or
CD4 CD8
or
ation
CD8 CD45 activ tein ZAP-70
ro
of p kinases lck
protein s in e fyn
tyro CD154
tyrosine TCR:CD3
TCR:CD3 CD154 phosphatase
CD45
CD28/CD152 activation of
CD28/CD152
phospholipase se of 2+ complex
rea [Ca ]cytosol
inc formation
PI-PLC-g 1
PIP2 IP3 with
calmodulin
DAG
activation of
activation
phosphatases
of kinases
PKC calcineurin
proteins phosphoproteins phosphoproteins proteins
n of
a c ti v a
atio
ti o
tiv
n
ac
of
DNA-binding proteins (e.g. NF-AT, NF-KB, AP-1)
T cell
signal 2 amplification
leads to
MHC-II upregulation
or MHC-II
MHC-I CD40 CD80/ or CD40
CD86 MHC-I CD8
0/C
D8
6
CD4
or CD4
CD8 or
CD8
CD45 TCR:CD3 CD154 CD28/ CD154 CD2

8/CD
le a d s t o 152
CD152 CD45 TCR:CD3
u pre g
ula ti o n
p f
activation of iI no
tio
va
n
tio
it va
iza
a c
stabil
NF-AT AP-1 CD28RE

tio
n IL-2 protein ion
NF-KB la lat IL-2 protein
s
ns
tran
tra
IL-2 mRNA IL-2 mRNA

ti o n
io n
cr i p
ip t
cr
nss
ss
an
tr
tra
chr. 4q promotor region IL-2 gene promotor region IL-2 gene
nucleus
Fig. 4 Activation of hapten-specific T cells. T-cell recep- molecules present on the outer cellular membranes of APC
tor (TCR) triggering by hapten–major histocompatibility and T cells. T cells, stimulated in this way, activate nuclear
complex (MHC) complexes (“signal 1”) is insufficient for responder elements (e.g., CD28RE). Together with nuclear
T-cell activation. But “professional” antigen-presenting transcription factors (NF), produced upon TCR triggering,
cells (APC), such as Langerhans cells, can provide the these nuclear responder elements enable transcription of
required costimulation (“signal 2”), involving secreted T-cell growth factors, e.g., IL-2. APC–T cell interaction
molecules, such as cytokines, or sets of cellular adhesion gives rise to mutual activation (“amplification”): on APC,
CCR4, 6, 10
IL-17
Stat3, RORγT
‘danger’ IL-22 Effector
T cells
TH17/22 CCR5, CXCR3, 6
Stat1,T-bet IFN -γ
TNF
TH1
IL-6, TGF-β
IL-21, IL-23 IL-12
allergen IFN-γ
CCR3, 4, 8
IL-4
Stat6,GATA3 IL-5
IL-4 IL-13
naive TH TH2
CCR4, 5, 7
IL-2 IL-10
TGF-β TGF-β Stat5, FoxP3 TGF-β
TH3
CCR4, 5, 8
Tr1
no Regulatory
‘danger’
Stat5, (FoxP3) IL-10 T cells
Fig. 5 Spectrum of allergen driven CD4+ T cell differentia- TGF-β, IL-21, and IL-23 stimulates the generation of TH17/
tion: current schematic view. Depending on the immunolog- Th23 cells. Development of TH1 cells is stimulated by the
ical microenvironment (amount of allergen, danger signals, presence of IL-12 and IFN-γ, and the development of TH2 is
and other soluble mediators), activated naïve T cells are favored by IL-4. The absence of sufficient danger signals
skewed into distinct phenotypes. The presence of allergen stimulates the development of tolerogenic phenotypes,
and sufficient danger signals leads to the development of including TH3 and Tr1 (Larsen 2009; Dong 2008; Zhu
effector T cell phenotypes of ACD. Presence of IL-6, 2008; Duhen 2009; Ward 2009; Cavani 2008; Sallusto 2009)
der Merwe 2003; Trautmann and Randriamampita ligation of CD40L (CD154) on T cells with
2003). The costimulatory signals may involve CD40 molecules, APC reach a superactivated
secreted molecules, such as cytokines (IL-1), or state, characterized by overexpression of
sets of cellular adhesion molecules (CAMs) and several CAMs, including CD80 and CD86
their counter-structures present on the outer cellu- (Fig. 4) (Acuto and Michel 2003; Quezada et al.
lar membranes of APC and T cells. Expression 2004). In turn, these molecules bind to and
levels of most of these CAMs vary with their increase expression of CD28 on T cells. This
activational status, and thus can provide positive interaction stabilizes CD154 expression,
stimulatory feedback loops. For example, as men- causing amplified CD154–CD40 signaling
tioned above, after specific TCR binding and (Dong et al. 2003).
Fig. 4 (continued) ligation of CD40 with CD154 mole- expression, causing amplified CD154–CD40 signaling,
cules on T cells induces overexpression of several and preserves strong IL-2 production, finally resulting in
costimulatory molecules, including CD80 and CD86. In abundant T-cell expansion
turn, these molecules bind to and increase expression of
CD28 on T cells. This interaction stabilizes CD154
The activational cascade is, as illustrated cells can show at least five distinct cytokine pro-
above, characterized by mutual activation of files, generally associated with helper/effector or
both hapten-presenting APC and hapten-reactive regulatory/suppressive functions (Fig. 5). Type-1
T cells. Whereas this activation protects the APC Th cells are characterized by a predominant
from apoptotic death and prolongs their life to release of IFN-γ, IL-2, and TNF-β, all known as
increase the chance of activating their cognate T prototypical pro-inflammatory and cytotoxic
cells, only the latter capitalize on these interac- cytokines. Type-2 Th cells secrete IL-4, IL-5,
tions by giving rise to progeny. As discussed IL-13, which have distinct pro-inflammatory
below, to promote T-cell growth, cellular adhesion activities but are most prominent in promoting
stimuli need to be complimented by a broth of humoral antibody production, e.g., along mucosal
cytokines, many of which are released by the surfaces where IgA contributes to exclusion of
same APC. Together, elevated expression levels microbial entry (Dabbagh and Lewis 2003; Faria
of (co-)stimulatory molecules on APC and local and Weiner 2006). Next, the Th3 subset is distin-
abundance of cytokines overcome the relatively guished by its release of transforming growth
high activation threshold of naive T cells (Viola factor (TGF)-β, which displays anti-inflammatory
and Lanzavecchia 1996). activities (Allan et al. 2008; Faria and Weiner
2006). Recently, Th-17 cells have been recog-
nized as a separate lineage of pro-inflammatory
6 Proliferation and T cells, characterized by production of IL-17A
Differentiation of Specific and IL-17E, as well as IL-22, all of which play
T Cells pivotal roles in auto-immune diseases, e.g., by
recruiting neutrophils and macrophages (Korn
T-Cell Proliferation. Upon their activation, naive et al. 2009; Louten 2009). Finally, still another
allergen-specific T cells start producing several subset of CD4+ T cells is recognized for its strong
cytokines, including IL-2, the classical T-cell regulatory role in controlling inflammatory reac-
growth factor (Crispin 2009; Malek 2009). In tivities, i.e., the Tr1 cells or “inducible Tregs,”
particular, ligation of T cell-bound CD28 recep- characterized by the secretion of IL-10 (Zhu and
tors unleashes full-scale IL-2 production in T cells Paul 2008; Allan et al. 2008; Sallusto 2009).
by increasing IL-2 transcription and mRNA sta- This CD4+ T-cell population is phenotypically
bilization (Pei 2008). T-cell IL-2 production peaks remarkably heterogeneous, with part of the cells
within 24 h and declines subsequently (Villarino expressing high amounts of the high affinity IL-2
2007). Concomitant upregulation of the IL-2 receptor (“CD25 high”), either or not accompanied
receptor α-chain facilitates the assembly of high- by expression of the transcription factor FoxP3
affinity IL-2 receptor complexes which augment (Romagnani 2006; Feuerer 2009; Cavani 2008)
autocrine T-cell responsiveness, thus providing a (Fig. 5). Tr1 cells have essential roles in mainte-
positive feedback loop leading to T-cell clonal nance of immune homeostasis, regulating effector
expansions up to 1,000 fold (Lan 2008). The T-cell responses and preventing their potentially
process of proliferation can be visible as an pathogenic effects by various indirect ways, e.g.,
impressive, sometimes painful lymph node by suppressing macrophage functions (Wu et al.
swelling. 2007; Shevach 2009). Each of these five cytokine
T-Cell Differentiation. Whereas allergen spec- profiles is under control of distinct sets of tran-
ificity remains strictly conserved along with their scription factors which are shown in Fig. 5, but
proliferation, within few days T cells show dis- discussed further elsewhere (e.g., Zhu and Paul
tinct expression of transcription factors associated 2008; Wilson 2009; Zhou and Littman 2009;
with varying cytokine production profiles and Basso et al. 2009; Dong 2008).
surface marker expression (Zhu and Paul 2008; To some extent the same distinct cytokine pro-
Sallusto 2009; Dong 2008; Oboki 2008). Thus, files may develop in CD8+ T cells, where at least
the recent offspring of allergen-specific CD4+ T type 1 and 2 cytokine-releasing CD8+ cells are
known to contribute to allergic contact dermatitis (Zhu and Paul 2008; Takatori et al. 2008; Iliev
(Kimber and Dearman 2002; Coulter et al. 2010). et al. 2009). Apparently, in conjunction with
Several factors are thought to contribute to the IL-10 production, e.g., produced by mucosal B
above-described polarized cytokine production cells, allergen-stimulated T cells rapidly initiate
profiles in allergen-specific T cells, including endogenous TGF-β production thus revealing the
(1) the site and cytokine environment of first aller- Th3 phenotype (Izcue et al. 2009). These cells
genic contact, (2) the molecular nature and con- may stimulate IgA production along the mucosae,
centrations of the allergen, and (3) the but elsewhere immunosuppressive activities pre-
neuroendocrine factors. vail. Interestingly, in conjunction with abundant
Cytokine Environment. In the skin-draining local IL-2 production, such as induced by strong
lymph nodes, allergen-activated LC and dermal antigenic stimulation involving most effective
dendritic cells rapidly produce large amounts of CD28 triggering, TGF-β favors skewing toward
IL-12, switching off IL-4 cytokine production, IL-10 production, thus providing an effective
thus promoting the differentiation of Th1 cells immunoregulatory feedback loop (Hoyer et al.
(Nakamura et al. 1997b; Kang et al. 1996; 2008; Letourneau 2009). Still, in the presence of
Pulendran 2004). Of note, since Th1 cells retain, strong and persistant microbial molecule-induced
next to IL12R, high IL-4R expression they remain danger/growth signals, e.g., IL-6, IL-21, and
sensitive to IL-4 as a growth factor (Kubo et al. IL-23, TGF-β induces the development of Th17
1997). Thus, they also retain the capacity to shift and/or Th22 cells, which both have been postu-
cytokine production toward the type-2 profile. In lated to contribute to various allergic and autoim-
contrast, type-2 T cells, e.g., developing in mune disorders (Larsen 2009; Oboki 2008;
mucosa-draining lymph nodes, rapidly lose the Louten 2009; Oukka 2008; Takatori et al. 2008)
genes encoding the IL-12-R β2 chain and thus, (Fig. 5).
type-2 differentiation is irreversible (Rogge et al. Thus, ACD may be caused by any combination
1997; Zhou et al. 2009). of at least three distinct types of effector T cells,
Early differentiation of type-1 T cells is pro- releasing type-1, -2, and -17/22 cytokines, respec-
moted by microbial danger-signal-induced IL-12 tively. Considering that contact allergens will
and IL-18, leading to IFN-γ release by nonspecific mainly enter via the skin, type-1 pro--
“bystander” cells, e.g., DC and NK cells, within inflammatory T cells are thought to represent the
the lymph nodes (Nakamura et al. 1997; Orange primary effector cells in ACD (Edele et al. 2007;
and Biron 1996). IFN-γ interferes with skewing Fyhrquist-Vanni et al. 2007). Nevertheless, in sen-
toward other cytokine profiles. Since Th1 cells sitized individuals, type-2 T cells also play a role,
rapidly lose functional IFN-γR expression, these as shown by both IL-4 production and allergen-
cells, in contrast to e.g., Th2, Th3 and Th17 cells, specific type-2 T cells in the blood and at ACD
become refractory to the growth-inhibitory effects reaction sites (see Sect. 7) (Werfel et al. 1997;
of IFN-γ (Groux et al. 1997; Gajewski and Fitch Probst et al. 1995; Grewe et al. 1998). Their role
1988; Takatori et al. 2008). Interestingly, T-cell may increase along with the longevity of sensiti-
skewing may also be facilitated by primary zation, since several factors contribute to shifting
contact-mediated signals, e.g., Th1 skewing by type-1 to type-2 responses, including reversibility
CD154 ligation through APC-bound CD40 of the former and not of the latter T cells, as
[124], or Th2 skewing by ligation of CD134 mentioned above (Perez et al. 1995; Ulrich et al.
(OX40) through APC-bound CD252 (Ohshima 2001). Still, other sets of cytokines, including
et al. 1997; Croft et al. 2009). IL-17 and/or IL-22, are important in immune
In the process of T-cell skewing toward the defense mechanisms, and thus Th17 and or Th22
other major cytokine profiles, TGF-β plays a cen- cells have also been found to mediate allergic and
tral role. TGF-β can be produced by various cell autoimmune disorders (van Beelen et al. 2007).
types, including Th3 cells themselves, but is most Given rapid local release of both IL-4 and TGF-β
prominently produced by mucosal epithelial cells within mucosal tissues, mucosal allergen contacts,
if accompanied by strong danger signals, may lead 1 T-cell and ACD reactivity. DHEA, like testos-
in particular to Th2 and Th17 effector cells. With- terone, may favor differentiation of type-1 T cells
out these signals, rather immunoregulatory subsets by promoting IFN-γ and suppressing IL-4 release
(Th3, Tr1) would develop, as is observed in the (Morfin et al. 2000; Cutolo et al. 2002). In con-
induction of “oral tolerance” (see below) (Mucida trast, the female sex hormone progesterone fur-
and Salek-Ardakani 2009). thers the development of type-2 CD4+ T cells and
Nature of the Allergen. A second factor in even induces, at least transient, IL-4 production
determining T-cell cytokine-production profiles, and CD30 expression in established type-1 T cells
although still poorly understood, is the molecular (Kidd 2003; Piccinni 1995). Type-2 T-cell polar-
character of the contact allergen itself, and the ization is also facilitated by adrenocorticotrophic
resulting extent of TCR triggering (Constant and hormone (ACTH) and glucocorticosteroids
Bottomly 1997; Constant et al. 1995). For both (Vieira et al. 1998), and by prostaglandin (PG)E2
protein and peptide antigens, high doses of anti- (Calder et al. 1992). PGE 2, released from mono-
gen might favor type-2 responses, whereas inter- nuclear phagocytes, augments intracellular cAMP
mediate/low doses would induce type-1 T-cell levels, resulting in inhibition of pro-inflammatory
responses (Constant and Bottomly 1997; cytokine production, like IFN-γ and TNF-α
Bretscher et al. 1997). Strong antigenic stimula- (Uotila 1996; Demeure et al. 1997; Abe et al.
tion was also shown to upregulate CD40L expres- 1997; Kalinski et al. 1997), and thus can influence
sion on T cells and, in combination with the development of effector T cells in ACD.
microbial-induced IL-6, to promote, Th17 differ-
entiation (Lezzi 2009). To what extent this trans-
lates to contact allergens is still unclear. Certainly, 7 Systemic Propagation
endogenous capacities of contact allergens to proof the Specific T-Cell Progeny
vide danger signals and activate the
“inflammasome,” in combination with their T-Cell Recirculation. Upon sensitization via the
capacity to induce differentiation-skewing cyto- skin, the progeny of primed T cells is released via
kines (in particular IL-4, IL-6, IL-12, and IL-23), the efferent lymphatic vessels of the skin draining
will affect the outcome (Toebak and Moed 2006; lymph nodes and the thoracic duct into the blood
Watanabe 2008). In this respect, some contact (Fig. 6). If the first encounter with allergen occurs
allergens are notorious for inducing type-2 via the intestinal route (e.g., along with induction
responses, even if their primary contact is by the of oral tolerance), priming will take place in the
skin route, e.g., trimellitic acid, which is also Peyer’s patches and mesenteric lymph nodes, and
known as a respiratory sensitizer (Kanerva et al. primed T cells will be released from there to the
1997). circulation. The subsequent recirculation and hom-
Neuroendocrine Factors. Diverse neuroendo- ing pattern of primed T cells is guided by adhesion
crine factors co-determine T-cell differentiation molecules and chemokine receptors which they
(Geenen and Brilot 2003; Luger and Lotti 1998, express on the cell membrane (Table 1). As
2002). An important link has been established outlined below, expression of these molecules is
between nutritional deprivation and decreased T- determined by the site of priming, as well as by the
cell-mediated allergic contact reactions (Lord activational state of the T cells. In addition, there is
et al. 1998). Apparently, adipocyte-derived leptin, a distinct relationship between the sets of chemo-
a hormone released by adequately nourished and kine and homing receptors expressed by T cells and
functioning fat cells, is required for type-1 T-cell their type of differentiation.
differentiation. Administration of leptin to mice First, primed T cells have different homing
restored ACD reactivity in mice during starvation receptors depending on the site of priming, a
(Lord et al. 1998). Also, androgen hormones and process called “imprinting” (Woodland 2009;
adrenal cortex-derived steroid hormones, e.g., Edele 2008). During priming of allergen-specific
dehydroepiandrosterone (DHEA), promote type- T cells in the skin draining lymph nodes, both
skin venula
re
nd
o
th
eli
um
CD62E (ligand for CLA)
arterial afferent
system lymphatic
other vessel
organs
venous
system
CCL19 & 21
(ligand for CCR7)
DT efferent lymphatic vessel
PNAd
heart (ligand for CD62L)
lymph node
Fig. 6 Systemic propagation of hapten-specific T cells. effector/memory T cells can still enter lymphoid tissues
From the skin-draining lymphoid tissue, the progeny of and settle in paracorticale areas by binding to its ligands
primed T cells is released via the efferent lymphatic vessels CCL19 and CCL21. But increased expression of skin-
and the thoracic duct (DT) into the blood and becomes part homing molecules, e.g., cutaneous lymphocyte antigen
of the circulation. Like their naïve precursors, these CCR7 + (CLA), facilitates their spontaneous migration in the skin
CD4+ and CD8+ T cells are stimulated to express Whereas for the imprint of gut homing retinoic
cutaneous lymphocyte antigen (CLA; Fuhlbrigge acid was identified as a crucial factor, for the
et al. 1997) and the chemokine receptors CCR4 imprint of skin homing, the active metabolite of
and CCR10, a phenotype that predisposes for vitamin D3 was shown to be essential, because it
eventual migration to the skin. In the mesenteric induces CCR10 expression in T cells
lymph nodes, on the other hand, T cells are stim- (Sigmundsdottir 2008). Still, for induction of
ulated to express the integrin α4:β7 and the che- CLA and thus for establishing the full skin hom-
mokine receptor CCR9, a phenotype which ing profile, cell-cell contact and/or other media-
predisposes for gut homing. An instructive role tors like IL-12 seem to be required (Edele 2008).
of the peripheral tissues in this imprinting process After priming and imprinting, circulating gut
was demonstrated in a mouse model on T cell homing memory T lymphocytes, bearing the
priming by dendritic cells, where either dermal α4:β7 integrin, can attach to intestinal endothelial
or intestinal cells were added to the cultures, cells by binding to the mucosal vascular addressin
resulting in T cells expressing mouse “CLA” or MAdCAM-1. Further infiltration in the mucosa is
α4:β7 integrin, respectively (Edele 2008). guided by chemokines, such as CCL25, produced
Table 1 Molecules involved in the migration of hapten-specific T lymphocytes
Receptor/ Ligand T Cell Ligand / Receptor Cell Tissue References
CD62L CD34, GlyCAM-1 Janeway 2008,

HEV
lymph node
(L-selectin) (PNAd) Sallusto 2004
CCR7 Tnaive TCM C C L 19 , C C L 2 1 Stromal cells, DC Sallusto 2004
CD11a/CD18 increased upon CD54, CD102 Endothelial cells Janeway 2008

(αL:β2-integrin, LFA-1) activation (ICAM-1, ICAM-2)
CD49d increased upon CD106, fibronectin Endothelial cells Janeway 2008

(α4:β1-integrin, VLA-4) activation (VCAM-1)
CD162 increased upon CD62P Endothelial cells W oodland 2009

(P-selectin ligand, PSGL-1) activation (P-selectin)
CLA skin homing CD62E Cutaneous Woodland 200

(E-selectin) endothelial cells
EM
skin
T
CCR4 T h2 CCL17 Keratinocytes W oodland 2009

(TARC)
CCR5 T h1 CCL2 (MCP-1)? Keratinocytes (a.o.) Meller 2007, Gaga 2008

CCL3 (MIP-1α)
CCR6 Th17 CCL20 Langerhans cells Larsen 2009

(MIP-3α / LARC) Endothelial cells Meller 2007
CCR10 Th22, CLA+ CCL27 Keratinocytes Duhe 2009, Homey 2002,

(CTACK) Langerhans cells Kagami 2008, Woodland
2009
CXCR3 T h1 CXCL9 and CXCL10 Keratinocytes Moed 2004

(Mig and IP-10) Meller 2007
α4:β7-integrin gut homing MAdCAM-1 Endothelial cells Janeway 2008

T cells
gut
CCR9 T cells CCL25 (TECK) Epithelial cells Grimm 2008; Miles 2008
by small intestinal epithelial cells (Miles 2008). T cells (T EM). Like their naive precursors, T CM
Thus, along the gut, T lymphocyte progeny is can still enter the peripheral lymphoid tissues, due
attracted that has been generated in other mucosal to the fact that they continue to express CD62L
tissues. Likewise, in the skin, CLA-positive cells and CCR7, allowing for binding to high endothe-
are attracted that have been generated in skin lial venules in the lymph nodes and migration into
draining lymph nodes. CLA binds to E-selectin the paracortical areas. T EM, on the other hand,
(CD62E) on dermal endothelial cells, while have lost these molecules and migrate, due to
CCR4 and CCR10 expression allow the lympho- simultaneous upregulation of several other adhe-
cytes to migrate in the skin toward CCL17 and sion molecules, preferentially to peripheral
CCL27 produced by keratinocytes in the inflamed tissues. T EM are characterized by rapid
epidermis. effector function upon antigenic stimulation, but,
At least as important for the recirculation and in the absence of antigenic stimuli, T EM eventu-
homing characteristics of T cells is the activational ally convert to T CM by reacquiring CCR7 and
state of the cells. In this respect, primed T cells can CD62L. In turn, T CM may convert to T EM upon
be divided into two main subsets: the central antigenic restimulation (Sallusto et al. 1999,
memory T cells (T CM) and the effector memory 2004; Woodland 2009; Sallusto 2009).
Peripheral endothelial binding and extravasa- macrophage effector functions. The ACD reaction
tion of T cells to inflamed tissues requires the is, however, a dynamic process, in which the first
expression of both selectins and integrins on the influx of cells influences the local chemokine
T cell membrane, such as LFA-1, VLA-4, and environment and determines the type of subse-
PSGL-1. The vascular expression of their respec- quent infiltrating cells. Thus, upon repeated expo-
tive ligands (Table 1) is strongly increased by sure to contact allergens gradually Th2 cells and
cytokines released at inflammatory sites. The den- regulatory cells may dominate (Kitagaki 1997).
sity of adhesion molecules on the T cell membrane Interestingly, also at the T-cell level modulation of
is generally upregulated upon activation, in par- the cytokine and chemokine receptor profiles may
ticular in T EM. Since their expression is highest occur, thereby maintaining plasticity of the
only for short periods after activation, only immune response (Wilson 2009; Sallusto 2009).
recently activated T cells show a unique propen- Of note, the actual composition of the T-cell infil-
sity to enter skin sites and exert effector functions. trate in ACD skin lesions does not only depend on
Third, the differentiation of T cells (Th1, Th2, the influx of lymphocytes, but should rather be
etc.) is clearly associated with distinct homing regarded as the resultant of infiltration, apoptosis,
chracteristics. T cells biased toward a and retention of lymphocytes, next to their emi-
pro-inflammatory phenotype show a higher pro- gration to the lymphatics.
pensity to enter skin sites, as compared to mucosal Finally, the antigen specificity of T cells con-
tissues (Austrup et al. 1997; Fuhlbrigge et al. tributes to their migration pattern. Allergens pen-
1997; Larsen 2009; Duhen 2009). In mice, the etrated via the epidermis and displayed at the
early influx of type-1 T cells into delayed-type dermal endothelial surface may be recognized by
hypersensitivity (DTH) reactions was found to allergen-specific T cells, thus resulting in activa-
be more efficient than that of type-2 T cells, tion, immobilization, and transendothelial migra-
although both cell types expressed CLA. Here, tion of these cells at sites of allergen exposure
CD162, highly expressed by type-1 T cells, was (Ward 2009).
found to be important for this preferential homing Allergen-Specific T-Cell Recirculation:
(Borges et al. 1997). Also the pattern of chemo- Options for In Vitro Testing. The dissemination
kine receptors differs between the Th subsets and recirculation of primed, allergen-specific T
(Table 1). Some receptors, such as CXCR3, are cells in the body suggests that peropheral blood
preferentially expressed on Th1 cells, whereas offers a most useful and accessible source for T
others like CCR4 and CCR8 are in particular cell based in vitro assays for ACD (Fig. 6). A
expressed by Th2 cells (Ward 2009; Cavani major advantage of in vitro testing would be the
2008; Hudak 2002; Sallusto 2009). The latter noninterference with the patient’s immune sys-
chemokine receptors are not only overexpressed tem, thus eliminating any potential risk of primary
on type-2 cytokine-producing T cells, but also on sensitization and boosting by in vivo skin testing.
basophils and eosinophils. Together, these cells Although such tests have found several applica-
strongly contribute to local immediate allergic tions in fundamental research, e.g., on recognition
hyperresponsiveness. The more recently of restriction elements, cross-reactivities and
described Th17 and Th22 lymphocyte subsets cytokine-profile analyses, their use for routine
expressing CCR4, CCR6, and CCR10 (Ward diagnostic purposes is still limited. Even in highly
2009; Duhen 2009) are attracted to the skin by sensitized individuals, frequencies of contact
epidermal CCL17, CCL20, and CCL27, respec- allergen-specific memory/effector cells may still
tively (Table 1, Fig. 5). Overall, results obtained be below 1 per 104 (Cavani et al. 1998;
thus far favor the view that the pro-inflammatory Lindemann 2008; Kalish 1990). Given the rela-
subsets (Th1 and Th17/22) will be the first to enter tively small samples of blood obtainable by
skin sites upon local inflammatory stimuli, their venepuncture (at only one or a few time points),
primary function being an early control of anti- numbers of specific T cells in any culture well
genic pressure, e.g., through amplification of used for subsequent in vitro testing would
typically be below 100 cells/well. For compari- compensate for suboptimal APC function
son, in vivo skin test reactions recruit at least (Rustemeyer et al. 1999, 2004; Moed 2005).
1,000 times more specific T cells from circulating
lymphocytes passing by for the period of testing,
i.e., at least 24 h (von Blomberg et al. 1991). 8 The Effector Phase of Allergic
Therefore, the sensitivity of in vitro assays, Contact Dermatitis
e.g., allergen-induced proliferation or cytokine
production may not always be sufficient to pick Elicitation of ACD. Once sensitized, individuals
up weak sensitization. Intermediate or strong sen- can develop ACD upon reexposure to the contact
sitization is, however, readily detected in vitro by allergen. Positive patch test reactions mimic this
both proliferation and cytokine production assays process of allergen-specific skin hyperreactivity.
(Lindemann 2008; Bordignon 2008; Minang Thus, skin contacts induce an inflammatory reac-
2005; Moed 2005). With respect to the latter, tion that, in general, is maximal within 2–3 days
both the “Elispot” assay, where allergen induced and, without further allergen supply, declines
cytokine production is evaluated at the single cell thereafter (Fig. 7). Looked at superficially, the
level, and the cytokine evaluation in allergen- mechanism of this type of skin hyperreactivity is
stimulated culture supernatants provide adequate straightforward: allergen elicitation or challenge
information (Rustemeyer et al. 2004; Spiewak leads to the (epi)dermal accumulation of contact
2007; Minang 2005). Notably with respect to allergen-specific memory/effector T lymphocytes
cytokine production, type-2 cytokines appear to which, upon encountering allergen-presenting
provide most specific parameters for contact sen- cells, are reactivated to release pro-inflammatory
sitization in these assays (Rustemeyer et al. 2004; cytokines. These, in turn, spark the inflammatory
Minang 2008), although generally both Th1 and process, resulting in macroscopically detectable
Th2 cytokines are being produced in vitro by erythema and induration. As compared to imme-
allergic individuals upon allergen exposure diate allergic reactions, developing within a few
(Moed 2005; Minang 2006). minutes after mast-cell degranulation, ACD reac-
Importantly, most of the above-mentioned, tions show a delayed time course, since both the
successful in vitro studies evaluated hydrophilic migration of allergen-specific T cells from the
allergens, like nickel, chromium, and palladium dermal vessels and local cytokine production
salts. Reports on successful in vitro assays with need several hours to become fully effective.
other hydrophobic and more toxic allergens are Still, the picture of the rise and fall of ACD reac-
scarce (Moed 2005; Wahlkvist 2007; Skazik tions is far from clear. Some persistent issues are
2008). Appropriate allergen presentation is a discussed below, notably: (1) irritant properties of
major hurdle in in vitro studies, because of the allergens, (2) role of early-phase reactivity,
broad range of requirements for different allergens (3) T-cell patrol and specificity, (4) effector
with unique solubilities, toxicities, and reactivity T-cell phenotypes, and (5) down regulatory
profiles. Moreover, in the absence of LC, mono- processes.
cytes are the major source of APC, and their Irritant Properties of Allergens. Within a few
numbers in peripheral blood vary substantially hours after allergenic skin contact, immunohisto-
within and between donors. Of note, optimal pathological changes can be observed, including
APC function is particularly critical for in vitro vasodilatation, upregulation of endothelial adhe-
activation of resting memory T cells, since, in the sion molecules (Goebeler et al. 1993, 1995), mast-
absence of repeated allergenic contacts, activated cell degranulation (Walsh et al. 1990; Waldorf
effector memory T cells (T EM) may finally revert et al. 1991), keratinocyte cytokine and chemokine
to a more naïve phenotype, with a higher thresh- production (Spiekstra 2005; Meller 2007), influx
old for triggering (Sallusto et al. 2004; Boyman of leucocytes (Bangert et al. 2003; Houck et al.
2009). Supplementing in vitro test cultures with 2004), and LC migration toward the dermis
appropriate mixtures of cytokines may, however, (Rambukhana et al. 1995; Silberberg-Sinakin
a b hapten
0 hours 0-4 hours
KC KC
IL-1β
LC
IL-1α
TNF-α
GM-CSF
B cell (?)
γ δ T cell (?)
vasoactive DC
DC amines IL-4
mast cell
NKT cell
IL-4, IFN-γ
CLA ligand
(CD62E) blood
capillary
afferent
lymphatic
vessel
c 2-6 hours
d 4-8 hours
KC KC
IFN-g
inflammatory
chemokines
inflammatory
chemokines
DC
DC
adhesion molecules
(e.g. CD54, CD106,
CD49d/CD29, CD62E/L/P)
Fig. 7 (continued)
12-48 hours
e f
KC
48-120 hours
IL-1
KC 0P
GE
2
Immunosuppressive
mediators
PGE2
TGF-β
inflammatory
cytokines
DC
Fig. 7 The effector phase of allergic contact dermatitis. by inflammatory chemokines. (d) 4–8 h: Hapten-activated
(a) 0 h: In resting skin relatively few randomly patrolling, T cells release increasing amounts of inflammatory medi-
skin-homing CLA+ T cells are present. (b) 0–4 h: ators, amplifying further cellular infiltration. (e) 12–48 h:
Reexposure of the contact allergen, binding to (epi)dermal The inflammatory reaction reaching its maximum, charac-
molecules and cells, induces release of proinflammatory terized by (epi)dermal infiltrates, oedema, and spongiosis.
cytokines. (c) 2–6 h: Influenced by inflammatory media- (f) 48–120 h: Gradually, downregulatory mechanisms take
tors, activated epidermal Langerhans cells (LC) start over, leading to decreased inflammation and disappearance
migrating toward the basal membrane and endothelial of the cellular infiltrate. Finally, primordial conditions are
cells express increased numbers of adhesion molecules. reconstituted except for a few residual hapten-specific T
Endothelial cell-bound hapten causes preferential extrava- cells causing the local skin memory. KC keratinocyte, DC
sation of hapten-specific T cells, which are further guided dendritic cell
et al. 1976; Hill et al. 1990; Toebak 2009). These chemokines, such as the Th1 associated
pro-inflammatory phenomena, which are also chemokines CXCL9, CXCL10 (IP-10), and
observed in non-sensitized individuals (Sterry CXCL11 (I-TAC/IP-9) ([206], Meller 2007) or
et al. 1991) and in T-cell-deficient nude mice the Th2-related chemokines CCL11, CCL17,
(Herzog et al. 1989), strongly contribute to aller- and CCL22 (Flier et al. 1999; Meller 2007). Cer-
genicity (Saint-Mezard et al. 2003). Clearly most, tainly, pro-inflammatory effects of contact aller-
if not all, of these effects can also be caused by gens increase, in many ways, the chance of
irritants and, therefore, do not unambiguously allergen-specific T cells meeting their targets.
discriminate between irritants and contact aller- The first cells affected by skin contact, i.e.,
gens (Willis et al. 1986; Hoefakker et al. 1995; keratinocytes and LC, are thought to represent
Brasch et al. 1992; Spiekstra 2005). Apparently, major sources of pivotal mediators such as IL-1β
true differences between these types of com- and TNF-α (Enk 1992; Kondo and Sauder 1995).
pounds depend on whether or not allergen- First, as described in “Hapten-Induced Activation
specific T cells become involved. Thus, only of Allergen-Presenting Cells,” these cytokines
after specific T-cell triggering distinctive features cause hapten-bearing LC to mature and migrate
might be observed, e.g., local release of certain toward the dermis (Kimber et al. 1998; Steinman
et al. 1995; Toebak 2009). But, these cytokines Buchanan and Murphy 1997). Thus, like the
also cause (over)expression of adhesion mole- very early events in the effector phase reaction,
cules on dermal postcapillary endothelial cells the final response to a contact allergen is antigen-
and loosen intercellular junctions. Thereby, non-specific. It is therefore not surprising that
extravasation of leucocytes, including allergen- allergic and irritant reactions are histologically
specific T cells, is strongly promoted (Wardorf alike.
et al. 1991; Pober et al. 1986; Shimizu et al. Early Phase Reactivity. In the elicitation phase
1991; Ward 2009). Moreover, haptens can stimu- allergen-specific T cells are triggered by
late nitric oxide (NO) production of the inducible MHC-bound allergen, just like in the afferent
NO-synthase (iNOS) of LC and keratinocytes, phase. The role of Langerhans cells in allergen
which contributes to local edema, vasodilatation, presentation upon elicitation is, however, less
and cell extravasation (Ross et al. 1998; Rowe prominent, and also other cells, like mast cells,
et al. 1997; Virag et al. 2002). In addition to macrophages and keratinocytes may now contrib-
these pathomechanisms that contribute to inflam- ute, since effector T cells are easily triggered and
matory responses, toll-like receptors (TLR) can be do not require professional antigen presentation.
involved in triggering sensitization. Recent stud- The role of keratinocytes in the onset of the ACD
ies have indicated that at least the contact allergen reaction is important, because of the cytokines and
nickel can specifically trigger human TLR-4, chemokines they produce upon hapten application
which adds to the release of unspecific danger (Meller 2007; Spiekstra 2005), thereby facilitat-
signals (Rothenberg 2010; Schmidt et al. 2010). ing the influx of effector T cells. In addition, a
Histopathological analyses support the view variety of other cells and mediators may contrib-
that the major causative events take place in the ute to the initiation of the ACD reaction, as sum-
papillary dermis, close to the site of entry of marized below.
allergen-specific T cells, for instance at hair folli- The role of neutrophils in the onset of ACD
cles, where haptens easily penetrate and blood reactions has not been well established, though
capillaries are nearby (Szepietowski et al. 1997). recent studies in mice demonstrate that skin reac-
Here, perivascular mononuclear cell infiltrates tivity to haptens largely depends on CXCL1,
develop, giving the highest chance of encounters released from endothelial cells when the first
between allergen-presenting cells and specific T hapten-specific CD8 T cells encounter the allergen
cells. Once triggered, extravasated T cells will and produce IL-17. CXCL1 may then attract neu-
readily enter the lower epidermal layers, in trophils to the elicitation site, thus facilitating
which haptenized keratinocytes produce further influx of allergen-specific T cells (Kish
lymphocyte-attracting chemokines, like CXCL9/10, 2009). In the human system, neutrophil infiltra-
CCL17, CCL20, and CCL27 (Flier et al. 1999; tion was also observed in skin biopsies from
Larsen 2009; Meller 2007; Woodland 2009, nickel patch tests, presumably as a result of
Table 1). Subsequently, since effector memory T IL-17/IL-22-mediated inflammation (Larsen
cells can also be triggered by “non-professional” 2009). Moreover, it has been shown that IL-8/
APC, including KC, fibroblasts, and infiltrating CXCL8, a potent neutrophil chemoattractant, is
mononuclear cells, ACD reactivity is amplified in readily produced by human antigen presenting
the epidermis (Hommel 2004; Viola and cells upon hapten exposure (Toebak et al. 2006);
Lanzavecchia 1996). Together, these events result this could also contribute to an early influx of
in the characteristic epidermal damage seen in neutrophils in ACD reactions.
ACD, such as spongiosis and hyperplasia. Nota- The role of an antibody-mediated early phase
bly, in ongoing ACD reactions, the production of reaction in the development of ACD is still
chemokines attracting lymphocytes and mono- unclear in man, although Askenase and his col-
cytes/macrophages, in addition to the production leagues have generated robust data to support this
of cytokines, adds to the nonspecific recruitment view in murine models (Askenase 2000): Hapten-
and activation of leucocytes (Yu et al. 1994; specific IgM, produced upon sensitization by
distant hapten-activated B-1 cells, can bind anti- repertoire such as Tγδ cells have been reported to
gen early after challenge and activate comple- contribute in a non-antigen-specific, probably
ment. The resulting C5a causes the release of non-MHC-restricted manner, to (early) elicitation
serotonin and TNF-α from local mast cells and responses (Dieli et al. 1998).
platelets, leading to vascular dilatation and To conclude, using various mouse models, dif-
permeabilization, detectable as an early ear swell- ferent types of early allergen specific reactivity
ing peaking at 2 h (Van Loweren et al. 1983). have been claimed to play initiating roles in
Furthermore, C5a and TNF-α induce the ACD, but clinical evidence for such mechanisms
upregulation of adhesion molecules on local is still lacking.
endothelial cells (Foreman et al. 1994; Groves T-Cell Patrol and Specificity of T-Cell Infil-
et al. 1995), thereby contributing to the recruit- trates. Whereas early nonspecific skin reactivity
ment of T cells in hapten challenge sites (Groves to contact allergens is pivotal for both sensitiza-
et al. 1995; Tsuji et al. 1997). In addition, human T tion and elicitation, full-scale development of
cells were found to express the C5a receptor and ACD, of course, depends on allergen-specific T
are chemoattracted to endothelium-bound C5a cells within the (epi)dermal infiltrates. In healthy
(Nataf et al. 1999). However, against most contact skin there is a constant flow of memory T cells
allergens, including nickel, no antibodies have ending up in the draining lymph nodes: about
been detected in man, arguing against humoral 200 T cells/h/cm 2 skin (Brand et al. 1999,
mechanisms playing more than a minor role in Fig. 6). Since one single antigen-specific T cell
clinical ACD (Wilkinson et al. 1994; Shirakawa can already trigger visible skin inflammation
et al. 1992). Interestingly in mice, immunoglobu- (Milon et al. 1981; Marchal et al. 1982), randomly
lin light chains, which have long been considered skin-patrolling memory/effector T cells might
as the meaningless remnants of a spillover in the account for the initiation of the allergen-specific
regular immunoglobulin production of B cells, effector phase. However, since frequencies of
were discovered to mediate very early hypersen- hapten-specific T cells in sensitized individuals
sitivity reactions by mast cell activation may still remain below 1 in 10,000, this does not
(Redegeld and Nijkamp 2003; vd Heyden 2006). seem to be a realistic scenario. Thus, augmented
In addition to an auxiliary role of B cells and random and/or specific T-cell infiltration accom-
antibodies, natural killer (NK) cells have been panies the development of ACD. Apparently,
reported to play a role in the onset of ACD reactions. local chemokine release upon allergen contact is
Mice lacking both T- and B-cells (RAG2 / ) pivotal in this respect (see T-Cell recirculation;
could still be sensitized to contact allergens Meller 2007). Chemokine gene expression evalu-
and Thy1+ NK cells were identified here as effec- ated 48 h after NiSO4 application was increased
tor cells with a prominent role for the activating for both Th1-related cytokines (CXCL9,
NK receptor NKG2D (O’Leary 2006). Interest- CXCL10, and CXCL11) and Th2-related cyto-
ingly, another NK-like cell, the invariant NKT kines (CCL11, CCL17, and CCL22). CCL27, on
cell, that recognizes CD1d bound glycolipids the other hand, which attracts preferentially
resulting in rapid IL-4 and IFN-γ release, was CCR10 bearing Th17/22 cells is constitutively
also found to play a role in the elicitation of produced in resting skin, but is rapidly released
contact sensitivity in mice: Blocking of CD1d upon allergen contact to accumulate in the
prevented both sensitization and elicitation by draining lymph nodes (Huang 2008).
contact allergens (Nieuwenhuis 2005). Notably, The question concerning the specificity of
in human ACD reactions relatively high frequen- ACD T-cell infiltrates has so far received little
cies of invariant NKT cells have been observed, attention. In a guinea pig model, preferential
ranging from 1.7% to 33% of total infiltrating T entry of dinitrochlorobenzene (DNCB)-specific
cells, which is 10–100 fold higher than the fre- T cells was observed within 18 h after elicitation
quency found in the circulation (Gober 2008). of skin tests with DNCB, as compared to
Also other T cells with relatively restricted TCR non-related compounds (Scheper et al. 1985).
Probably, extravasation of hapten-specific T cells are rather found to be regulatory, as shown by the
benefits from T cell receptor-mediated interac- fact that contact sensitization to weak allergens
tions with endothelial MHC molecules, pre- succeeded only after depletion of the CD4+ T cells
senting hapten penetrated from the skin (Ward (Vocanson 2006). Of note, most model allergens
2009). Within minutes after epicutaneous applica- studied in mice are hydrophobic molecules like
tion, hapten can indeed be found in dermal tissues DNFB and oxazolone, whereas in human studies
and on endothelial cells (Goebeler et al. 1993; very often water soluble metal salts, such as NiSO
Macatonia et al. 1987; Lappin et al. 1996). Indeed, 4 are used as model allergen. This could, at least
the frequency of allergen-specific cells in positive partly explain the different T-cell subsets involved
patch tests to urushiol was found to be 10- to (Figs. 2 and 5 MHCI/II presentation). So, taken
100-fold higher than in the blood (Kalish 1990). together, it has become clear that both CD4+ and
Interestingly, whereas preferential entry may CD8+ T cells can act as effector cells in DTH and
already contribute to relatively high frequencies ACD reactions. Likewise, neither of these subsets
of allergen-specific T cells (within 48 h up to 10%) can be regarded simply as regulatory or suppres-
(Probst et al. 1995; Milon et al. 1981), at later sor cells, although both of these subsets may,
stages, when the ACD reaction fades away, the depending on the allergen models and read-out
local frequency of allergen-specific T cells may assays, play such roles (Kimber et al. 2002; Abe
increase even further, due to allergen-induced et al. 1996).
proliferation and rescue from apoptosis. Thus, at An essentially similar conclusion holds true for
former skin reaction sites these cells can generate T-cell subsets (whether CD4+ or CD8+), releasing
“local skin memory” (see Sect. 8). type-1, type-2, or type-17 cytokines or combinations
Effector T-Cell Phenotypes. The debate on thereof. Whereas type-1 cytokines, in particular
phenotypes of effector T cells in ACD is still IFN-γ, display well-established pro-inflammatory
ongoing and the number of T cell subsets poten- effects by increasing MHC and ICAM-1 expression
tially involved is growing every year (Fig. 7). (Saulnier 1995; Kish 2009) thereby contributing to
Consensus exists, however, on the phenotype of improved allergen presentation and infiltration,
the skin homing T cell, i.e., CLA postive. This IL-4, a hallmark type-2 cytokine, can cause ery-
molecule enables binding to cutaneous endothe- thema and induration, when released in the skin
lial cells via E-selectin (CD62E) and thus migra- (Rowe and Bunker 1998; Asherson et al. 1996).
tion into the dermis. Indeed, blockage of IL-4 can interfere with ACD
Since cutaneous infiltrates show a clear pre- (Asherson et al. 1996). IL-17 plays a role in recruit-
ponderance of CD4+ T cells, it is not surprising ment and activation of neutrophils. It was shown to
that these cells have most often been held respon- be produced both by CD8+ T cells (in mouse models
sible for mediating ACD. In nickel allergic indi- with DNFB; Kish 2009) and by CD4+ T cells
viduals, indeed, allergen-responding cells were (in human nickel patch tests; Larsen 2009). The
found to be CD4+CLA+ memory T cells (Moed latter study shows, interestingly, that within a few
2004a, 2004b). Other studies, however, revealed hours after challenge CCL20 expression is
CD8+CLA+ nickel reactive T cells as most dis- upregulated in the skin, attracting CCR6 positive
criminating for allergic individuals, since CD4+ cells. Since all Th17 cells do express this receptor,
nickel-reactive T cells were also found in healthy an early preferential influx of Th17, and as a conse-
controls (Cavani et al. 1998). While the effector quence IL-17 and IL-22 production, could be an
mechanism of CD4+ T cells is mainly based on essential early event in the development of the
cytokine production, CD8+ T cells may mediate ACD reaction.
skin inflammation also through killing of hapten- Thus, a picture emerges in which ACD reactions
bearing target cells. In mice, generally CD8+ T can be caused both by allergen-specific type-1, type-
cells are found to cause contact sensitivity reac- 2, and type-17 T cells (Cavani et al. 1998;
tions, certainly to strong allergens, like DNFB Rustemeyer et al. 2004; Moed 2004; Larsen 2009;
(Kish 2009; Gober 2008). In mice CD4+ T cells Gober 2008; Oboki 2008). In retrospect, the down
regulatory effects of IL-4 on ACD reactions activities, including suppression of antigen-

observed earlier in some mouse models (Asada presenting cell and macrophage functions ([110],
et al. 1997) might be ascribed to accelerated Lalani et al. 1997; Morel and Oriss 1998). In
allergen-clearance rather than to blunt suppression. addition, the release of factors, such as PGE2 and
Still, both with time and repeated allergen-pressure, TGF-β, derived from activated keratinocytes and
type-2 responsiveness may rapidly take over infiltrated leucocytes, e.g., type-3 T cells, contrib-
(Kitagaki et al. 1995; Kitagaki 1997). Allergen- ute to dampening of the immune response
specific T cells isolated from skin test sites of sensi- (Epstein et al. 1991; Lawrence et al. 1997).
tized individuals, as compared to blood, showed a Release of PGE2, on the one hand, inhibits pro-
strong bias toward type-2 cytokine profiles (Werfel duction of pro-inflammatory cytokines (Kalinski
et al. 1997). Additional local IFN-γ release seems, et al. 1997; Walker et al. 1983) and, on the other
however, indispensable, since for a broad panel of hand, activates basophils (Weston and Peachell
contact allergens, clinical ACD reactions were char- 1998). These may constitute up to 5–15% of infil-
acterized by increased expression of mRNA trating cells in late phase ACD reactions (Dvorak
encoding IFN-γ-inducible chemokines (Flier et al. et al. 1976) and are also believed to contribute to
1999). In addition, transgenic mice expressing down regulation of the inflammatory response
IFN-γ in the epidermis showed strongly increased (Marone et al. 1994; Lundeberg et al. 1999).
ACD reactivity (Carroll et al. 1997). TGF-β silences activated T cells and inhibits
Downregulatory Processes. Resolution of further infiltration by down regulating the
ACD reactions and risk factors for the develop- expression of adhesion molecules on both endo-
ment of chronicity are not yet fully understood. Of thelial and skin cells (Sallusto et al. 2004).
course, if the allergen source is limited, as with Regulatory cells producing these suppressive
skin testing, local concentrations of allergen usu- mediators might even predominate in skin
ally rapidly decrease, thus taking away the critical sites, frequently exposed to the same allergen,
trigger of the ACD reaction cascade. Since even and known to show local (allergen-specific)
ACD reactions due to chronic exposure to aller- hypo-responsiveness [283]. It is of interest in
gen seldom result in permanent tissue destruction this context that CD4+ memory T cells expanded
and scarification, immunoregulatory factors most from late DTH reactions could be educated
likely contribute to prevention of excessive cyto- to become CD4+CD25++ regulatory T cells
toxicity and fatal destruction of the basal mem- expressing Foxp3 (Vukmanovic 2008).
brane. Both IL-1 and heparinase, secreted from
activated keratinocytes and T cells, protect
keratinocytes from TNF-α-induced apoptosis 9 Flare-Up and Retest Reactivity
(Lider et al. 1995; Kothny-Wilkes et al. 1998).
Moreover, activated effector T cells can undergo Local allergen-retention. Flare-up reactivity of for-
activation-induced cell death (AICD) during the mer ACD and patch test reaction sites is sometimes
resolution phase (Orteu et al. 1998). Notably, observed (Jensen et al. 2003; Hindsen et al. 2001;
pro-inflammatory type-1 T cells, expressing high Larsson et al. 1997). From the basic mechanisms of
levels of Fas-ligand (CD95L) and low amounts of ACD, it can be inferred that allergen-specific flare-
apoptosis-protecting FAP-1 protein, are more sus- up reactions depend either on local allergen or
ceptible to AICD than type-2 cells (Zhang et al. T-cell retention at these skin sites. Upon short-
1997). This may partly explain the shift toward lasting, low-dose contacts, e.g., by skin testing,
type-2 reactivity that is observed upon prolonged local allergen retention usually does not exceed a
allergen exposure (Kitagaki et al. 1995). More- 2-week period, which is actually long enough to
over, during the late phase of ACD, keratinocytes, exceed the time required for active sensitization. In
infiltrated macrophages and T cells start produc- experimental guinea-pig studies we observed that
ing IL-10 (Enk 1992; Schwarz et al. 1994; Berg skin tests with DNCB, chromium or penicillin
et al. 1995), which has many anti-inflammatory could become positive even if primary sensitization
was postponed to 1 week after skin testing. Appar- flare-up reactivity at such sites can be understood
ently effector T cells released into the circulation at by considering that just one specific effector T cell
that late time still detected sufficient residual aller- can be sufficient to generate macroscopic reactiv-
gen at the former skin test sites to cause flare-up ity (Marchal et al. 1982). Moreover, a very high
reactivity (Scheper et al. unpublished results). Max- frequency of the residual T cells may be specific
imum allergen-persistence for around 14 days was for the allergen, as discussed above in “The Effec-
also reported by Saint-Mezard et al. (2003), using tor Phase of Allergic Contact Dermatitis.” Appar-
the hapten fluorescein-isothiocyanate in a mouse ently, local specific T-cell retention is highly
model for flare-up reactivity. Also in humans flare- advantageous in combating microbial infections,
up reactions due to locally persisting allergen can since memory T cells localized in peripheral tis-
be observed, when from about 4–6 days after pri- sues contribute to robust protection e.g., to viral
mary sensitization, peripheral effector T-cell fre- infections (Woodland 2009). Only in highly sen-
quency increases (Skog 1976). Clinically, this sitized individuals unrelated skin test sites may
phenomenon can explain anomalous results from also show flare-up reactions (Scheper et al.
patch testing with multiple contact allergens. When 1983) and even generalized erythematous macu-
a patient suspected for penicillin allergy was patch lar eruptions can be observed with higher allergen
tested with cross-reactive penicillin derivatives, a doses (Polak 1968). The latter reactivities proba-
regular 24–72 h reaction was only observed to one bly relate to the fact that recently activated T cells
of the penicillins, but all others also became posi- show strong expression of adhesion and homing
tive from about 8–9 days after skin testing. The first molecules, e.g., CLA and chemokine receptors,
penicillin derivative turned out to release formalde- such as CCR5, facilitating random migration into
hyde to which the patient was found to be allergic. peripheral tissues and thus allergen-specific T-cell
Positive reactivity to formaldehyde apparently had patrol in the skin (Moser et al. 1998; Woodland
potentiated primary sensitization to penicillin, 2009). Upon subsequent allergen entry from the
causing the other, previously negative reaction circulation, these allergen-specific T cells could
sites to flare up (Neering, personal communica- mediate generalized erythematous reactions
tion). Thus, skin test sites may occasionally flare- (Hindsen et al. 2001).
up if the testing dose itself led to the release or Interestingly, local allergen-specific T-cell
activation of sufficiently high numbers of effector retention/“local skin memory” can be clinically
T cells in the circulation. exploited to discriminate between simultaneous
Local T-cell retention. In contrast, allergen- sensitization to different sensitizers (“concomitant
specific T cells may persist for at least several sensitization”) and cross-reactivity between dif-
months in the skin causing “local skin ferent sensitizers (Rustemeyer et al. 2002; Matura
memory”(Fig. 8) (Scheper et al. 1983; Moed 1998; Inerot and Moller 2000). Using several
2004). Thus, locally increased allergen-specific different combinations of contact allergens in a
hyperreactivity, detectable through either acceler- guinea pig model, we retested guinea pigs previ-
ated “retest” reactivity (after repeated allergenic ously sensitized to DNCB and methyl methacry-
contact at the same skin site) or flare-up reactivity late (MMA), with the same allergens and some
(after allergen entry from the circulation, e.g., other methacrylate congeners. Accelerated retest
derived from food ingestion), may be observed reactivities were observed with the latter conge-
for long periods of time at former skin reaction ners on the former MMA, but not DNCB, patch
sites (Christensen et al. 1985; Hindsen and test sites (Rustemeyer et al. 2002). Thus, with
Christensen 1992). Typically, the erythematous preferential local retention of MMA-specific T
reactions peak between 2 and 6 h after contact cells at the MMA skin test site, no accelerated
with the allergen. Histological examination of retest reactivity could be elicited with DNCB,
such previously positive skin reaction sites but to varying degrees with all four
shows that the majority of remaining T cells is MMA-related compounds. In clinical practice
CD4+ CCR10+ (Moed 2004). The remarkable using this approach, Matura et al. (1998)
weeks/months after ACD reaction retest reaction

hapten 2-6 hours
KC
KC
LC
CCL27
inflammatory
cytokines
+
CD4
CCR10+
vasoactive
DC amines DC
Fig. 8 Local skin memory. In former allergic contact der- hapten contact can induce a rapid onset of an erythematous
matitis sites a few hapten-specific T cells can remain, mainly reaction, sparked off by the residual hapten-specific T cells.
close to dermal dendritic cells (DC). Retest reaction: renewed KC keratinocyte, LC Langerhans cell
confirmed positive cross-retest reactions for (as described above in “Recognition of Allergen-
cloprednol and tixocortol pivalate, both belonging Modified Langerhans’ Cells”) allergen presented
to group A, and budesonide, amcinonide, and by e.g., immature Langerhans’ cells may anergize
triamcinolone, all belonging to group B cortico- naive T cells, i.e., cause receptor-downregulation
steroids (see also Isaksson and Bruze 2003). associated with an unresponsive state, eventually
leading to their death by apoptosis (Fig. 10) (Zin-
kernagel 2004; Piccirillo and Thornton 2004;
10 Hyporeactivity: Tolerance Benson and Whitacre 1997). With increasing den-
and Desensitization sities of MHC-antigen complexes on the surface
of professional APC, at least three different
Of course, uncontrolled development and expres- levels of T-cell tolerance may be induced, charac-
sion of T-cell-mediated immune function would terized by active suppression, anergy or deletion
be detrimental to the host. During evolution, sev- (Ferber et al. 1994; Morgan et al. 1999).
eral mechanisms developed to curtail lymph node Unresponsiveness of T cells, induced by aller-
hyperplasia or to prevent excessive skin damage genic contacts at skin sites where LC/DC func-
upon persisting antigen exposure. tions have been damaged, e.g., by UV irradiation,
Regulation of Immune Responses. First, aller- or are naturally absent, e.g., in the tail skin of
gen contacts, e.g., by oral or intravenous admin- mice, may be ascribed to T-cell anergy, frequently
istration, may lead to large-scale presentation of associated with TCR/CD4 or CD8 down regula-
allergen by cells other than skin DC (Fig. 9). In the tion, and apoptosis/deletion (Shreedhar et al.
absence of appropriate costimulatory signals 1998; Semma and Sagami 1981). Whereas anergy
antigen ingestion skin contact(s) 48h after

reexposure
hypersensitivity
tolerance
Fig. 9 Induction of oral tolerance. Hapten ingestion, prior to potential sensitizing skin contact(s), can induce hapten-
specific tolerance
and deletion reflect “passive” unresponsiveness, naive animals (Dieli et al. 1998; Rustemeyer
tolerance by active suppression may also be et al. 2001). Active suppression, as revealed by
induced under similar circumstances (Taams these adoptive cell transfers, is a critical event in
et al. 1999). Actually, with increasing dose and regulating T-cell responses to contact sensitizers,
exposure times, even regular epicutaneous aller- and to all possible peptide/protein antigens,
genic contacts not only induce T effector cells but including bacterial, autoimmune, and graft rejec-
also lymphocytes controlling T-cell proliferation tion antigens (Miller et al. 1977; Polak 1980;
(afferently acting regulatory cells) and/or causing Weiner 1997).
decreased skin reactivity (regulatory cells of Like effector T cells in ACD, regulatory cells
effector phase). Thus, allergic contact hypersensi- are not a single subpopulation of cells. As outlined
tivity is the resultant of a delicate balance between above, depending on e.g., the nature of the aller-
effector and regulatory mechanisms (Boerrigter gen and route of exposure, ACD can be mediated
and Scheper 1987; Girolomoni et al. 2004). by both CD4+ and CD8+ T cells, either or both
Cellular Basis of Active Tolerance. Upon pref- releasing Th1, Th2, Th3, Th17/22 cytokines. With
erential stimulation of regulatory cells, e.g., by distinct effector phenotypes for particular aller-
feeding non-primed, naïve individuals with con- gens, each of the other phenotypes can act as
tact allergens, strong and stable allergen-specific, regulatory cells (Weigle and Romball 1997;
active tolerance may develop (Mayer et al. 2001; Arnaboldi 2009). Notwithstanding, type-2 cyto-
Weiner 1997; Wang 2008). The concept of active kine producing cells are prominent in regulating
regulatory (“suppressor”) cells controlling ACD ACD, with allergic contact hypersensitivity
is based on the fact that, in experimental animal enhanced and tolerance reversed by interfering
models, such allergen-specific tolerance can be with type-2 T-cell functions (Zembala and
transferred by lymphoid cells from tolerant to Ashershon 1973; Boerrigter and Scheper 1984;
APC
MHC CD80/
CD86
Ag
TCR CD28/
CD152
naive
T cell
signal 1 signal 2 signal 1Io signal 2 signal 1med signal 2 signal 1hi signal 2
Th1 Th2
Th17/22 Tr1
IL-2 IL-4 Th3 TCR
IL-17
IFN γ
β
IL-22 γ IL-10
IL-5 TGF IL-2
TNP IL-13
effector T cells regulator T cells anergic T cells T cell apoptosis
tolerance tolerance tolerance

sensitization (active suppression) (anergy) (deletion)
Fig. 10 The character of the APC–T-cell interaction secretion profiles. Tolerance: In the absence of appropriate
determines the immunological outcome. Sensitization: costimulatory signals, immunological tolerance may
Naïve T cells, activated by antigen-presenting cells (APC) develop. With increasing density of MHC-hapten com-
providing both hapten-specific (“signal 1”) and appropriate plexes on the surface of APC, activating “signal 1” T-cell
costimulatory (“signal 2”) signals, develop into effector T pathways, multiple levels of T-cell tolerance might be
cells, characterized by Th-17/22, -1, and -2 cytokine induced
Mokyr et al. 1998). Also, interferons and IL-12, Regulatory Mechanisms of the Effector Phase.
both impairing Th2 and Th17/22 cells, were A critical feature of the regulatory principles
shown to inhibit regulatory cells and to stimulate involving mutual regulation of T-cell subpopula-
effector-cell functions in mouse models (Knop tions by Th1, Th2, Th3 and Th17/22 cytokines, is
et al. 1982; Zhang and Michael 1990; Claessen that regulatory functions are most effective during
et al. 1996). In particular after mucosal allergen initiation of immune responses (Fig. 5). Thus,
contact stimulation, T cells producing IL-10 once established, effector T cell and cytokine pro-
and/or TGF-β (type-3 cytokine profile), many of files show remarkable stability and refractoriness
which co-expressing CD4, CD25 and the transcrip- to regulatory forces. Down-regulation of allergic
tion factor Foxp3 (Treg), may act as regulatory cells skin reactions may, therefore, take considerable
(Bridoux et al. 1997; Cavani et al. 2003; Feuerer time. Of course, the preliminary factor facilitating
2009). These T cells promote anti-inflammatory decreased allergic skin reactivity is removal of
immunity, e.g., by switching antibody production hapten by exudate and innate immune cells of
to IgA, which mediates secretory immunity and the inflammatory infiltrate. But, at chronically
thus contributes to antigen exclusion in the exposed sites also specific regulatory mechanisms
lumen, e.g., of the gastro-intestinal tract (Hafler can be involved, such as CD8+ T cells, acting
et al. 1997). Of note, TGF-β strongly suppresses either as regulator/suppressor (CD28 CD11b+)
development of both type-1 and -2 effector or cytotoxic (CD28+CD11b ) T cells (Lonati et al.
T cells, and can silence T cells in a semi-naïve 1998; De panfilis 1998), which may downregulate
state (O’Garra 1998). skin reactivity by targeting allergen-presenting
DC [331]. Multiplicity and reduncancy of regula- of the latter concept of active suppression is
tory mechanisms have thus far hampered devel- the bystander effect, in which the response to any
opment of robust clinical treatments exploiting antigen can be downregulated by immunosuppres-
regulatory T-cell functions to provide for sive cytokines acting in a local tolerogenic micro-
allergen-specific downregulation of the effector environment (von Herrath 1997). The latter was
phase of ACD. The development of potential observed for both protein antigens (Fowler and
therapeutic applications of regulatory cells in var- Weiner 1997) and methacrylate contact allergens
ious disorders, such as allergic contact dermatitis (Rustemeyer et al. 2001). Stable polarization/
and autoimmune diseases, therefore, needs much skewing may also explain why even low,
more time than envisioned earlier (Ilan 2009). non-sensitizing doses of nickel applied to the
Redundancy of Tolerance Mechanisms. skin prevented subsequent tolerance induction
Besides regulatory T cells, producing different by feeding the metal allergen (Van Hoogstraten
cytokines, or exerting distinct cytotoxicities, et al. 1994). Apparently, the progeny of naïve
other mechanisms may also contribute to immune allergen-specific cells, once “on the stage,”
regulation and tolerance. Clearly, the risk of have been triggered to a “subclinical” degree
excessive immune reactivity should be very low. toward effector cell differentiation and become
These mechanisms involve allergen-specific T refractory to regulatory cell action (Fig. 10).
cells shedding truncated T-cell receptors, acting This may also have contributed to incomplete
as antagonists and blocking allergen presentation tolerance induction in earlier clinical studies
(Kuchroo 1998), and high-dose allergen-induced when feeding with poison ivy-/oak-derived aller-
anergic T cells (Morgan et al. 1999). Possibly, the gens (Epstein 1987). Indeed, to our knowledge,
latter cells, by actively suppressing DC functions, permanent reversal of existing ACD in healthy
can function as “active” suppressor cells (Taams individuals has, as yet, never been achieved.
et al. 1998, 2000). Interestingly, DC, becoming Nevertheless, as described above, effector cells
suppressive by this mechanism (Taams et al. still seem susceptible, though transiently, to
1998) or by suppressive cytokines like IL-10 and the downregulation of allergen reactivity, as
PGE 2 (Kumar and Sercarz 1998; Kalinski et al. was observed in desensitization procedures
1998), can, in turn, act themselves as suppressor (Van Hoogstraten et al. 1994; Morris 1998).
cells by conferring antigen-specific anergy to sub- Transient Desensitization in Primed Individ-
sequently encountered T cells (Steinbrink et al. uals. For dermatologists, methods by which
1999; Taams et al. 2000). Although, at present, patients might be desensitized for existing ACD
consensus has been reached about a critical role of would be a welcome addition to the currently
regulatory/suppressor cells in the development prevailing symptomatic therapies, and investiga-
and expression of ACD, the relative contributions tors have made a wide variety of attempts to
of each of the various mechanisms are still far achieve this goal. Unfortunately, as mentioned
from clear. above, therapeutic protocols involving ingestion
Induction of Lasting Tolerance Only in Naive of poison ivy allergen, penicillin, or nickel sul-
Individuals. Both clinical and experimental find- fate were of only transient benefit to the patients
ings indicate that full and persistent tolerance can (Epstein 1987; Wendel et al. 1985; Panzani et al.
only be induced prior to any sensitizing allergen 1995; Tammaro et al. 2009). Similarly in animal
contacts (Van Hoogstraten et al. 1989; Strobel and models, only a limited and transient degree of
Mowat 1998; Wang 2008). Upon primary aller- hyposensitization was obtained by Chase (1946)
genic contacts, naive T cells differentiate to produce when feeding DNCB-contact-sensitized guinea
polarized cytokine profiles (Figs. 5 and 9). Once pigs with the allergen, whereas, for achieving
polarized, however, T-cell profiles are irreversible, persistent chromium-unresponsiveness in pre-
due to loss of cytokine (receptor) genes, or at least sensitized animals, Polak and Turk (1968a, b)
very stable, due to the mutually suppressive activ- needed a rigorous protocol involving up to lethal
ities of T-cell cytokines. An important corollary doses of the allergen. As outlined above,
mechanisms underlying specific desensitization uncovered. Also, the basic immunology of ACD
in ACD probably depend on direct interference is now well-defined, including T-cell migratory
of allergen with effector T-cell function, by patterns, recognition of distinct allergens, interac-
blocking or downregulating T-cell receptors, tions with other inflammatory cells to generate
leading to anergy and apoptosis (Polak and inflammation, and cytokine profiles. But new com-
Rinck 1978). As the onset of desensitization is plexities have emerged. For instance, in contrast to
immediate, no suppressor mechanisms may ini- earlier belief, many of the currently known T-cell
tially be involved. Apparently in the absence of subpopulations can act either or both as effector and
LC, MHC class II-positive keratinocytes can regulatory cells, depending on the nature of the
serve as APC and are very effective in rendering allergen, the route of entry, frequency of exposure,
allergen-specific effector cells anergic (Gaspari and many other, still ill-defined factors. In particu-
et al. 1988). Moreover, at later stages active lar, the poor understanding of regulatory mecha-
suppression may come into play resulting from nisms in ACD still hampers further therapeutic
secondary inactivation of DC function by progress. So far, no methods of permanent desen-
anergized T cells (Shreedhar et al. 1998). Never- sitization have been devised.
theless, major problems with in vivo desensiti- Nevertheless, next to the established anti-
zation procedures relate to the refractoriness inflammatory drugs, recently defined cellular
of effector T cells to regulatory cell functions, interaction molecules and mediators provide
and the rapid replacement of anergized effector promising targets for new generations of anti-
cells by naïve T cells from relatively protected inflammatory drugs, some of which have already
peripheral lymphoid tissues provides a source entered clinical trials. Clearly, drugs found to be
of new effector cells upon sensitizing allergen effective in preventing severe T-cell-mediated
contacts. The same conclusions can be drawn conditions, e.g., rejection of a vital organ graft,
from attempts to achieve local desensitization. should be very safe before their use in ACD would
It was found that local desensitization by seem appropriate. To date, prudence favors alter-
repeatedly applying allergen at the same native measures to prevent ICD and ACD, be it
skin site did not result from local skin hardening through legal action to outlaw the use of certain
or LC inactivation, as local reactivity to an materials or through avoiding personal contact
unrelated allergen at the site was unimpaired with these materials. In the meantime, for
(Boerrigter and Scheper 1987). Persistence of difficult-to-avoid allergens, further studies on the
cellular infiltrates, in the absence of erythema- potential value of tolerogenic treatments prior to
tous reactivity, at a desensitized skin site possible sensitization seem warranted.
could reflect local anergy, but also locally
active regulatory cells. Upon discontinuation
of allergen exposure, however, local References
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Phototoxic Dermatitis
15
Margarida Gonçalo
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
3 General Mechanisms of Phototoxicity from Exogenous Chemicals . . . . . . . . . 192
3.1 Phototoxicity Versus Photoallergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
4 Clinical Patterns of Phototoxicity from Exogenous Chemicals . . . . . . . . . . . . . . 195
4.1 Acute Patterns of Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
4.2 Subacute Patterns of Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
4.3 Delayed and Late Effects of Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
5 Main Sources of UV Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
6 Main Causes of Topical and Systemic Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . 198
6.1 Plants Causing Phytophotodermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
6.2 Photosensitive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
7 Diagnostic Procedures and Preventive Measures in Phototoxicity . . . . . . . . . . 204
8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Abstract Topical and systemic drugs are a frequent

Phototoxicity is more frequent than photo- cause of photosensitivity, often with photo-
allergy, but it is not always easy to distinguish toxic aspects.
between these two patterns of photosensitivity. The main clinical pattern of acute phototox-
Phytophotodermatitis from plants contain- icity is an exaggerated sunburn, but bullae,
ing furocoumarins is one of the main causes of purpura, pseudoporphyria, photoonycholysis,
phototoxic contact dermatitis. and dyschromia can also occur.
Exposure to phototoxic drugs is increasingly
associated with enhanced skin carcinogenesis.
M. Gonçalo (*)
Clinic of Dermatology, Unit of Skin Allergy, University Keywords
Hospital and Faculty of Medicine, University of Coimbra, Photosensitivity · Phototoxicity · Photoallergy ·
Coimbra, Portugal Drug photosensitivity · Phytophotodermatitis
e-mail: mgoncalo@fmed.uc.pt; mmgoncalo@gmail.com

https://doi.org/10.1007/978-3-319-68617-2_15
192 M. Gonçalo
1 Core Messages and photoallergy) may coexist, and it is some-

times difficult to distinguish the contribution of
• Phototoxic dermatitis from exogenous each of these pathomechanisms in each case of
chemicals can be polymorphic. photosensitivity.
• It is not always easy to distinguish phototoxic- Awareness of photosensitivity is increasing
ity from photoallergy. due to the new patterns of life with increased
• Phytophotodermatitis from plants containing exposure to natural or artificial light (Elkeeb
furocoumarins is one of the main causes of et al. 2012) and the more frequent exposure to
phototoxic contact dermatitis. chemicals with photosensitizing properties
• Topical and particularly systemic drugs are a (drugs, UV filters and cosmetics), but more atten-
frequent cause of photosensitivity, often with tion is also taken on the pre-marketing studies to
phototoxic aspects. evaluate the photosensitizing potential of
• The main clinical pattern of acute phototoxic- chemicals (Kim et al. 2015; Onoue et al. 2017).
ity is an exaggerated sunburn. Phototoxicity is mostly related with acute or
• Subacute phototoxicity from systemic drugs chronic exposure to topical or systemic exoge-
can present as pseudoporphyria, photo- nous chemicals (plants and drugs). It is probably
onycholysis, and dyschromia. frequent and certainly underreported as it may
• Long term exposure to phototoxic drugs can present as minor symptoms (skin prickling/burn-
enhance skin carcinogenesis. ing or erythematous sunburn) that resolve with no
medical intervention or it may occur under clinical
patterns that may not immediately be recognized
2 Introduction as exogenous photosensitivity (lichenoid reac-
tions, telangiectasia, lupus erythematosus, actinic
Phototoxicity is included within the spectrum of keratosis, and skin cancers) (Sontheimer et al.
photosensitive disorders and represents an abnor- 2008; Gonçalo 2011; Dawe and Ibbotson 2014;
mal skin reaction to the sun or other sources of Khandpur et al. 2017).
light, mostly ultraviolet light (UV). It is due to the
presence of an abnormal chromophore in the skin,
either an endogenous or exogenous chemical that 3 General Mechanisms
is selectively activated by solar radiation and will of Phototoxicity from
ultimately induces aggression of skin cells and Exogenous Chemicals
inflammation (Ferguson 1999; Gonçalo 2011).
A state with reduced skin defense against UV The skin has natural chromophores (aminoacids,
aggression (vitiligo, low niacin levels, xeroderma DNA bases, melanin, porphyrins, etc.) in order to
pigmentosum) may potentiate the acute reaction be prepared to live under the sun and benefit
and lower the thresholds for the acute inflamma- from sunlight, namely, with the activation of
tion or the effects of chronic phototoxicity 7-dehydrocholesterol by UVB to form pro-vitamin
(Gonçalo and Giménez-Arnau 2015; Khandpur D3, subsequently converted into Vitamin D. But
et al. 2017). there are also harmful effects of the activation of
Phototoxicity does not involve a specific cutaneous biologic systems by sunlight, namely,
T-cell-dependent response to the chromophore. photoaging and photocarcinogenesis.
This is the hallmark of photoallergy. Nevertheless, Photosensitivity develops when the concentra-
phototoxicity generates an innate immune tion of a natural chromophore is higher than nor-
response with significant danger signals that may mal or when an abnormal chromophore,
promote the presentation of the chemical or one of endogenous or mostly exogenous, is present in
its photoproducts to the immune system, therefore the skin that is simultaneously exposed to light.
favoring T-cell sensitization and photoallergy. The chromophores involved in cutaneous pho-
Both patterns of photosensitivity (phototoxicity tosensitivity are chemicals, usually with double
15 Phototoxic Dermatitis 193
bonds or halogenated aromatic rings (Mang et al. Several phototoxic substances, like psoralens,
2011) that can be selectively activated by photons chlorpromazine, some nonsteroidal anti-
with a particular wavelength, particularly UVA inflammatory drugs and fluorquinolones, apart
(320–400 nm), seldom UVB (290–320 nm), or from the capacity to generate free radicals and
visible light. Even though some chromophores cell death responsible for acute phototoxicity,
absorb in the UVB which is more energetic, also enhance chromosomal damage in the pres-
UVA penetrates the skin more deeply and, partic- ence of UV, both in vitro and in vivo (Seto et al.
ularly for systemic chromophores, this is certainly 2010). They are photo-genotoxic and photo-
the most important spectrum for inducing photomutagenic and usually also enhance photo-
sensitivity (Elkeeb et al. 2012). Only exceptional immunosupression, with consequent implications
cases have a well-documented exogenous photo- in photocarcinogenesis (Müller et al. 1998;
sensitivity exclusively from UVB (Fujimoto et al. Klecak et al. 1997; Marrot et al. 2003; Lhiaubet-
2009; Elkeeb et al. 2012). Vallet et al. 2009; Palumbo et al. 2016). Epidemi-
The molecular processes conducting to photo- ological studies and several clinical reports also
toxicity are complex, and each chromophore may show enhancement of photocarcinogenesis in
induce particular mechanisms conducting to pho- humans exposed to photoactive chemicals
tosensitivity. In general, the electrons in the outer (Placzek et al. 1999; Karagas et al. 2007; Jensen
orbits receive the energy of the UV photons and et al. 2008; Cowen et al. 2010; Miller et al. 2010;
the molecule becomes excited. The chemical can Siiskonen et al. 2013; Dawe and Ibbotson 2014).
then undergo several types of modifications
within itself (isomerization, breaking of double
bounds, oxidation) or react with neighboring mol- 3.1 Phototoxicity Versus
ecules, in the presence of absence or oxygen, Photoallergy
eventually forming free radicals or reactive oxy-
gen species (ROS). If the cellular repair mecha- Photosensitivity from exogenous chemicals is
nisms do not act immediately (antioxidant mainly caused by phototoxicity, but many of
systems, endonucleases for DNA repair), there is these phototoxic chemicals can also induce photo-
modification of unsaturated lipids of cell mem- allergy in susceptible individuals, and sometimes
branes, aromatic amino acids of proteins, and both mechanisms may coexist and overlap (Dawe
pyrimidine bases of DNA or RNA causing cellu- and Ibbotson 2014; Gonçalo and Giménez-Arnau
lar lesion or death. The activation of intracellular 2015).
signaling pathways (NF-κB, MAP-kinases, the Classically, phototoxicity is more frequent and
Nrf-2 antioxidant response element pathway, and develops in every individual, as long as enough
the inflammasome) generates soluble inflamma- photosensitizer and sun exposure are simulta-
tory mediators (prostaglandins, leukotriene, inter- neously present. It is dependent on the dose of
leukins (IL)-1, 6, 8, other cytokines and UV and the photosensitizing chemical. The reac-
chemokines) with consequent inflammation and tion can occur on a first and single contact, with no
skin lesions (Hawk 1999; Ferguson 1999; Mang flare-ups or cross-reactions in further exposures,
et al. 2011). In photoallergy, the energy of the appears mainly as a sharply demarcated erythema
photon transforms the chromophore into a stable exclusively on sun-exposed areas (mimicking
photoproduct or enhances its reaction with an sunburn), resolves with hyperpigmentation and,
endogenous peptide forming a hapten or an aller- on histology, apoptotic keratinocytes (sunburn
gen. This is captured by skin antigen-presenting cells) are abundant.
cells and sensitizes T cells, that in a further expo- On the other extreme, photoallergy develops
sure to the same chemical will generate a specific only in a limited number of individuals and needs
T-cell immune reaction – adaptive immunity/type previous sensitization but can develop also with
IV hypersensitivity reaction (Mang et al. 2011; cross-reactive chemicals. It is not dose-dependent,
Peiser et al. 2012; Elkeeb et al. 2012). can occur even with low UV exposure, and
194 M. Gonçalo
appears mostly as eczema that can spread to non- allergens that have an inherent “irritant” potential
UV-exposed sites and, on skin biopsy, there is that awakens the innate immune system and pro-
mainly T-cell infiltration, spongiosis, and vesicles motes sensitization (Neves et al. 2008), most
(Table 1). photoallergens also have some phototoxic poten-
These are the typical aspects of the polar tial. This innate inflammatory reaction can be the
aspects of photosensitivity, but it is not always “danger signal” necessary to initiate sensitization.
possible to distinguish them based on the clinical Photosensitivity developing on the first expo-
aspects, histopathology or photopatch or photo- sure to the chemical is typical of phototoxicity,
provocation test results, or even by the culprit whereas photoallergy needs several exposures to
chemical. induce sensitization before lesions develop. Nev-
Except for a few chemicals with no intrinsic ertheless, in an enigmatic way, photoallergy to
phototoxic potential that give rise to stable photo- piroxicam and ketoprofen occurs often at the
products, like piroxicam and olaquindox, and first exposure. This is explained as individuals
induce only photoallergy (Figueiredo 1994), are previously sensitized or photosensitized to a
most substances can induce both phototoxic and molecule similar to their photoproducts, namely
photoallergic reactions. Actually some individ- the contact allergen thimerosal and its moiety
uals develop photoallergy from highly phototoxic thiosalicylic acid, in the case of piroxicam
chemicals like psoralens (Ljunggren 1977; Möller (Gonçalo et al. 1992; Ikezawa et al. 1992; Hariva
1990; Karimian-Teherani et al. 2008; Bonamonte et al. 1993; Figueiredo 1994) or cinnamic alcohol
et al. 2010), phenothiazines (Kerr et al. 2008b; or a benzophenone, in the case of ketoprofen (Foti
Cardoso et al. 2009), or fluorquinolones et al. 2008; Avenel-Audrun et al. 2010; Stingeni
(Kurumajin and Shono 1992; Gonçalo 1998; et al. 2010).
Oliveira et al. 1996). Very probably, as for contact Phototoxicity is considered to occur in every
patient as long as enough chromophore and sun
are present at the same time, but there is some
Table 1 Distinction between acute phototoxicity and individual susceptibility that is not completely
photoallergy
understood. In systemic drug photosensitivity,
Phototoxicity Photoallergy
we may suspect that differences in drug metabo-
Frequency High Low
lism may generate different amounts of the photo-
Latency period/ No Yes
sensitization active metabolite and thickness of the horny layer
Doses of High Low or the degree of melanin pigmentation may
UV/photosensitizer influence both systemic drug phototoxicity,
Cross-reactions No Yes
phytophotodermatitis, or contact phototoxicity
Morphology of Sunburn, Eczema,
lesions polymorphic erythema (Zaheer et al. 2016), but other susceptibility fac-
multiforme tors for developing phototoxicity need further
Sharp limits Yes No investigation.
Covered areas Not involved Possibly
Acute phototoxicity presents mainly as an
involved
Resolution Quick May recur, exaggerated sunburn reaction, but it may develop
persistent vesicles and bullae that may be difficult to distin-
reactors guish from photoallergy. Hyperpigmentation, typ-
Residual Yes No
hyperpigmentation
ical of phototoxicity, may also develop as a
Histology Sunburn cells Eczema consequence of photoallergy, as in cases induced
Pathomechanism DNA/cell damage Type IV by fragrances (Gonçalo et al. 1991).
ROS/inflammation hypersensitivity Photoallergic reactions may recur and become
photoproduct
Photopatch tests Not indicated Positive,
persistent and eventually progress to chronic actinic
Nonspecific particularly in dermatitis with extreme photosensitivity in the
positive reaction photoallergic absence of exposure to the culprit chemical (Hawk
contact dermatitis
2004; Béani 2009), whereas phototoxic reactions
are considered transient. Nevertheless it is important 12–24 hours or a few days (acute phototoxic or
to be aware that phototoxic reactions or even sub- photo-allergic reactions), several days or weeks
clinical phototoxicity may induce long-term damage (pseudoporphyria, photo-onycholysis or subacute
(photoaging and photocarcinogenesis). lupus erythematosus), or months or years (drug-
enhanced photoaging and photocarcinogenesis).
Localization of the lesions depends on whether
4 Clinical Patterns the photoactive chemical is directly applied on the
of Phototoxicity from skin (photocontact dermatitis) or the photosensi-
Exogenous Chemicals tizer reaches the skin after systemic exposure.
In photosensitivity from a topical agent, der-
Photosensitivity from exogenous chemicals can matitis draws the area of application and concom-
present under various clinical patterns with acute itant sun exposure, but distant lesions can occur in
and delayed lesions: urticaria, eczema or ery- areas of accidental contact, as in a contralateral
thema multiforme-like lesions (mainly in acute limb (kissing faces of the legs), and in areas of
photoallergy), erythema, edema and bullae inadvertent spread by the hands or contaminated
with progression to hypo or hyperpigmentation objects (Hindsén et al. 2004; Lasa Elgezua et al.
(mainly in acute phototoxicity), or as lichenoid 2004). Connubial/consort dermatitis can also
reactions, subacute or chronic cutaneous lupus occur from contact photosensitizers (Fernández-
erythematosus, photoaging and actinic keratosis, Jorge et al. 2008). Some topical nonsteroidal anti-
and squamous cell carcinomas (late reactions). inflammatory drugs (NSAIDs) are considerably
Lesions can be very evocative of phototoxicity, absorbed through the skin and lesional distribu-
as in phytophotodermatitis, acute exaggerated sun- tion can mimic systemic photosensitivity.
burn, or photoonycholysis, but sometimes the diag- In systemic photosensitivity, the reaction usu-
nosis or even the suspicion of photosensitivity is ally involves, in a symmetric distribution,
not so obvious (cutaneous lupus erythematosus or UV-exposed areas of the face, the V-shaped area
telangiectasia) particularly when there is no imme- of the neck and upper chest, dorsum of the hands
diate or evident relation with exposure to the sun and forearms, and occasionally also the legs and
and the exogenous chemical (actinic keratosis and dorsum of the feet. UV-shaded areas of the face
skin cancer) (Table 2). and neck are spared like the upper eyelids, upper
Skin lesions can occur immediately after sun lip, deep facial wrinkles (Fig. 1), retroauricular
exposure (photocontact urticaria), within areas, a submandibular rhomboid area, and areas
covered by the beard, hair, or clothing. In systemic
Table 2 Clinical patterns of photosensitivity photosensitivity or after using oral solutions, the
lower lip can be mainly or almost exclusively
Predominant in
Predominant in phototoxicity photoallergy involved, because of its higher UV exposure and,
Exaggerated “sunburn” Urticaria in very probably, because of the thinner corneal layer
sun-exposed area more prone to phototoxic reactions (Auffret et al.
Pseudoporphyria Acute or subacute 2006; Cardoso et al. 2009; Canelas et al. 2010).
eczema Large body folds, like the axillae, groins, finger
Photoonycholysis Erythema multiform- webs, and areas covered by clothing or other
like
accessories (watch strip, shoes) (Fig. 2), are also
Hyperpigmentation/ Lichenoid reactions
hypopigmentation (vitiligo- usually spared. Involvement of these shaded areas
like lesions) suggests dermatitis from an airborne allergen or
Telangiectasia and/or Purpura Subacute or chronic irritant.
lupus erythematosus Asymmetric sun exposure, as in car drivers
Pellagra-like reactions who only expose the left arm, or limited exposure
Actinic keratosis and to artificial light can change localizations
accordingly.
196 M. Gonçalo
Fig. 1 Acute phototoxicity from amiodarone, mimicking

sunburn, and sparing the deep facial wrinkles
Fig. 2 Photosensitivity from systemic lomefloxacin, spar-
ing the sunshaded areas of the trunk, arm, and front covered
4.1 Acute Patterns of Phototoxicity by clothing and hat and also the wrist protected from the
watch
4.1.1 Immediate Reactions

Immune-mediated or nonimmune urticaria as a can progress to vesicles and bullae, but eczema-
manifestation of photosensitivity from an exoge- tous lesions with small vesicles or multiforme-like
nous chemical has been described with lesions are not usual. Photo-induced Stevens-
5-aminolevulinic acid used in photodynamic ther- Johnson syndrome/toxic epidermal necrolysis
apy (Kerr et al. 2007), oxybenzone in sunscreens has also been associated with drug phototoxicity
(Collins and Ferguson 1994), and chlorpromazine (Redondo et al. 1996; Moghaddam and Connolly
(Lovell et al. 1986). Some drugs, like amiodarone, 2014).
benoxaprofen (removed from the market), and Like in exaggerated sunburn, large sheets of
vemurafenib, induce immediate prickling and necrotic epidermis will detach within the next
burning with transient erythema as a manifesta- days and hyperpigmentation may occur (Fig. 2).
tion of photosensitivity (Ferguson 1999; Dummer
et al. 2012; Gelot et al. 2013; Brugière et al. 2014).
4.2 Subacute Patterns
4.1.2 Acute Phototoxic Dermatitis, of Phototoxicity
Mimicking Sunburn
The main clinical pattern of acute phototoxicity Some clinical patterns of phototoxicity develop
(exaggerated sunburn) develops within 12–24 h within days or weeks after exposure to the
of sun exposure with a sharply demarcated ery- photosensitizer and the sun: pseudoporphyria,
thema with prickling and burning, eventually with photoonycholysis, hyper- or hypopigmentation,
skin pain but typically without pruritus. Erythema telangiectasia, and purpura.
4.2.1 Pseudoporphyria
Pseudoporphyria presents as chronic skin fragility
with flaccid bullae and easy bruising on non-
inflamed exposed skin, which resolve completely
or occasionally, with milia formation. It resembles
porphyria cutanea tarda both clinically and on
histopathology (bullae formation below the lam-
ina densa and a poor dermal inflammatory infil-
trate). It occurs in individuals with no inborn error
of porphyrin metabolism and no increase of
endogenous porphyrins (Glatz and Hofbauer
2012; Dawe and Ibbotson 2014; Gonçalo and
Giménez-Arnau 2015; Gonçalo 2016).
Fig. 3 Photoonycholysis from chlortetracycline
Pseudoporphyria was initially described in
individuals exposed to phototoxic drugs like Photoonycholysis occurs mainly with tetracy-
nalidixic acid, furosemide, tetracyclines and clines (demeclocycline, doxycycline) (Passier et al.
naproxen, predominantly in children (Ferguson 2004; Goetze et al. 2017), psoralens, NSAIDs
1999; Gonçalo and Giménez-Arnau 2015; Rok (diclofenac), and fluorquinolones (Baran and
et al. 2015). More recently others drugs have Juhlin 2002; Glatz and Hofbauer 2012; Al-Kathiri
been associated with this phototoxic reaction pat- and Al-Asmaili 2016). There is no definite expla-
tern: ciprofloxacin (Schmutz et al. 2008), nation for the isolated nail involvement: the nail
celecoxib (Cummins et al. 2000) (Schmutz et al. bed is relatively unprotected from sunlight with
2006), voriconazole (Auffret et al. 2006; Tolland fewer melanocytes and the nail plate may work as
et al. 2007; Hickman et al. 2010; Riahi and Cohen a lens focusing the energy to cause the inflamma-
2011), torsemide (Pérez-Bustillo et al. 2008; tory reaction and induce detachment of the nail
Quaiser et al. 2015), imatinib (Timmer-de Mik plate from the nail bed (Baran and Juhlin 2002;
et al. 2009; Berghoff and English 2010), finaste- Passier et al. 2004; Gregoriou et al. 2008;
ride (Santo Domingo et al. 2011), and metformin Al-Kathiri and Al-Asmaili 2016).
(Lenfestey et al. 2012), and in Australia, it has
been associated with detoxifying drinks rich in 4.2.3 Dyschromia
chlorophyll (Zhao et al. 2016). Hyperpigmentation following an acute phototoxic
Pseudoporphyria represents a typical photo- reaction is similar to the normal UV response
toxic reaction where the drug, as the uroporphyrin with IL-1alfastimulating keratinocytes to pro-
in the hereditary disease, induces phototoxicity duce melanotropins and activate melanocytic
probably through singlet oxygen (Ferguson pigmentation (Rok et al. 2015; Khandpur et al.
1999; Figueiredo 1994). 2017). This hyperpigmentation occurs typically
with psoralens, namely in phytophotodermatitis
4.2.2 Photoonycholysis (Fig. 3).
Photoonycholysis is a typical pattern of phototox- Hypopigmentation has been described in
icity, occurring most often as the single manifes- flutamide-induced photosensitivity (vitiliginous
tation (Fig. 3). It presents most often as a lesions with sharp limits after the acute reaction)
half-moon distal onycholysis of one or several (Vilaplana et al. 1990; Gonçalo et al. 1999),
nails, but it can occur as a circular notch in a single and photoleukomelanoderma has been observed
finger, a yellow staining of the nail bed or a bullae after chronic exposure to hydrochlorothiazide
under the nails (Baran and Juhlin 2002). It appears (Khandpur et al. 2017).
late (2–3 weeks after drug intake and sun expo- Dyschromia from the dermal accumulation
sure), sometimes preceded by pain in the nail of the photoactive drug or its metabolites occurs
apparatus. in a smaller percentage of patients after acute
198 M. Gonçalo
phototoxicity from amiodarone (Ammoury et al. Recent reports and epidemiological data also corre-
2008; Kosior 2014), minocycline, imipramine, late chronic human exposure to photoactive drugs
clozapine, or phenothiazines (Vassileva et al. with an increased risk of developing actinic kerato-
1998; Khandpur et al. 2017). Some patients with ses, nonmelanoma skin cancer, and even, malignant
lower phototypes also develop a golden-brown, melanoma. In 1999, the group of Przybilla showed
slate gray, or bluish color on sun-exposed areas, an association between actinic keratosis and the use
which persists much longer than residual of potentially photosensitizing chemicals (Placzek
melanocytic hyperpigmentation (Ammoury et al. et al. 1999). More recent studies tend to confirm an
2008; Khandpur et al. 2017). increased risk for skin cancer in patients chronically
exposed to psoralens, fluoroquinolones, NSAIDs,
4.2.4 Other Clinical Patterns and diuretics (Jensen et al. 2008) and voriconazole
Telangiectasia as a manifestation of photosensi- (McCarthy et al. 2007; Epaulard et al. 2013; Goyal
tivity has been reported with calcium channel 2015). Also, patients with severe chronic photosen-
blockers, like nifedipine and amlodipine (Glatz sitivity develop skin cancers in photoexposed areas,
and Hofbauer 2012), and the telangiectatic pattern like squamous cell carcinoma with ciprofloxacin
of photoaging with lesions mainly in the lateral (personal experience) and both squamous cell carci-
folds of the neck, sparing the shaded rhomboid noma and melanoma with voriconazole (Cowen
area under the chin, is frequently observed in et al. 2010; Miller et al. 2010).
patients chronically exposed to the sun and/or Photoaging, with solar lentigines and actinic
photoactive drugs. Petechial purpura with sharp keratosis, may also be enhanced by the exposure
limits on the transition to the shaded areas was to topical or systemic photosensitizers.
described with ciprofloxacin (Urbina et al. 2006).
Pellagra is associated with the prolonged use of
isoniazid that consumes niacin for its metabolism, 5 Main Sources of UV Exposure
and pellagra-like reactions were reported with the
anticancer and immunosuppressive drugs, like Recreational and/or occupational sun exposure is
6-mercaptopurine and 5-fluorouracil and azathio- the main source of UV radiation for phototoxicity.
prine (Oliveira et al. 2011; Khandpur et al. 2017). Farmers, gardeners, construction workers, fisher-
men, sailors, policemen, ski instructors, oil-field
workers, and road workers are occupations where
4.3 Delayed and Late Effects sun exposure can be heavy and prolonged and
of Phototoxicity begin at an early age.
Artificial UV light sources are present in some
Patients that are chronically exposed to photoactive occupational settings (electric arc welding, solar-
drugs may develop other patterns of skin lesions, ium and phototherapy units, plants for UV curing
like chronic actinic dermatitis and lupus of printing inks, lacquers, dental or nail acrylates)
erythematosus where autoimmune reactions are pre- and artificial illumination with UVA light-
dominantly involved, or accelerated photoaging and emitting bulbs with no plastic/glass cover may
skin cancers, which can be explained by the photo- be an additional UVA source.
genotoxic effect of some phototoxic molecules.
There is a consensual agreement on the increased
risk of nonmelanoma skin cancers after long-term 6 Main Causes of Topical
therapeutic exposure to PUVA therapy (Stern 2012; and Systemic Phototoxicity
Archier et al. 2012) but, apart from psoralens,
naproxen, chlorpromazine, and the fluorquinolones, Plants and drugs are the main causes of phototoxic
particularly lomefloxacin, also augment in vitro reactions, but there is a large and increasing list of
UV-induced DNA aggression and increase epider- photoactive molecules, particularly drugs,
mal neoplasia in animals (Klecak et al. 1997). reported to cause photosensitivity (Table 3).
Table 3 Main agents causing exogenous phototoxicity UV filters, particularly the benzophenones,
Plants Umbelliferae butylmethoxydibenzoylmethane, octocrylene, and
Ammi majus cinnamates, represent the main topical photosensi-
Apium graveolens (celery) tizers diagnosed by photopatch testing (Darvay
Pastinaca sativa (parsnip) et al. 2001; Sheuer and Warshaw 2006; Cardoso
Petroselinum crispum (parsley) et al. 2009; EMCPPTS Taskforce et al. 2012), but
Heracleum mantegazzianum they represent almost exclusively contact allergic,
(giant hogweed) photoallergic, or photoaggravated reactions; there-
Rutacea
fore, they will not be further referred.
Citrus spp.
In recent decades, premarketing assessment of
Citrus aurantica v. bergamia
(bergamot) the phototoxic potential of cosmetics, consumer
Citrus aurantifolia (lime) products, and drugs has been reinforced, and
Citrus limon (lemon) many photosensitizers have been removed
Ruta graveolans (common rue) or highly reduced in our ambience. Some are
Dictamus albus (burning bush) now considered “historical” photosensitizers:
Moracea musk ambrette and natural bergamot oil
Ficus carica (fig) removed from perfumes; the sunscreens iso-
Hypericaceae propyl–dibenzoylmethane, withdrawn in 1994,
Hypericum perforatum (Saint John’s wort) and PABA (para-aminobenzoic acid) which
Drugs Antimicrobials sensitized about 4% of the American population
Tetracyclines (demeclocycline, doxycycline, in the 1950s (Lowe 2006), are no longer used;
minocycline)
olaquindox, an antibiotic added to swine feed,
Sulphonamides (sulfametoxazole)
was banned in 1998 by the European
Fluorquinolones (lomefloxacina, b,
ciprofloxacina, b) Commission (Emmert et al. 2007); the haloge-
Voriconazoleb, griseofulvin, efavirenz nated salicylanilides were removed from disinfec-
Nonsteroidal anti-inflammatory drugs tants and hygiene products in most countries since
(NSAIDs) 1976, and the phototoxic NSAIDs carprofen and
Arylpropionic acidsa, b: Ketoprofen, tiaprofenic benoxaprofen were before 2000. Nevertheless,
acid, suprofen, naproxen, ibuprofen, even though not available in Europe, these
ibuproxam, carprofen
chemicals can be “imported” and still induce pho-
Benzydaminea, etofenamatea
tosensitivity (Emmert et al. 2007; Waters et al.
Azapropazone, diclofenac, fenilbutazone,
indometacine, celecoxib 2009; Gonçalo et al. 2013).
Phenotiazines
Chlorpromazinea, thioridazine
Promethazinea, Chorproethazinea
Antidepressants 6.1 Plants Causing
Clomipramine, imipramine, sertraline Phytophotodermatitis
Cardiovascular drugs
Amiodarone, quinidine, nifedipine, Photoactive furocoumarins, e.g., bergapten (5-
amlodipine, diltiazem methoxypsoralen), 8-methoxypsoralen, 5,6
Furosemide, indapamide and thiazide diureticsb
dimethoxyisopsoralen, sphondin (6-methoxy-iso-
Anticancer agents
psoralen), and isobergapten (5-methoxy-iso-
Paclitaxel, 5-fluoruracil, Dacarbazine,
methotrexate, azathioprine, vemurafenibb
psoralen) run in the sap of several plants in
Miscellaneous amounts that vary, for instance, according to the
Flutamide, sulfonylureas, fenofibrate, seasons. They are beneficial for the plant as a
simvastatin, pirfenidone, vandetanib protection against fungus and insects.
a
Also reported to cause frequent photoallergic reactions Since the antiquity, these substances have been
b
Associated with enhanced photocarcinogenesis used in folk medicine in the treatment of vitiligo
200 M. Gonçalo
and, more recently, in photochemotherapy hyperpigmentation, allowing a retrospective diag-

(PUVA). Aromatic oils rich in furocoumarins, nosis (Gonçalo 2004).
used in tanning oils, were considerably reduced, Other patterns of phytophotodermatitis are the
as the accelerated tanning they induce is consid- “strimmer dermatitis,” a more diffuse involve-
ered more harmful than protective. ment as the sap of the plant is sprayed all over
The natural bergamot oil, extracted from the the body by the string trimmer, leg dermatitis in
rind of Citrus bergamia, previously included in walkers who develop lesions only above the
oils and perfumes, was responsible for a very socks, and blisters around their mouth in children
particular type of phototoxic dermatitis, “breloque who make trumpets or pea shooters from the
dermatitis,” or berlock dermatitis. It presented as hollow stems of the giant hogweed (Heracleum
erythema followed by hyperpigmentation in the mantegazzianum) (Lovell 2000).
shape of a pendant, simulating a breloque, usually Plants used in “folk medicine” can cause sys-
beginning in the face or upper neck and temic or contact phototoxicity, namely, the inges-
descending down to the collar. It corresponds to tion of celery, parsnip, infusions of St. John’s wort
the area of application of the perfume drop and the (Hypericum perforatum L.) for depression (Lovell
subsequent dependent draining area. The natural 2000; Schempp et al. 2002; Elkeeb et al. 2012), or
oil of bergamot is no more used in perfumes and the application of infusions of Ruta graveolens to
breloque dermatitis is an image of the past, but relieve pain in fibromyalgia (Arias-Santiago
phototoxicity from psoralens is still observed with et al. 2009).
aromatic citrus oils used in sauna and massages Plants causing phytophotodermatitis occur all
(Lovell 2000; Zink and Ring 2014). over the globe and belong mainly to the families
At present, phototoxic dermatitis from of Umbelliferae, Rutacea, and Moracea (Table 3).
psoralens occurs mainly from inadvertent contact
with plants, either during recreation or in occupa-
tional settings. Main occupational exposures 6.2 Photosensitive Drugs
occur in rural workers or gardeners who harvest
fruits or vegetables (parsnip, figs) or cut bushes Drugs used systemically or applied topically are
and weeds like common rue (Ruta graveolens), the main cause of exogenous photosensitivity,
burning bush (Dictamnus albus), fig trees (Ficus particularly in Southern European countries
carica) (Gonçalo et al. 1989; Lovell 2000) or (Leonard et al. 2005; La Cuadra-Oyanguren
giant hogweed (Heracleum mantegazzianum), et al. 2007; Cardoso et al. 2009; EMCPPTS
which has become widespread in Poland causing Taskforce et al. 2012). Although most relevant
severe occupational cases of phototoxicity data are from positive photopatch test results that
(Klimaszyk et al. 2014). Barmen who squeeze evaluate photoallergy, many of these drugs are
and peal the lime (Citrus aurantifolia) and other also phototoxic.
citrus fruits to prepare cocktails in the sunny Drugs manipulated in an occupational setting
weather can also develop contact phototoxic der- can induce contact photosensitivity: carprofen in
matitis, usually with less severe lesions (Wagner workers who manufacture the drug for animals
et al. 2002; Gonçalo 2004) (Fig. 4). (Walker et al. 2006; Kerr et al. 2008a), chlorprom-
In 1934 Oppenheim described the most typical azine in nurses and family members who smashed
pattern of phytophotodermatitis – dermatosis the tablets of to give their patients/relatives (Car-
bullosa striata pratensis – with prickling linear doso et al. 2009; Monteagudo-Paz et al. 2011),
erythematous skin lesions that correspond to the and olaquindox or cotrimoxazole in farmers who
contact with the damaged leaves of the plant. contact pig or rabbit feed (Emmert et al. 2007;
They develop within 12–48 h after the contact Watanabe et al. 2009).
with the plant and sun exposure, may be followed Systemic drugs that more frequently cause
by painful vesicles and bullae (Figs. 5 and 6) and phototoxicity include antimicrobials, antifungals,
gradually turn into long-lasting brown linear NSAIDs, phenothiazines, cardiovascular and
Fig. 4 Residual
pigmentation in the
forearms in a barman who
squeezed limes and lemons
for cocktails, during an
outdoor summer festival
(note limit due to glove
protection)
Fig. 5 Phytophotodermatitis with linear streaks of erythema and hyperpigmentation in a patient who contacted Ruta
graveolens from her garden
anticancer drugs, and a miscellaneous group and pseudoporphyria (Vassileva et al. 1998;
(Glatz and Hofbauer 2012; Dawe and Ibbotson Kuznetsov et al. 2011). Minocycline, though less
2014; Monteiro et al. 2016). After topical appli- phototoxic, can also induce a bluish persistent
cation, NSAIDs are by far the most frequent cause pigmentation and has caused photoonycholysis,
of photosensitivity, mostly photoallergy (Leonard like lymecycline (Wlodek and Narayan 2014;
et al. 2005; La Cuadra-Oyanguren et al. 2007; Monteiro et al. 2016).
Cardoso et al. 2009; EMCPPTS Taskforce et al. The fluorquinolones with an halogen at C-8
2012). (fleroxacin, lomefloxacin, sparfloxacin, pefloxacin)
frequently induce phototoxic reactions (4–15%
6.2.1 Antimicrobials of treated patients), which are less frequent with
Systemic tetracyclines, doxycycline, and particu- ciprofloxacin, norfloxacin, ofloxacin, and eno-
larly demeclocycline, are highly phototoxic and xacin (Monteiro et al. 2016). Like the first quino-
induce exaggerated sunburn, photoonycholysis, lone, nalidixic acid, ciprofloxacin has caused
202 M. Gonçalo
Fig. 6 Phytophotodermatitis with linear bullous lesions in the arms, after cutting a fig tree during a sunny day
pseudoporphyria (Vassileva et al. 1998; Schmutz photo-distribution of skin lesions and subacute
et al. 2008) and also purpura on photoexposed lupus erythematosus in patients with anti-Ro anti-
areas (Urbina et al. 2006) and photo-induced Ste- bodies (Farhi et al. 2006; Murad et al. 2015).
vens-Johnson syndrome (Moghaddam and Voriconazole is the only triazole antifungal
Connolly 2014).Although in vitro and in vivo tests consistently associated with severe phototoxicity
prove the high phototoxic potential of that can affect more than 40% of patients, partic-
fluorquinolones, photoallergy has also been ularly children treated longer than 4–6 months
reported with lomefloxacin (Oliveira et al. 1996; (Goyal 2015; Sheu et al. 2015). Voriconazole
Kurumajin and Shono 1992) and enoxacin phototoxicity presents initially as exaggerated
(Vassileva et al. 1998), sometimes with cross- sunburn, cheilitis, pseudoporphyria (Tolland
reaction to other fluorquinolones (ciprofloxacin et al. 2007; Frick et al. 2010) and within 1 or
and flerofloxacin) (Kimura and Kawada 1998; 2 years as accelerated photoaging with solar
Correia et al. 1994). lentigines, actinic keratosis, and enhanced photo-
Moreover, the fluorquinolones also photosen- carcinogenesis, with the occurrence of multiple
sitize DNA and may be photomutagenic and and aggressive nonmelanoma skin cancers and
photocarcinogenic in vitro and in animal experi- also malignant melanoma (Auffret et al. 2006;
ences (Klecak et al. 1997). In our experience a McCarthy et al. 2007; Cowen et al. 2010; Miller
patient on long-term ciprofloxacin therapy for et al. 2010; Goyal 2015; Epaulard et al. 2013).
multiresistant tuberculosis developed photosensi- A metabolite of voriconazole – N-oxide-vori-
tivity and a highly aggressive squamous cell car- conazole – formed in the liver but possibly also
cinoma of the face (personal experience). in skin cytochromes, and other photoproducts of
Sulfonamides, sulfa-drug analogs (thiazide voriconazole under UVA exposure have been
diuretics, hypoglycemic sulfonylureas, and cele- shown to be responsible for phototoxicity and
coxib), and dapsone (diaminodiphenylsulfone) photocarcinogenesis (Haylett et al. 2013; Goyal
have been reported to cause photosensitivity 2015). The immunosuppressed background of
within the spectrum both of UVB and UVA, but most patients that need long-term voriconzaole
this side effect is not so frequent with cotrim- treatment may also enhance cutaneous carcino-
oxazole (Vassileva et al. 1998; Yazici et al. 2004). genesis, but the type and aggressive behavior of
Grisefulvin is a known phototoxic drug that the skin cancers related to voriconazole are dis-
can aggravate lupus erythematosus, and tinct from those described in organ-transplanted
terbinafine induced Rowell syndrome with or other immunosuppressed patients, therefore
reinforcing the effect of the drug (Epaulard et al. The antiarrhythmic amiodarone is a well-
2013). known photosensitizer. Apart from erythema in
sun-exposed areas, it induces a bluish-gray hyper-
6.2.2 Nonsteroidal Anti-inflammatory pigmentation in sun-exposed areas due to the
Drugs accumulation of drug metabolites in the dermis
Benoxaprofen marketed between 1980 and 1982 (Ammoury et al. 2008; Kosior 2014). Other car-
called the attention to photosensitivity from this diovascular drugs have been associated with
class of drugs. Thereafter, photosensitivity was photo-induced reactions, like amlodipine and
reported with all the other arylpropionic deriva- nifedipine (telangiectasia), diltiazem (lichenoid
tives (carprofen, naproxen, suprofen, tiaprofenic reaction with hyperpigmentation), the thiazide
acid, ketoprofen, and ibuprofen), particularly for diuretics, and furosemide/torsemide (pseudo-
tiaprofenic acid, which induced typical toxic reac- porphyria, subacute lupus erythematosus,
tions in more than half of the patients photopatch photoonychoysis).
tested with tiaprofenic acid (5% pet) and 5 J/cm 2 Some anticancer drugs are also associated with
of UVA (Gonçalo and Figueiredo 1992; Figuei- photo-induced lesions, like methotrexate (sun-
redo 1994; Neumann et al. 2000). NSAIDs from burn recall reaction), 5-fluoruracil, 6-mercapto-
other groups (azapropazone, diclofenac, pir- purine and azathioprine (pellagra-like reactions),
oxicam, fenilbutazone, celecoxib, benzydamine, paclitaxel and other taxanes (drug-induced lupus
and etofenamate) have been associated with erythematosus) (Lamond et al. 2013), imatinib
photosensitivity. (pseudoporphyria), vandetanib (Chang et al.
Ketoprofen and piroxicam cause most cases of 2009; Giacchero et al. 2012), and particularly
photosensitivity (EMCPPTS Taskforce et al. Vemurafenib used in metastatic melanoma. Pho-
2012; Gonçalo et al. 2013), particularly photo- tosensitivity occurs in more than 50% of patients
allergy and with a peculiar pattern of cross- under veramufenib therapy and presents as burn-
reactions with contact allergens or photoallergens ing and painful sensation with a sharply demar-
(Imai et al. 2005; Béani 2009; Cardoso et al. cated erythema and edema that appear still during
2009): cinnamic alcohol, oxybenzone, UV irradiation, resembling solar urticaria, but
octocrylene, and fenofibrate for ketoprofene erythema and edema last longer as in erythropoi-
(Pigatto et al. 1996; LeCoz et al. 1998; etic protoporphyria (Dummer et al. 2012; Gelot
Devleeschouwer et al. 2008; Foti et al. 2008; et al. 2013; Brugière et al. 2014). The mechanism
Avenel-Audrun et al. 2010), and thimerosal and is not yet fully understood, but consistently there
thiosalicylic acid for piroxicam (Gonçalo et al. is a very low minimal erythema dose (MED) for
1992; Hariva et al. 1993). UVA during therapy that normalizes shortly after
Chronic use of phototoxic NSAIDs has also its suspension (Dummer et al. 2012; Gelot et al.
been associated with enhanced photo- 2013; Brugière et al. 2014). Studies have shown
carcinogenesis, including malignant melanoma either normal or elevated erythrocyte porphyrins
(Siiskonen et al. 2013) and reduced PP vitamin (Gelot et al. 2013),
whereas others show the capacity of Vemurafenib
6.2.3 Other Drugs as Photosensitizers and its UVA photoproducts to incorporate in cell
Phenothiazines used systemically (chlorproma- membranes and generate toxic radicals and singlet
zine and thioridazine) can induce photosensitivity, oxygen that are lethal to the cells even at very low
often with a lichenoid pattern and with residual doses (Teixeira et al. 2016).
pigmentation (Ferguson 1999). They are typically Another highly phototoxic drug was approved
phototoxic but photoallergy occurs frequently in 2011 for pulmonary fibrosis – pirfenidone.
when promethazine is used as topical antipruritic Photosensitivity can be observed in about 50%
(Cardoso et al. 2009; Katsarou et al. 2008) or of treated patients, but this is a known phototoxic
chlorproethazine cream is used for muscle pain chemical and a warning is included in the bulla
(Barbaud et al. 2001a; Kerr et al. 2008b). (Jiang et al. 2012; Adachi et al. 2015; Gaikwad
204 M. Gonçalo
and Mukherjee 2016; Papakonstantinou et al. histology is performed, there are many sunburn
2016). cells in the epidermis. On the other hand, a pruritic
There is a never-ending list of drugs that may erythema with vesicles, diffuse limits extending
cause photosensitivity, and new drugs are beyond the chamber limit, which increase in
released, some of them despite a known photo- intensity until 48–72 h after UV irradiation (cre-
toxic potential. Therefore, whenever a patient has scendo reaction), suggests photoallergy (Neu-
a photosensitive eruption a systematic inquiry for mann et al. 1994). But sometimes the clinical
drugs should be carefully conducted. pattern of a positive photopatch test reaction is
difficult to interpret, in agreement with the diffi-
culties in the interpretation of clinical cases.
7 Diagnostic Procedures Photoprovocation tests calculating MED by
and Preventive Measures irradiating a 2.5 2.5 cm area of the skin with
in Phototoxicity increasing doses of UVA, UVB, or with a selected
wavelength using a monochromator can give inter-
Phototoxicity can have such typical lesions, as in esting information, even in systemic phototoxicity.
phytophotodermatitis or in exaggerated sunburn The different MED values when the patient is
after the use of a systemic phototoxic drug, that exposed to the drug and after its suspension con-
no further diagnostic procedures are needed. firm that the drug is reducing tolerance to UV and
Photopatch and photoprovocation tests will be defines the UV spectrum responsible for the reac-
positive in the great majority of individuals tion and, if irradiation is performed in a skin area
when tested with phototoxic chemicals; therefore, pretreated with different sunscreens, the test may
these tests are of little use for confirming the evaluate the possible protective effect of a sun-
etiology of a phototoxic reaction. Photopatch screen and the best UV filter or combination of
tests are mainly indicated for the etiologic diag- UV-filters that prevents the phototoxic reaction.
nosis of photallergic contact dermatitis and sys- For instance, UV filters that protect against
temic drug photoallergy (Gonçalo 1998; Barbaud UVA have shown to be effective against
et al. 2001b) but can disclose a hidden photo- vermurafenib phototoxicity (Dummer et al. 2012).
allergy in a photosensitive reaction. Apart from efficient sunscreens and protective
Photopatch testing should be performed clothing, a reduction of the drug dose or the quan-
according to a standardized procedure (Bruynzeel tity of UV exposure can prevent some phototoxic
et al. 2004), using the baseline photopatch tests reactions. Taking the drug by the end of the day
series and additional substances according to may reduce circulating drug concentrations dur-
patient exposure (Gonçalo et al. 2013). Irradia- ing midday when UV exposure is more likely,
tion of one set of allergens at day 1 or day eventually reducing the phototoxic reaction.
2 should be performed with 5 J/cm2 of UVA.
Readings should be done immediately after irra-
diation and also 48 and/or 72 h thereafter 8 Conclusions
(Johansen et al. 2015).
Photopatch test results have to be carefully Phototoxic, photoallergic, and overlapping photo-
interpreted. A reaction only in the irradiated side sensitive reactions are still a frequent problem.
mainly with erythema and edema, without pruri- They have a highly polymorphic clinical presen-
tus, exclusively limited to the test chamber area, tation, with different time courses and variations
with very sharp limits that begins shortly after in the responsible agents, depending on geo-
irradiation, has its highest intensity by 24 h and graphic areas and evaluated years. Therefore, the
regresses by 48/72 h (decrescendo reaction) with dermatologist must be highly alert to search for a
hyperpigmentation, suggesting a phototoxic reac- possible involvement of an exogenous chromo-
tion. A similar reaction may be observed in many phore in a photosensitive patient. A correct ques-
individuals tested in the same conditions and, if tionnaire should be conducted (Cazzaniga et al.
2015) and, although not so important in typical Berghoff AT, English JC (2010) Imatinib mesylate-
phototoxic cases, complementary tests including induced pseudoporphyria. J Am Acad Dermatol
63(1):e14–e16
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tribute to the final etiologic diagnosis and, conse- (2010) Photoallergic contact dermatitis to 8-MOP in
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Bruynzeel DP, Ferguson J, Andersen K, Gonçalo M,
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Photoallergic Contact Dermatitis
16
James Ferguson and Alastair C. Kerr
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
3 Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
4 Mechanism of PACD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
5 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
6 Historical Photosensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
7 Current Photohaptens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
7.1 Sunscreens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
7.2 Topical NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
8 Photopatch Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
8.1 Irradiation Source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
8.2 Performing a UVA MED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
8.3 Photopatch Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
8.4 Interpretation of Photopatch Test Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
9 Investigating Occupational PACD/Factory Visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Photoallergic contact dermatitis · Photopatch
testing · Sunscreens · Topical NSAIDs • Topical photoallergic contact dermatitis (PACD)
is thought to represent a delayed-type hypersen-
sitivity reaction when an exogenous agent com-
J. Ferguson bines with some component of the skin in the
Photobiology Unit, Ninewells Hospital and Medical presence of ultraviolet (UV) and/or visible light.
School, Dundee, UK • Although PACD is relatively rare, it is also
e-mail: j.ferguson@dundee.ac.uk
underdiagnosed as a cause of sunlight-exposed
A. C. Kerr (*) site dermatitis.
Department of Dermatology, Queen Elizabeth University
Hospital, Glasgow, UK
• Photopatch testing is the investigation of
e-mail: Alastair.Kerr@ggc.scot.nhs.uk choice for topical PACD, and a European

https://doi.org/10.1007/978-3-319-68617-2_16
212 J. Ferguson and A. C. Kerr
consensus methodology and baseline series

for photopatch testing should allow greater
comparison between centers.
• Currently, organic UV sunscreen absorbers
and topical nonsteroidal anti-inflammatory
drugs (NSAIDs) are the commonest photo-
haptens encountered by patients.
• Clinicians should be aware of potential new
photohaptens in the environment and have a
low threshold for photopatch testing such
agents.
Fig. 1 Chronic actinic dermatitis (CAD) showing a

photoexposed site dermatitis, with sparing in the photo-
2 Introduction protected area behind the ear and under the chin
Photoallergic contact dermatitis (PACD)

describes the reaction seen in the skin when fragrances, or sunscreens, can cause dermatitis
an exogenous agent comes into contact with the with a predominantly exposed site distribution.
skin topically in the presence of ultraviolet (UV) Chronic actinic dermatitis (CAD) – CAD is a
or visible light. Therefore, it presents as a derma- syndrome which has severe photosensitivity and
titis which predominantly affects sunlight- usually multiple contact allergies. It may arise on
exposed skin. a background of chronic dermatitis (atopic
or contact) and can present as either a sunlight-
exposed site dermatitis or may be entered
3 Differential Diagnoses into via a contact dermatitis presentation. Mono-
chromator or solar simulator phototesting
Phototoxicity – Whether this is due to systemic will show objective evidence of photosensitivity
exposure to a drug or topical exposure to a drug with skin biopsy of phototest responses reveal-
or chemical, it does cause diagnostic difficul- ing a dermatitis histopathology, rather than a
ties. Phototoxicity (which does not involve an sunburn reaction as seen in a phototoxic reaction
immune mechanism) will arise in any individ- (Fig. 1).
ual, providing there is enough chemical and Polymorphic light eruption (PLE) – PLE
subsequent light exposure of appropriate wave- more commonly presents as a pruritic, papular,
length within the skin. The clinical history is of or papulovesicular rash of the sunlight-exposed
key importance to determine the temporal rela- skin (Fig. 2). However, atypical forms may have a
tionship between commencement of medication scaling or dermatitic appearance during resolu-
and onset of the eruption. Although in many tion. Actinic prurigo may also cause diagnostic
cases this may be weeks, it can also be many problems (Fig. 3a, b).
months or years. Phototoxicity is more common Cutaneous lupus – Cutaneous manifestations
than PACD and often presents as a sunburn-like of systemic lupus erythematosus (SLE) as well as
confluent erythema or lichenoid eruption. Well- subacute cutaneous lupus erythematosus (SCLE)
described groups include phytophotodermatitis can present as an erythematous and scaling erup-
(usually due to psoralen exposure) or tar pitch tion affecting the sunlight-exposed skin (Fig. 4).
phototoxicity and on some occasions phototoxic In such cases, there may be other systemic mani-
dyestuffs, such as benzanthrone. festations of lupus. Skin biopsy with direct immu-
Allergic contact dermatitis (ACD) – Certain nofluorescence and peripheral blood autoimmune
contact allergens, such as airborne allergens, tests should aid diagnosis.
16 Photoallergic Contact Dermatitis 213
Porphyria – Porphyria cutanea tarda (PCT) and milia may be present, and a peripheral blood
and other cutaneous porphyrias can lead to a sun- porphyria plasma scan should aid diagnosis.
light-exposed skin eruption. Skin fragility, bullae, Pseudoporphyria due to drug phototoxicity with
or without renal failure may present in a similar
fashion, although the porphyrin assay is usually
within the normal range.
4 Mechanism of PACD
The exact molecular basis of topical PACD has

not been fully elucidated. However, experimental
evidence suggests that in most cases, an exoge-
nous low molecular weight compound (photo-
hapten) binds to an endogenous substance in
the skin or circulation, most likely a protein. The
resulting protein–hapten conjugate is then recog-
nized as antigenic by antigen presenting cells
within the body and leads to a delayed-type hyper-
sensitivity reaction. Crucially, the conjugation of
protein and hapten will only occur in the presence
of UV and/or visible light.
5 Incidence
PACD is relatively uncommon. Among patients

that have been referred to tertiary referral centers
Fig. 2 Polymorphic light eruption (PLE) showing an ery- with a photoexposed site dermatosis, a frequency
thematous papulovesicular rash on the photoexposed skin of between 2% and 15% has been reported
the face with relative sparing of the forehead due to the fringe (Bell and Rhodes 2000; Darvay et al. 2001;
Fig. 3 (a, b) Actinic prurigo showing an excoriated papulo-nodular rash on the photoexposed skin of the face, with
characteristic involvement of the tip of the nose
PACD (Wilkinson 1961). After their strong

photoallergic potential was discovered, their
usage was gradually reduced and the problem
essentially cleared.
In the 1970s, musk ambrette, a synthetic com-
pound added to men’s fragrances, became a recog-
nized photohapten (Raugi et al. 1979). As with
halogenated salicylanilides, usage of these agents in
Europe and the USA has all but ceased, although
interestingly it remains available for purchase via the
Internet.
In the 1970s, the veterinary food additive
quindoxin was reported as a cause of PACD
among pig farmers in Europe (Scott and Dawson
1974). Again, it was withdrawn from the market-
place and replaced with a derivative, olaquindox.
Unfortunately, this compound also proved to be a
photohapten and was itself removed from further
usage (Schauder et al. 1996).
The major tranquilizer, chlorpromazine, was also
shown to elicit photoallergy as well as phototoxicity
(Epstein 1968). PACD was often seen among carers
of psychiatric patients who had to crush up tablets
for those with swallowing difficulties, but the sub-
Fig. 4 Cutaneous lupus erythematosus (LE) showing an sequent introduction of a syrup formulation contrib-
infiltrated and scaly eruption affecting the photoexposed
skin uted to a reduction in this problem.
Bryden et al. 2006; Mesa and Jimenez 2016). 7 Current Photohaptens

The true incidence in the general population
is not known but will be significantly lower 7.1 Sunscreens
than this.
Organic UV sunscreen absorbers are currently the
largest group of photohaptens that most people
6 Historical Photosensitizers come into contact with regularly. They are freely
available to consumers over the counter without
Historically, many diverse compounds have been prescription and are very widely used by all age
recognized as responsible for PACD. Epstein was groups of healthy individuals. They are found not
among the first to use the term “photoallergy,” only in products marketed primarily as sun protec-
when investigating skin problems due to topical tion products but also in many other cosmetics,
sulfanilamide in 1939 (Epstein 1939). However, many of which are marketed with “antiaging” prop-
it was not until an outbreak of PACD due to erties. Absorbers are also added to prolong the shelf
the halogenated salicylanilides in the 1960s life of products in translucent packaging by helping
that clinicians became generally aware of its to slow photodegradation of other constituents.
importance. Salicylanilides were compounds When a consumer purchases a proprietary sun-
added to soaps as germicidal agents, and it was screen, this can contain 30 or more individual
the use of these with subsequent sunlight expo- ingredients, only 3–6 of which may be active
sure that led to many, sometimes severe, cases of organic UV absorbers. These absorbers work by
absorbing sunburn-causing, shorter UVB and highlighted (Luiti and Borrego 2015; Aerts et al.
UVA wavelengths, which raise the molecule to 2015). If there is no alternative product or if
an excited state. As the molecule returns to the the patient wishes more in-depth investigation,
ground state, it releases the energy in the form of the clinician must then attempt to obtain all the
less harmful, longer UVA wavelengths. A sun- individual excipients of the product by contacting
screen may also contain inorganic filters such as the manufacturer. Often the manufacturer may
titanium dioxide or zinc oxide. These work as oblige and provide the various ingredients in a
physical reflectants of incoming UV and seem to form suitable for photopatch testing.
have little or no photoallergic potential. Two situations the clinician should be aware
When a patient presents with possible sun- of are the unsuspecting sunscreen user who is
screen-related photoallergy, it is important to unaware that they are exposed to an organic UV
attempt to ascertain which organic UV absorbers absorber in the form of an “antiaging” cream or
may be implicated. If the patient has brought the a cosmetic product that contains an absorber for
bottle which contained the sunscreen to the the purpose of extending its shelf life. Another
clinic, the ingredients may be listed. Unfortu- problem is the incorrect assumption that the ingre-
nately, over time, many of the individual dients of a named commercial product remain
absorbers have acquired many synonyms, constant. This is certainly not the case, and all
due to the complex nature of their chemical products should be checked by examination of
structures and also due to the use of commer- the ingredient list on the box or product itself,
cial/proprietary names. Where possible, which may be revealing.
clinicians should use the International Nomen- When photopatch testing organic UV sun-
clature of Cosmetic Ingredients (INCI) name screen absorbers, petrolatum is a suitable vehicle
and, if necessary, the Chemical Abstracts Service for most although occasionally other vehicles may
(CAS) number when ordering agents and be required (e.g., terephthalylidene dicamphor
performing patch and photopatch testing. Table 1 sulfonic acid, which needs to be tested in water).
lists some commonly used organic UV sunscreen In the European Union, no organic absorber can
absorbers with their CAS numbers and a list of be used in cosmetic products at a concentration
synonyms. As can be seen from the table, if a of greater than 15%. However, in some across-
positive contact allergic or photocontact allergic the-counter (ATC) products, there are agents
reaction is demonstrated in a patient, it would be which use much lower concentrations. This has
advisable to provide the patient with all synonyms the advantage of reducing the potential for induc-
of the agent to aid future avoidance. tion of PACD. Although the optimum concentra-
When photopatch testing to sunscreens, as tion to perform photopatch tests has not yet been
with conventional patch testing, it is important to fully elucidated, most absorbers can be photo-
test the patient’s own proprietary product “as is.” patch tested at a concentration of 10%, without a
It is possible that testing to individual absorbers significant risk of leading to false-positive irritant
that are within the product may be negative, while responses (Kerr et al. 2009). Most agents are,
the “as is” product testing is positive. There may therefore, usually photopatch tested at 10%
be several reasons for this including differing concentration.
absorber concentration, different absorber vehi- While most organic UV absorbers have been
cle, and unknown effects of the many other reported as causing both contact and photocontact
excipients when tested under photopatch test con- allergies, certain agents seem to have a greater
ditions. Indeed, it is possible that other excipients photoallergic potency than others (Schauder and
within the product have been the cause of the Ippen 1997). Over time, the accumulation of
contact or photocontact allergy. As an example, reports citing adverse cutaneous effects have led
in recent years the roles of both decyl glucoside to the withdrawal of certain absorbers (e.g.,
and xanthan gum being causes of ACD to PABA and isopropyl dibenzoylmethane). A high
the sunscreen agent Tinosorb ®M have been level of literature reports may not simply be due to
Table 1 Commonly used organic UV absorbers with their CAS number, INCI name, USAN, and commercial synonyms
Chemical
Abstracts United States
Service International Adopted Proprietary/trade
(CAS) Nomenclature of Cosmetic Name names (all registered
number Ingredients (INCI) name Other names (USAN) trademarks)
150-13-0 PABA 4-Aminobenzoic acid
118-60-5 Ethylhexyl salicylate Octyl salicylate Octisalate Escalol 587, Eusolex
OS, Neo Heliopan OS
8045-71-4 Homosalate Homomenthyl salicylate Homosalate Eusolex HMS, Neo
Heliopan HMS
6197-30-4 Octocrylene Octocrylene Octocrylene Escalol 597, Eusolex
OCR, Neo Heliopan
303, Parsol 340, Uvinul
539 T
5466-77-3 Ethylhexyl Octyl methoxycinnamate Octinoxate Escalol 557, Eusolex
methoxycinnamate 2292, Neo Heliopan
AV, Parsol MCX,
Tinosorb OMC, Uvinul
MC 80
71617-10-2 Isoamyl Amiloxate Neo Heliopan E1000
p-methoxycinnamate
131-57-7 Benzophenone-3 Oxybenzone Escalol 567, Eusolex
4360, Neo Heliopan
BB, Tinosorb B3,
Uvinul M40
4065-45-6 Benzophenone-4 Sulisobenzone Escalol 577, Uvinul
MS 40
70356-09-1 Butyl 4-Tert-butyl-40 - Avobenzone Escalol 517, Eusolex
methoxydibenzoylmethane methoxydibenzoylmethane 9020, Neo Heliopan
357, Parsol 1789
36861-47-9 4-Methylbenzylidene Enzacamene Eusolex 6300, Neo
camphor Heliopan MBC, Parsol
5000, Uvinul MBC 95
27503-81-7 Phenylbenzimidazole Ensulizole Eusolex 232, Neo
sulfonic acid Heliopan Hydro
207574-74-1 Polysilicone-15 Parsol SLX
88122-99-0 Ethylhexyl triazone Octyl triazone Uvinul T150
154702-15-5 Diethylhexyl butamido Iscotrizinol Uvasorb HEB
triazone
90457-82-2 Terephthalylidene Ecamsule Mexoryl SX
dicamphor sulfonic acid
302776-68-7 Diethylamino Uvinul A Plus
hydroxybenzoyl hexyl
benzoate
180898-37-7 Disodium phenyl Bisdisulizole Neo Heliopan AP
dibenzimidazole disodium
tetrasulfonate
187393-00-6 Bis-ethylhexyloxyphenol Bemotrizinol Escalol S, Tinosorb S
methoxyphenyl triazine
103597-45-1 Methylene bis- MBBT Bisoctrizole Tinosorb M
benzotriazolyl
tetramethylbutylphenol
155633-54-8 Drometrizole trisiloxane Mexoryl XL,
Silatrizole
the photoallergic contact potential of a particular (OTC) drugs. Nearly all such products are regu-
agent. For example, the quantity and concentra- lated under the Final Monograph for Sunscreen
tion of use may impact, with some ubiquitous Drug products for over-the-counter (OTC) use,
sunscreens having a greater number of reports which was published on May 21, 1999, and can
simply due to a greater exposure rather than be accessed via the FDA Web site. The time and
greater photoallergic potency. extent application (TEA) is a regulatory process
When a new drug or sunscreen is now devel- that may allow the inclusion of new agents, not
oped, photosafety testing during product devel- yet included in the monograph, if sufficient data
opment is increasingly required. This is capable on long-term use from other countries exists
of picking up photoallergy as well as phototox- (Holman and Shetty 2005; Murphy 2005; U.S.
icity and can be studied first in the laboratory Food and Drug Administration 1999).
with the guinea pig maximization test before However, this process has been criticized by skin
considering human volunteer testing. Within cancer groups in recent years. Such lobbying by
the European Union, sunscreens are classed as stakeholders eventually led to the bipartisan Sun-
cosmetic ingredients and a “list of UV filters screen Innovation Act (SIA) being signed into law
which cosmetic products may contain” is avail- under President Obama in 2014 (U.S. Food and
able under Annex VII of the CosIng section of Drug Administration 2014). This legislation sup-
the European Commission Web site (European plements the TEA process by compelling the FDA
Commission, Growth, CosIng 2010). This annex to make more timely decisions on the inclusion or
contains information about the maximum con- otherwise of new agents which have been used for
centration at which each absorber can be used many years in other countries. It is hoped that in
as well as links to existing safety data for particular, it will expedite the availability of sev-
each absorber. eral new UVA absorbers to US consumers, many
In order to create and update such regulation, of which have been used in Europe safely for
the EU works closely with Cosmetics Europe over a decade.
(formerly known as Colipa), the European cos- In order to keep up with consumer and indus-
metics trade association which represents com- try demand for more UVA and broad-spectrum
panies working in the cosmetics industry. absorbers, new agents continue to be developed,
Cosmetics Europe continually collects, reviews, and it is likely that some of these may also cause
and presents data on usage of UV sunscreen photoallergy. Only by intermittently performing
absorbers. This data (plus other sources avail- large multicenter photopatch studies which
able) is then studied by a group of independent include existing and new absorbers will it be
scientists (a Scientific Committee on Consumer possible to reliably guide clinicians as to which
Products – SCCP), and a report is published with agents should be included in test series. As
their opinion of the safety of a substance. This above, all such data helps inform regulators and
information is circulated by the European com- industry as to which agents to use at which
mission to an Ad Hoc Working Party (AHWP), concentration.
on the cosmetic directive not all of whom are
scientifically trained and decisions made about
inclusion or updating of information in the annex 7.2 Topical NSAIDs
(Mascotto 2005).
In the USA, the Food and Drug Administration Nonsteroidal anti-inflammatory drugs (NSAIDs)
(FDA) regulates products which contain a sun- are administered most commonly by systemic
screen active ingredient but make no claim for routes as analgesic and anti-inflammatory
sunburn protection (e.g., products with a sun- agents. However, over recent years, there has
screen added to protect color) as cosmetics. been an increase in the number and usage of
Those products which do claim sunburn protec- NSAIDs within topical preparations. These
tive qualities are regulated as over-the-counter agents are usually made up as gels which are
semisolid thickened aqueous solutions 2010). The ability of ketoprofen to lead to cross-
containing high molecular weight polymers. reactions with the sunscreen absorbers benzophe-
They dry after application, leaving a film of the none-3 and octocrylene was further underlined in
active ingredient on the surface of the skin. Such 2012 by the results of the European Multi-centre
preparations have the advantage of improving Photopatch Test Study (EMCPPTS) (EMCPPTS
symptoms at the local site of application without Taskforce 2012). This ability has subsequently fur-
any associated potential systemic adverse thered concern that there may be significant poten-
effects, a mechanism supported by some obser- tial for consumers to develop PACD and/or ACD to
vations (Guy and Maibach 1983). However, octocrylene-containing sunscreens if they have
because many NSAIDs are photohaptens, there been sensitized to ketoprofen earlier in their life
have been consequent reports of PACD to such (de Groot and Roberts 2014).
products (Ophaswongse and Maibach 1993). In As with sunscreens, anybody may potentially
some cases, NSAIDs are incorporated into adhe- come into contact with topical NSAIDs through
sive dressings, and the patient may not forward treating musculoskeletal injuries. However, an
this information, possibly erroneously assuming occupational history may reveal that an individual
the skin reaction to be due to some other constit- is an employee of a pharmaceutical company
uent of the dressing. which is involved in the manufacture and packag-
As with organic sunscreen absorbers, NSAIDs ing of NSAIDs. Alternatively, a careful social
seem to vary in their photoallergic potency (Diaz history may reveal the patient is a pet owner
et al. 2006). Some molecules, notably ketoprofen who has been administering their pet the veteri-
and carprofen, appear to be very potent, with expo- nary NSAID carprofen.
sure to even minute quantities capable of eliciting
severe PACD (Hindsen et al. 2004; Kerr et al.
2008). When photopatch testing, cross-reactions 8 Photopatch Testing
between different members of the same class of
NSAID are described. As one would expect, close Like patch testing, photopatch testing is based
chemical structural similarity appears to increase upon provocation of the eczematous reaction
the likelihood of such reactions occurring. Within produced by an exogenous agent on the skin.
the arylpropionic acid derivatives, reactions are However, it requires the additional step of irra-
more common between ketoprofen and tiaprofenic diation of the skin with an external light source.
acid than with either ibuprofen or naproxen The perceived added complexity of irradiation is
(Le Coz et al. 1998). The benzophenone moiety one of the reasons that it is underused as an
of ketoprofen (and benzophenone-like ring in investigation by clinicians in comparison to
tiaprofenic acid) can also lead to cross-reactions patch testing. This has not been aided by histor-
with non-NSAID molecules, for example, benzo- ical discrepancies in methodology between
phenone UV sunscreen absorbers and the lipid- different centers. However, a consensus method-
lowering agent fenofibrate (Leroy et al. 1997; ology for Europe now exists and should allow
Le Coz et al. 1998; Hindsen et al. 2006) (Fig. 5). easier comparison of results across different cen-
Patients who develop photoallergy to ketoprofen ters (Bruynzeel et al. 2004). Other factors that
may also cross-react with and develop contact have contributed to the underuse of photopatch
allergy to certain fragrance substances, notably testing are the presence of obsolete agents in
the cinnamic derivatives (Girardin et al. 2006). standard commercially available test series and
By 2010, accumulation of concerns over an apparent lack of confidence in the use of the
ketoprofen had led the European Medicines UVA irradiation source.
Agency to recommend that topical ketoprofen As with patch testing, the first step is to
should become prescription-only and consumers record a careful history to guide the selection of
should be given more warning about its potential appropriate agents for testing. Most clinicians
to cause PACD (European Medicines Agency performing patch testing are familiar with the
Fig. 5 Chemical structural O

similarity of benzophenone,
ketoprofen, tiaprofenic
acid, and fenofibrate
Benzophenone
O CH3
CH COOH
Ketoprofen
O O
H
S
O
CH3
Tiaprofenic acid
O CH3 O CH3
O C C O CH
CH3 CH3
Cl
Fenofibrate
use of a “standard” set and further more specific “extended” series of 15 further agents that
sets of allergens to investigate different likely could be considered for testing in certain cases
causative allergens (e.g., medicaments, oils, as well as outlining why 26 further agents were
plants). Although such series may vary between then thought unsuitable for photopatch testing
centers and countries, they have generally been due to decreasing exposure patterns and histori-
selected on the basis of experience and many cal relevance.
years of discussion between experts. Until rela- Over time, the most widely used organic UV
tively recently, no single multinational “stan- sunscreen absorbers are likely to change relatively
dard” series of photopatch test allergens frequently. This stems from the continual devel-
existed. However, the EMCPPTS conducted opment of new agents by industry to keep pace
across 12 European countries between 2008 with the demand for ever-better sunscreens. This
and 2011 provided up-to-date information on means that this baseline series may become obso-
which agents could be included in such a series lete more quickly than many agents used in patch
(EMCPPTS Taskforce 2012). Subsequent to the test series. For this reason, there must continue to
results of the EMCPPTS becoming available, be intermittent large multicenter photopatch test
interested parties convened and produced rec- studies which test these new agents and allow the
ommendations for a European photopatch test informed updating of such series.
baseline series, consisting of 20 agents deemed Despite such problems, many organic sunscreen
of most relevance currently (Goncalo et al. absorbers and topical NSAIDs are available com-
2013). This group also proposed a second mercially through patch test agent suppliers for
photopatch testing. As with patch testing, it is very photosensitivity include systemic drug-induced
important to consider photopatch testing “as is” any phototoxicity, chronic actinic dermatitis, and cuta-
of the patients’ own agents that they have identified neous lupus. In conventional MED testing, eight
as a potential source of PACD, as long as safety incremental doses of UVA are used (e.g., 1.0, 1.5,
data sheets are available and testing it would not be 1.8, 2.2, 2.7, 3.3, 3.9, and 4.7 Jcm2). The doses
dangerous (i.e., irritant/corrosive/toxic). Reference from 1.8 Jcm2 and above are approximately 20%
to textbooks and scientific literature on such agents increments from the previous dose. Such doses
can aid choice of concentration and vehicles for allow an even spread of values up to approximately
such agents (de Groot 1994). 5 Jcm2.
A UVA MED can be performed using an
automated device, or manually, where each
8.1 Irradiation Source incremental dose site is covered by hand sequen-
tially with a “door” of UV-opaque material after
Historically, various types of light source have the appropriate time corresponding to the dose
been used to irradiate photopatch tests. In the of UVA has elapsed. The area of each dose of
past, polychromatic sources (which contain UVB, the MED test series (often a 15 15 mm2) must
UVA, and visible light) have been employed, as be marked out on the skin to enable subsequent
have UVB sources. However, these have largely identification of any reactions after 24 h. In
fallen out of usage, as the doses of UVB required both cases, the remainder of the patient’s back,
to elicit a delayed-type PACD reaction are often neck, and head must be covered with UV-opaque
greater than that required to provoke a sunburn- material to avoid unnecessary irradiation of
like erythema, and so false positives can occur these areas. The (previously warmed-up) UVA
(Anonymous 1997). As a result, UVA sources source is then positioned at a distance of 20 cm,
are now the most widely employed when parallel to the skin of the MED test site.
performing photopatch testing. Ideal characteris- The actual irradiation time for each dose will
tics of a UVA source include a continuous, broad, depend on the output of the UVA source
and stable emission with high irradiance over a used. After 24 h (D1), prior to irradiation of
uniform field. Fluorescent UVA lamps, such the photopatch test site, the MED test site is
as those found in PUVA cabinets, are therefore visually inspected, and the dose at which mini-
suitable, although some metal halide or mono- mally perceptible erythema can be discerned is
chromators may also be suitable in some cases. recorded as the MED (Figs. 6, 7, 8, 9, 10, and
The output of the source must be measured at 11). If no erythema is seen at any dose, a dose
regular intervals using a calibrated meter to ensure of 5 Jcm2 can be safely used to irradiate the
accurate doses are used. Once the UVA source has photopatch test site. If erythema is seen, a dose
been decided upon, the first step of photopatch of 50% of the MED has been suggested as
testing is to perform a UVA minimal erythemal a reasonable dose for irradiation of the photo-
dose (MED). patch tests, but even this may be too high (Anon-
ymous 1997). If there is marked UVA sensitivity,
it is advisable not to irradiate the photopatch
8.2 Performing a UVA MED tests with any UVA as a large area of
confluent erythema at the photopatch test site
A UVA MED is usually performed on Day 0 (D0) may result.
on the skin of the back at a different area to the site
of photopatch testing. It is performed in order to
determine whether the patient has abnormal objec- 8.3 Photopatch Testing
tive photosensitivity to the UVA source that is to be
used for the subsequent irradiation of the photo- Once the photopatch test agents have been
patch test site. Possible causes of such selected for testing, two identical sets, one for
Fig. 6 The MED template is taped to the skin of Fig. 7 Each corner of each aperture should be marked
the patient’s back. It is composed of four layers of UV- with a dot from a skin-safe marker to allow later identifi-
opaque white polythene with eight square apertures of cation of the MED test site
15 mm2 area, arranged in two columns of four at 10 mm
intervals. Each aperture has its own door which can be
closed and held shut with adhesive tape The next step is to cover the control set of
photopatch test agents with a UV-opaque material
(such as a thick, flexible plastic-containing dressing
irradiation and one as control, are prepared. sheet). As with UVA MED testing, all other areas
They are applied under occlusion to the skin of of the back, neck, and head apart from the set of
the back as one would apply patch tests. The photopatch agents chosen for irradiation are then
length of application of photopatch test agents is covered with a similar material, to reduce unneces-
either 24 or 48 h. In many photobiology units, sary exposure of the patient to UVA. As with UVA
24 h is used, but in many contact dermatitis MED testing, the UVA source is then positioned
units, 48 h is used. It may be that application parallel to the set of photopatches to be irradiated at
for 48 h picks up more positive reactions a distance of 20 cm, and a dose of 5 Jcm2 (or less
(Batchelor and Wilkinson 2006), but clinicians if the UVA MED is reduced) is administered.
should choose a duration of application that Immediately following the removal of the UV-
does not disrupt the provision of care and other opaque material, the test site is again visually
investigations in their unit. After this time, the inspected, and any reactions are graded and
agents are removed and the test site is visually recorded. Readings of both sets of photopatch test
inspected. Any reactions seen should be agents are made at various time points after irradi-
recorded using the International Contact Der- ation, conventionally multiples of 24 h. The most
matitis Research Group (ICDRG) grading important of these is 48 h, although 24, 72, 96, and
scale (Wahlberg 2001) and their relevance 120 h readings can be performed depending on the
noted with a scale such as the COADEX system logistics of the local unit and patient availability
(Bourke et al. 2001). (Figs. 12, 13, 14, 15, 16, 17, and 18).
Fig. 8 The remainder of the patient is then covered with Fig. 9 The MED test site is then irradiated with the UVA
UV-opaque material source. This should be positioned parallel to the MED test
site at a distance of 20 cm. During the period of irradiation,
this distance should be episodically checked with a mea-
suring rod, as the patient may move slightly
8.4 Interpretation of Photopatch
Test Results
As above, positive photopatch test results are 3. Photoaugmentation of allergic contact derma-
graded and their intensity recorded, convention- titis – a positive reaction is seen in the control
ally using the ICDRG scale. Because there are two set, and a positive reaction which is at least
identical sets of reagents, one irradiated and the one ICDRG grade higher is seen at the same
other not, there are more potential combinations site in the irradiated set. This pattern is
of reactions that need interpreted than in standard uncommon.
patch testing. The main four patterns of immuno- 4. Photoinhibition of allergic contact dermati-
logically mediated reactions possible for a single tis – a positive reaction is seen in the con-
agent are summarized below: trol set, and a positive reaction which is at
least one ICDRG grade lower is seen at the
1. Photoallergic contact dermatitis – a positive same site in the irradiated set. This pattern
reaction (of any ICDRG grade) is seen in the is uncommon.
irradiated set only. The same site in the control
set is negative. As in standard patch testing, irritant
2. Allergic contact dermatitis – a positive reaction reactions can also occur, as well as non-immuno-
(of any ICDRG grade) is seen in the irradiated logical phototoxic reactions, which are classically
set, and a reaction of equal grade is seen at the flat, “decrescendo” reactions that do not extend
same site in the control set. out with the area of agent application.
Fig. 10 To deliver the eight doses required, each door Fig. 11 Twenty-four hours after irradiation, the UVA
is manually closed at the appropriate time. The person MED test site is visually inspected, and the dose at which
performing this should have their hand and arm protected minimally perceptible erythema is seen is recorded as the
by UV-opaque material and wear UV-protective eyewear. MED. In this case, no erythema is visible, indicating that
This view from above shows that the door of the first the MED is greater than 4.7 Jcm2 and a dose of 5 Jcm2
aperture has been closed using a handheld rod can be used for irradiation of the photopatch test site
at a time when there is no restriction of access to

9 Investigating Occupational any areas of the factory that may be relevant.
PACD/Factory Visits Because ultraviolet and/or visible light may be
involved in a PACD reaction, a portable
As with cases of occupational contact dermatitis, spectroradiometer may be useful to measure the
cases of PACD can arise within the workplace output of any sources in the factory. It may be
environment. In such cases, it may be necessary advisable to take a colleague (e.g., a medical
to perform a factory visit, possibly in a legal/ physicist) who is familiar with the correct
regulatory capacity. Such a visit is undertaken method for operating such a device.
to ascertain objective evidence as to the possibil- When in the factory, the exact nature of
ity of one or more employees being exposed to employee duties must be ascertained and
potential photohaptens there. It is important to recorded, if necessary by use of practical dem-
enter into open communication with the manage- onstration. In some cases, this should be with
ment of such a factory, often at an early stage as it an employee present as well as management
may conceivably be months or even years before so that an accurate account can be corrobo-
the actual visit goes ahead. Once communication rated by both sides. However, in certain cases,
is established, one should arrange a suitable time it may be necessary to get an account from the
for the visit to take place. Ideally, this should be employee alone, as they may not feel able to
Fig. 12 The agents for

photopatch testing are
prepared in duplicate. One
set to serve as a control and
one set for irradiation
Fig. 14 Before removal, the area of patch application is

Fig. 13 The duplicate sets of agents are then applied on marked with a skin-safe pen. The patches are then removed
the skin of the back and left in place for 24 or 48 h and the site visually inspected for any positive reactions
Fig. 15 A map of the photopatch application site is then Fig. 16 One set of photopatches is covered with UV-
made using a clear polythene sheet. Landmarks, including opaque material, leaving the other set exposed for
the spine and nevi, are marked to aid future placement irradiation
disclose all accurate information in the pres- PACD, which may otherwise not have been
ence of the employer, for fear of consequences made (Kerr et al. 2008).
for their job. By doing this, an idea can be Because of the additional possibility of UV
obtained as to the instances during an and/or visible light contributing to the devel-
employee’s work practices when they may opment of PACD, note must be made of such
come into contact with potential photo- sources if any are present. For windows, this
haptens. A record should also be made of the would include their position relative to
number of employees over time that may have employees, size, age, type, and number. Simi-
come into contact with potential photohaptens lar note must be made for artificial light
through a work practice. Note must be made sources, fluorescent, and others, along with
of the protective equipment provided and and the presence or otherwise of
level of usage by employees, the ventilation/ protective diffusers. There may also be other
extraction systems in operation, how many less obvious sources, such as UV insect-killing
areas the potential photohapten is present in, devices. These observations must be made for
and the potential for contamination of areas the main work area but also for other areas,
other than the main area of potential exposure. such as changing/washing areas. While poten-
By performing a factory visit, it may be pos- tial photohaptens may be present in the main
sible to confirm a diagnosis of occupational working area, perhaps as part of the main
Fig. 17 The set of exposed photopatch test agents is then

irradiated using a dose of UVA determined by the UVA
MED. As with UVA MED testing, the patient should be Fig. 18 At 24-h intervals after irradiation (i.e., 24, 48,
placed such that the irradiation site is 20 cm from the 72 h) the photopatch test site is visually inspected and any
parallel UVA source positive reactions graded and recorded using the ICDRG
scale. In this case, a positive result in the irradiated set only
at position 26 has confirmed a diagnosis of PACD to a
proprietary sunscreen preparation tested “as is”
processes taking place within the factory, one
should have a low threshold for suspecting
other potential agents. To illustrate this, in
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Airborne Contact Dermatitis
17
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
3 Airborne Offending Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
4 Classification of Occupational Airborne Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . 231
5 Occupational Airborne Irritant (Frictional and/or Chemical) Contact
Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
5.1 Airborne Irritant Contact Dermatitis Due to Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
5.2 Airborne Irritant Contact Dermatitis Due to Dust Particles . . . . . . . . . . . . . . . . . . . . . . 233
5.3 Airborne Irritant Contact Dermatitis Due to Sprays, Vapors, and Gasses . . . . . . . 234
6 Occupational Airborne Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . 235
6.1 Clinical Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
6.2 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
6.3 Main Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
7 Occupational Airborne Phototoxic and Photoallergic Contact
Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
8 Occupational Airborne (Immunological and/or Nonimmunological)
Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
9 Exacerbation of “Extrinsic” Atopic Dermatitis by Aeroallergens . . . . . . . . . . . 238
10 Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
11 Prevention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Keywords
Airborne irritant contact dermatitis · Airborne
allergic contact dermatitis · Airborne
phototoxic contact dermatitis · Airborne
J.-M. Lachapelle (*) photoallergic contact dermatitis · Airborne
Department of Dermatology, Catholic University of immunological contact urticaria · Dust
e-mail: Jean-marie.Lachapelle@uclouvain.be

https://doi.org/10.1007/978-3-319-68617-2_17
230 J.-M. Lachapelle
particles · “Extrinsic” atopic dermatitis · due to agents carried by or through the air, has
Fibers · Gasses · Latex proteins · Vapors been underestimated in the past. Pirilä (1950) was
the first to promote the concept of airborne der-
matoses on clinical and experimental grounds. In
1 Core Messages his extensive paper, the author called attention –
almost exclusively – to allergic conditions, refer-
• Occupational airborne irritant (frictional ring for instance to the cases of thiokol dermatitis
and/or chemical) contact dermatitis is due to he had observed in Finland after World War II.
fibers, dust particles, vapors, and/or gasses. Later on, examples of occupational dermatoses
• Occupational airborne allergic contact derma- closely related to airborne skin offenders were
titis is a common problem, provoked by a large occasionally reported throughout the relevant lit-
variety of allergens. erature (Pirilä et al. 1963).
• Occupational airborne phototoxic and/or In the 1980s, more attention was paid to the
photoallergic contact dermatitis is a rare but problem, after the publication of two review arti-
well-documented event. cles (Lachapelle 1986; Dooms-Goossens et al.
• Occupational airborne immunological contact 1986). Santos and Goossens (2007) have updated
urticaria can be caused by several chemicals in a review paper (2001–2006) a list of offending
and/or proteins. Allergy to latex proteins was agents able to provoke airborne contact dermati-
the main problem, but it is declining at the tis. They consider that the figures were
present time. underestimated for two main reasons: (a) many
• There is a vast range of procedures available to original cases are never published, and (b) in some
reach a proper etiological diagnosis of airborne papers, the term “airborne” does not appear in the
contact dermatitis. key words, and the publications are therefore
• Prevention and treatment of airborne contact omitted in general reviews.
dermatitis deserve special attention and must Nowadays, each year brings a blossom of new
be adapted to each individual situation. observations, coming from various parts of the
• “Extrinsic” atopic dermatitis (face and neck world. These publications reflect the diversity of
dermatitis) is related to the penetration into problems encountered, in relation with new
the skin of aeroallergens, particularly chemicals and/or modified technical procedures.
dust mite. A better knowledge of occupational airborne der-
matoses has practical implications, in terms of
diagnosis, treatment, and prevention. A new
2 Introduction updated list of aeroallergens has been actualized
(Swinnen and Goossens 2013). There is a clear
Most patients consulting in occupational derma- distinction to be made between airborne dermato-
tology are referred to as contact dermatitis cases; ses and the “sick building syndrome”; the latter
conceptually, the term “contact dermatitis” refers to epidemics of subjective symptoms
implies a direct contact of the skin with the (itching or burning sensations) without any clini-
offending (liquid and/or solid) agents. It is not cally visible signs, which occur in the work envi-
surprising that in this respect, hand dermatitis is ronment. This situation can be related, for
the major complaint; this is due to a direct manip- instance, to a low relative humidity rate in the air
ulation – at work – of thousands of different but may also represent a mass psychogenic illness
products. It is clear that other skin sites can also (Lachapelle 2014).
be affected, either directly or indirectly (transfer Two papers are of particular interest for initiat-
of chemicals by hands; so-called by proxy contact ing a differential diagnosis between both condi-
dermatitis). tions. One is referring to the skin disorders among
Apart from this “familiar landscape” the occur- construction workers following Hurricane Katrina
rence of occupational airborne dermatoses, that is, and Hurricane Rita (Noe et al. 2007); the other
17 Airborne Contact Dermatitis 231
deals with airborne occupational dermatoses 4 Classification of Occupational

experienced by aircrew (Legatt and Smith 2006). Airborne Skin Diseases
Two categories of occupational airborne skin dis-

3 Airborne Offending Agents eases have to be considered.
Airborne offending agents are present under var- (a) “Systemic” occupational airborne skin
ious forms: diseases
Some skin conditions are as a result of the
Fibers toxic effects of chemicals that have been
Different types of fibers can be implied absorbed by the body tissues either by inhalation
(Stam-Westerveld et al. 1994). The most clas- or by transdermal penetration. We have coined
sical example is fiberglass. Other examples the term “systemic” occupational airborne skin
include rock wool, carbon fibers, plastic mate- disease, by analogy with the term “systemic
rials such as polypropylene fibers, etc. Fibers contact dermatitis” (Lachapelle 2017).
can be chemically inert and provoke only The most classical example is chloracne
mechanical trauma to the skin. Carbon fibers’ that, although rare, may serve as an extremely
dermatitis and most cases of fiberglass derma- important indicator of internal poisoning and
titis are good examples of this condition. On should be recognized by physicians treating
the other hand, some fibers can produce aller- occupational skin disease. Cloracneigenic sub-
gic reactions, such as epoxy-coated fiberglass. stances such as polyhalogenated naphthalenes
Dust Particles are well known (Coenraads et al. 1994);
Dust is ubiquitous in the work environment. tetrachloro-2,3,7,8 dibenzo-p-dioxin was the
Dust particles are transported by air; they can agent incriminated in the Seveso catastrophe,
accumulate on the surface of the skin, in a which occurred in northern Italy in 1976.
visible way or not. Like fibers, some dust par- Another example of “systemic” occupa-
ticles are chemically inert but can provoke tional airborne skin disease is lepidopterism,
mechanical (frictional) injury to the skin, a syndrome including all symptoms due to
whereas others do contain chemicals which airborne contact with the barbed hairs of
are dissolved by the sweat; according to their pine tree processionary caterpillars, that is,
nature, these chemicals are responsible for sev- pruritic rash, conjunctival hyperemia, dys-
eral types of skin reactions (Lachapelle 1987). pnea, wheezing, and more exceptionally ana-
Sprays phylaxis. Foresters and agricultural workers
Water or other liquid-based products mov- are at risk. More generally, it is a growing
ing in a mass of dispersed droplets represent an public health problem: There is an increasing
important source of airborne offending agents. number of outbreaks. Children are also
Any of numerous commercial products, affected and often more severely than adults
including paints, cosmetics, and insecticides (Gottschling et al. 2007; Shkalim et al. 2008).
that are dispensed from containers in this man- A little while ago, there has been an invasion
ner, are good examples. Skin reactions are of caterpillars in Northern Europe, due to a
multifaceted: irritant, eczematous, urticarial, gradual warming of the atmosphere, whereas
or combined. they are usually confined to Southern Europe.
Vapors and Gasses (b) Occupational airborne contact dermatoses
Vapor is defined as barely visible or cloudy This group refers to all skin symptoms
diffused matter, such as mist, fumes, or smoke, directly related to airborne contact of the skin
suspended in the air. Gas has a more restricted with the accountable agents. In fact, all varie-
meaning. Vapors and gasses may be like ties of contact dermatoses due to direct
sprays: irritant, allergenic, or both. contactants can also be provoked by airborne
Table 1 Classification of occupational airborne contact

dermatoses
1. Occupational airborne irritant (frictional and/or
chemical) contact dermatitis
2. Occupational airborne allergic contact dermatitis
3. Occupational airborne phototoxic contact dermatitis
4. Occupational airborne photoallergic contact dermatitis
5. Occupational airborne (immunological and/or
nonimmunological) contact urticaria
6. Exacerbation of “extrinsic” atopic dermatitis by
aeroallergens
contactants. Furthermore, in many cases, direct

contact and airborne contact can occur simul-
taneously; contact urticaria to latex proteins
(Lagier et al. 1990) or allergic contact dermati-
tis to epoxy resins (Le Coz et al. 1999) repre-
sents two good examples of such situations.
A classification of occupational airborne
contact dermatoses has been proposed in
Table 1. Although no specific criteria do
exist to assess an airborne origin, some mor-
phological and/or topographical aspects can
help in the diagnostic procedure, as explained
in the next paragraphs. Fig. 1 Fiberglass dermatitis: tiny papules and scratch
marks
Objective symptoms are usually present but

5 Occupational Airborne Irritant vary in severity from case to case. Scratch
(Frictional and/or Chemical) marks, tiny papules, or a maculopapular rash is
Contact Dermatitis the usual lesion (Fig. 1). Severe cases could
involve secondary infection (pustules) from
5.1 Airborne Irritant Contact scratching. The most typical example quoted in
Dermatitis Due to Fibers the literature is fiberglass dermatitis. Symptoms
include itching and prickling in the skin areas
Subjective symptoms are always present. Itching, coming into contact with fiberglass spicules pre-
stinging, and burning sensations are the usual sent in the work environment. Scratch marks,
complaints of many patients, with or without papules, and pustules are sometimes present
objective signs. In particular, facial complaints (Fisher 1982; Koh et al. 1992). To some extent,
are not often accompanied by detectable lesions; it may resemble scabies.
they correspond to the so-called subjective irritant The presence of fibers encrusted in the horny
dermatitis. The eyelids, cheeks, nasal folds, and layer of epidermis is clearly shown by the skin
neck are commonly involved. surface biopsy technique (Marks and Dawber
Subjective symptoms may occur not only on 1971). The method consists of the following very
covered parts of the body, mainly in the flexures simple steps: (a) a drop of cyanoacrylate glue is
(axillae, groins, cubital, and/or popliteal fossae) placed on the skin; (b) a clear glass slide is gently
but also on the extensor aspects of the limbs or on pressed on the drop for 30 s; and (c) the slide is then
the trunk. removed. A slight modification consists of using
polyester tape instead of glass as holder (Lachapelle airborne. Most patients recovered quickly after
et al. 1977). Foreign material present at the surface treatment with emollients and changing the filters.
of the skin or encrusted in horny cells is removed And, finally, what about asbestos fibers? When
with the adhesive which remains attached to the asbestos was used extensively as an insulation
glass slide or the plastic sheet; it can be visualized procedure, very little was said about the potential
under the microscope. irritant properties of asbestos. This is probably
Fiberglass dermatitis is still a very important due to several factors: (a) asbestos is a mixture
problem in occupational dermatology, as men- of dust and fibers; (b) most fibers have a diameter
tioned in recent papers (Cusano and Mariano <1 mm; and (c) asbestos fibers can split longitu-
2007; Bordel-Gomez and Miranda-Romero dinally, which reduces even more the mean diam-
2008; Lundgren et al. 2014). A very interesting eter of fibers.
contribution has been made about the size and An extensive program of removal of asb-
configuration of glass fibers by scanning electron estos fibers is conducted in most industrialized
microscopy (Hsieh et al. 2001). countries, with their replacement by man-made
Other examples of fibers’ dermatitis include vitreous fibers, such as glass or ceramic fibers. It
glass wool, rock wool, carbon fibers, ceramic occurs nowadays that some workers who remove
fibers, polypropylene fibers, urea-formaldehyde asbestos fibers do complain of itching and prick-
insulating foam, etc. In all cases, the symptoms ling sensations, but this is certainly partly
are similar to those observed in fiberglass related to psychological factors, in relation
dermatitis but are usually milder. It is obvious with the propaganda fueled by the media on
that clinical manifestations are due to a mechan- the toxicological properties of asbestos
ical effect, either frictional or consecutive to (Lachapelle 2006).
encrustment of fibers into the skin. The diameter
of fibers seems crucial to explain the severity of
skin symptoms (Lachapelle 1986; Stam- 5.2 Airborne Irritant Contact
Westerveld 1997). Dermatitis Due to Dust Particles
In our experience, the diameter of most fibers
incriminated in airborne contact dermatitis was Two different situations have to be taken into
comprised between 6 and 20 mμ. Atopics are consideration:
undoubtedly more prone to develop severe symp-
toms than nonatopics (Björnberg et al. 1979). This (a) The dust particles are “chemically inert.”
can be clearly demonstrated when epidemics of Skin symptoms are related to the mechanical
fiberglass dermatitis do occur in factories. (frictional) properties of particles. It is not
Björnberg was a visionary at that time; his work clear whether the shape of the particles
has been underestimated, but nowadays, new (e.g., particles with sharp edges) plays an
developments in the comprehension of atopic der- important role or not (Fig. 2). Many other
matitis confirm his studies, based upon epidemi- concomitant factors are most probably
ological investigations. important, such as ambient heat, low humid-
More recently, an outbreak of eight cases of ity, sweating, and/or atopic state. The clinical
occupational airborne irritant contact dermatitis symptoms are quite similar to those observed
has been reported in intensive care unit employees with fibers. Facial complaints are usually
caused by synthetic (polypropylene and polyeth- prominent: the eyelids, cheeks, nasal
ylene) fibers from an air-conditioning filter folds, retroauricular folds, and neck are
(Patiwael et al. 2005). High filter pressure in the commonly involved. Workers wearing
intensive care air-conditioning system, ill-fitted masks sometimes complain of
maintained to establish an outward airflow and itching of the face, due to the accumulation
prevent microorganisms from entering the ward, of dust under the mask, particularly in the
probably caused fibers from the filter to become nasal folds. Subjective and objective
Fig. 2 Dust particles with sharp edges (polarized light;

100)
complaints can also occur on covered parts

of the body, due to the accumulation of dust
particles under the garments. Indeed, solid
particles can pass easily under protective
clothes, most often between sleeves and
gloves; dust particles can also accumulate
on the skin of the feet even when workers Fig. 3 Perchlorethylene fume irritant dermatitis after
wear safety shoes. cleaning an unventilated tank. Extensive erythematous
pruritic plaques on the lateral aspect of the neck
(b) The dust particles are not chemically inert.
They release irritant substances (acidic, alka-
line, or neutral) that are responsible for true
5.3 Airborne Irritant Contact
irritant (i.e., chemically-induced) contact
Dermatitis Due to Sprays,
dermatitis. When dust material is suspended
Vapors, and Gasses
in distilled water, the pH of the supernatant
can be very alkaline, as mentioned in some
On the contrary of fibers’ and/or dust particles’
reports (Lachapelle et al. 1984): anhydrite
dermatitis, which may affect covered as well as
(pH, 11.2), sewage sludge (pH, 11), and
uncovered parts of the body, occupational air-
trona (pH, 10.5). Dried industrial dyes
borne irritant contact dermatitis related to sprays,
show a wide range of pH. In these various
vapors, and/or gasses is almost exclusively lim-
situations, clinical symptoms are unequivo-
ited to uncovered parts.
cally typical of irritant contact dermatitis.
The face and neck are primarily involved. Clin-
Eyelids are preferentially involved, due not
ical symptoms are typical of irritant contact derma-
only to the accumulation of particles but also
titis. Itching, stinging, and burning sensations are
to the increased penetration of chemicals
the usual complaints that precede the occurrence of
into the skin.
a maculopapular rash (Fig. 3). The lesions may be
Periorbital dermatitis is a common problem limited to the eyelids (periorbital dermatitis) or
encountered in occupational dermatology. extend to the whole face and neck, sparing some
Differential diagnosis of this entity is often dif- partly protected areas, such as retroauricular folds
ficult. Airborne irritant contact dermatitis to or the margins of the scalp. Organic solvents,
dust particles has to be taken into consideration ammonia, and formaldehyde are often quoted as
as a potential etiological factor (Feser and classical offending agents, but many others can be
Mahler 2009). listed, such as acids and alkalis, domestic products
(e.g., cleansing products), industrial solvents, car- dermatitis might have developed, distinctly limited
bonless copy paper, or phenol vapors (Dooms- at the margins of the sleeves and collar. Because of
Goossens et al. 1986). the accumulation of dust and sweat, the elbow flex-
ures and the skin under a tight collar are often
lichenified. As already emphasized, airborne aller-
6 Occupational Airborne Allergic gic contact dermatitis has no specific clinical fea-
Contact Dermatitis tures. Therefore, there is no magic clue that leads to
an unequivocal diagnosis. Anamnestic data, analy-
Occupational airborne allergic contact dermatitis sis of symptoms, and patch test results are needed to
seems to be very frequent according to the recent reach a correct conclusion.
literature. In a recent observation, occupational conjunc-
Airborne “contact” allergens can be volatile tivitis was the sole manifestation of airborne con-
(vapors and/or gasses) or transported under the tact allergy to trimethylolpropane triacrylate
form of sprays (mini-droplets) or present in dust (Mancuso and Berdondini 2008).
particles: all physical forms are common in the
work environment.
6.2 Differential Diagnosis
6.1 Clinical Symptoms Differential diagnosis of facial airborne allergic

contact dermatitis includes the following:
Clinical symptoms are typical of allergic contact
dermatitis. There is no specific sign in relation (a) “True” (or direct) contact allergic contact derma-
with airborne contact. Eczematous lesions are sym- titis. Asymmetry of facial lesions is a clinical
metrical in most cases (Fig. 4); they are acute or sign in favor of “true” (or direct) allergic contact;
chronic, depending on the environmental condi- this assertion has to be moderate, due to the fact
tions: nature and/or concentration of the allergens, that some airborne allergens can be sprayed on
frequency of airborne contact, and so on. For the face in an asymmetrical way at the
instance, dermatitis from wood dust normally starts workplace.
on the eyelids (Fig. 5) or the lower half of the face, (b) Flare-up of the so-called id type, including
often preceded by a period of itching. Swelling and eventually systemic contact dermatitis.
redness spread to the neck, hands, and forearms. By (c) Atopic dermatitis limited to the face. The
the time the patient goes for treatment, a diffuse distinction between both conditions is
Fig. 4 Airborne allergic contact dermatitis to epoxy resin. The patch test to epoxy resin was positive
Table 2 Selected allergens responsible for occupational

airborne allergic contact dermatitis
Animal feeds
Bryozoans: Dogger Bank itch
Budesonide
Chromate, i.e., from cement dust or from welding fumes
Cinnamon
Cobalt, i.e., from cement dust
Colophony (in woodcutting and soldering)
Drugs (and/or chemicals used in the synthesis of drugs in
the pharmaceutical industry)
Epoxy resin when heated, epoxy hardeners, and epoxy
Fig. 5 Airborne allergic contact dermatitis to meranti reaction diluents
(exotic wood) dust particles. Extensive eczematous lesions Formaldehyde
of the eyelids Isothiazolinones
Parthenium
Pesticides
difficult to assess in many cases. The Plastics such as acrylates, phenol-formaldehyde resins,
complexity of the problem has increased in etc.
recent years due to the current knowledge Sesquiterpene lactones, such as in Compositae or
Frullania
that facial signs of atopic dermatitis could
Woods (wood dust from exotic or indigenous woods)
be triggered, worsened, or even provoked
by various allergens of high molecular
weight (mainly proteins) present in house 6.3 Main Allergens
dust, pollens, molds, etc. This important
current issue is discussed in detail in The list of allergens responsible for occupational
Sect. 9: “Exacerbation of ‘Extrinsic’ Atopic and/or environmental airborne allergic contact
Dermatitis by Aeroallergens.” dermatitis is countless. The most important
(d) Photoallergic contact dermatitis, bearing in groups of allergens are listed in Table 2.
mind that some photoallergic reactions can Some problems of current interest deserve spe-
be airborne related. In contrast to allergic air- cial attention:
borne contact dermatitis, some parts of the
face are partly or completely spared Occupational airborne allergic contact dermatitis
in non-airborne photoallergic reactions: to budesonide, even at very low concentra-
the eyelids, submental region, and tions, affecting nurses working in the hospital
retroauricular folds. In most cases, lesions of (Pontén 2006; Corazza et al. 2008; Baeck and
allergic airborne contact dermatitis are Goossens 2009).
symmetrical. Plastic resin systems have an increasing diverse
(e) Seborrhoeic dermatitis, sometimes worsened array of applications, which induce health haz-
by work conditions: irritant fumes or dusts, ards, in particular, occupational airborne aller-
high temperature involving increased sweat- gic contact dermatitis. These resin systems
ing, and so on. include epoxies, (meth)acrylics, polyure-
(f) “Sebopsoriasis” is not uncommon and has also thanes, phenol-formaldehydes, and polyesters,
to be taken into account in the differential amino resins (melamine-formaldehydes, urea-
diagnosis. It can be triggered by work condi- formaldehydes, etc.). Some papers summarize
tions, including contact with irritant fumes and the risks encountered (Cao et al. 2009; Geraut
dusts. Abundant sweating due to a high- et al. 2009).
temperature environment is a major cause of Parthenium dermatitis (Parthenium hyster-
worsening of skin symptoms. ophorus; parthenium weed) is a very common
problem of occupational airborne allergic Occupational airborne phototoxic agents

contact dermatitis in India and are rarely involved: coal tar and derivates,
was extensively studied in recent years. for example, anthracene, acridine, phen-
Dermatitis occurs in farmers, with exacer- anthrene, pyrene, dyes, and furocoumarins are
bations during summer. It is sometimes quoted in most textbooks. Photoallergenic
photoaggravated, and rare cases of chronic molecules include fragrance ingredients (in the
actinic dermatitis have been recorded. Patch cosmetic industry), coal tar derivates,
tests to Parthenium are positive (Sharma olaquindox, and several drugs (in the pharma-
and Sethuraman 2007; Agarwal and ceutical industry).
D’Souza 2009). Parthenolide could also be Combined airborne and photoaggravated
an effective choice for patch testing (Mahajan contact allergy, as seen with Compositae and
et al. 2014). lichens, presents difficulties in diagnosis
(Thune 1977).
There is a dramatic increase in the number of Parthenium dermatitis (mentioned above) is a
cases of allergic (non-airborne) and airborne aller- good example of such difficult problems.
gic contact dermatitis to isothiazolinones (mainly
but not exclusively methylisothiazolinone). Some
of them are undoubtedly of occupational origin, 8 Occupational Airborne
due to the presence of various isothiazolinones (Immunological and/or
used as preservatives in water-based paints and Nonimmunological) Contact
more recently in leather. The most complete Urticaria
review on the subject is the thesis of Olivier
Aerts (2017) at the University of Antwerp Occupational airborne contact urticaria has been
(Belgium). underestimated in the past. In most cases, it is the
clinical expression of an immunological reac-
tion, of the immediate type, mediated by IgE.
7 Occupational Airborne Allergy to natural rubber latex has now become
Phototoxic and Photoallergic a major health-care issue. Direct contact urticaria
Contact Dermatitis due to latex gloves affects both hands, but natu-
ral rubber latex proteins are absorbed onto the
Phototoxic and/or photoallergic chemicals can be maize starch powder of gloves; these are released
airborne. Practically, there is no clinical sign that into the air when the packets are opened or
allows a clear-cut distinction between direct con- gloves are pulled out of multipack boxes. The
tact and airborne contact. particles contaminate the air, and in operating
Both produce a similar type of eruption. On theaters with recirculated air systems, the aller-
theoretical grounds, phototoxic reactions are gens can be spread to the whole theater suite and
more sharply demarcated, whereas photoallergic cause different clinical problems: urticarial
reactions display ill-defined margins, but there plaques on the face (Fig. 6), conjunctivitis, rhi-
are many exceptions to the general rule. On the nitis, and even asthma (Handfield-Jones 1998).
other hand, it can be claimed that in non-airborne The problem is more or less under control now-
phototoxic or photoallergic reactions, some parts adays, due to the conjunction of three preventive
of the face are relatively or completely spared, measures: (a) the use of non-powdered latex
whereas in airborne ones, no part is spared. Once gloves; (b) the improvement in the quality of
again, the rule has many exceptions. Diagnosis is latex gloves, in terms of allergenicity (removal
therefore based on carefully completed anam- of immunogenic proteins); and (c) the increasing
nestic data, analysis of symptoms and signs, use of non-latex surgical gloves (Kean and
and patch test and photopatch test results Mc Nally 2009). Other offending agents
(Lachapelle et al. 1992). responsible for occupational airborne
elevated allergen-specific IgE level. This empha-

sizes the new concept of “extrinsic” atopic der-
matitis, related to filaggrin haploinsufficiency in
the stratum corneum; this allows an increased
penetration of high-molecular weight allergens
into the skin. The impact of these studies
has to be further evaluated in occupational
dermatology. (Diepgen 2014).
10 Diagnostic Procedures
The diagnosis of occupational airborne contact

dermatitis may be extremely difficult.
The approach of each individual case requires
various steps that can be discussed in an algorith-
mic way. The major issue is to determine whether
the clinical symptoms evocate or not such a diag-
nosis. The classical tools available for diagnosing
occupational contact dermatitis in general can be
applied to occupational airborne contact dermati-
tis. These include anamnestic data, clinical symp-
Fig. 6 Airborne immune contact urticaria of the face
caused by the dispersion of cornstarch particles with a toms, exacerbation (or not) of symptoms during
high latex protein content in a female operating theater work activities, determination of the occurrence
nurse presensitized by latex gloves of all offending agents at the workplace, knowl-
edge of the chemical nature of these agents, etc.
When an airborne contact is reasonably
immunological contact urticaria are cosmetics, suspected, the following strategy is recommended:
fruit, vegetables, animals’ hair, ammonium
persulfate, or anhydrides. (a) Patch testing and/or photopatch testing
Nonimmunological airborne urticarial reac- Patch tests and/or photopatch tests are
tions are less frequent in occupational life. performed in the usual way. There are no specific
techniques that are recommended for airborne
dermatitis. The methodology also includes addi-
9 Exacerbation of “Extrinsic” tional procedures, such as open tests, semi-open
Atopic Dermatitis by tests, ROAT’s, and eventually use tests.
Aeroallergens (b) Prick testing
Prick tests are needed when airborne
It is convincingly proven that patients suffe- contact urticaria or protein contact dermatitis
ring from atopic dermatitis of exposed sites (i.e., to latex or pollen proteins) is suspected.
(the so-called face and neck dermatitis) are wors- (c) Procedures useful in the diagnosis of
ened by airborne contact with aeroallergens, occupational irritant airborne contact dermatitis
especially house dust mite (Samochocki 2007). Some procedures are available that permit
A recent study (Hallai and Gawkrodger to evaluate the potential accountability of
2009) has shown that 77% of patients some offending agents for provoking airborne
presented with a positive atopy patch test reac- irritancy of the skin. This approach cannot be
tion to human dust mite (20% in pet; achieved without the collaboration of occupa-
Chemotechnique ®) at day 4, as well as an tional physicians and/or safety officers. It also
requires laboratory equipment and dermato- Systemic treatments are sometimes required;
logical expertise in the field. for example, in severe cases of parthenium der-
matitis, azathioprine is very useful and superior to
The following steps are usually recommended: betamethasone (Verma et al. 2008).
Visit of the dermatologist at the workplace and

analysis of the technical aspects of the work
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Acute and Recurrent Vesicular Hand
Dermatitis 18
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
3 Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
4 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
5 Causes and Aggravating Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
5.1 Atopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
5.2 Cutaneous Contact with Irritants and Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
5.3 Systemic Exposure to Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
5.4 Tinea Pedis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
5.5 Tobacco Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
5.6 Other Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
6 Differential Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
7 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7.1 Corticosteroid Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7.2 Topical Calcineurin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7.3 Botulinum Toxin-a Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7.4 Iontophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
7.5 Alitretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
7.6 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.7 Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.8 Mycophenolate Mofetil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.9 Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.10 Cromoglycate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
7.11 Etanercept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
7.12 Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Keywords
J. P. Thyssen (*) · T. Menné Acute · Atopic · Hand eczema · Reccurent ·
Department of Dermatology and Allergy, Herlev-Gentofte Treatment · Vesicular
e-mail: jacob.p.thyssen@regionh.dk;
Torkil.menne@regionh.dk

https://doi.org/10.1007/978-3-319-68617-2_18
242 J. P. Thyssen and T. Menné
1 Core Messages usually not inflamed, but inflammatory skin

changes may be observed following repeated
Acute and recurrent vesicular hand dermatitis is a eruptions (Veien 2009). Scales tend to appear
subtype of hand eczema. when the skin undergoes healing and returns to
This term covers dyshidrotic hand dermatitis its normal appearance, typically after 2–3 weeks
(eczema) and pompholyx, terms that should be (Menné and Hjorth 1983; Veien 2009). Many
abandoned. patients have frequent attacks, 6–12 times per
The disease is characterized by eruptive, vesic- year (Menné and Hjorth 1983). As the skin may
ular dermatitis reactions that affect the palms, the not clear between recurrent episodes, the patient
palmar and lateral aspects of the fingers, and the will present a chronic dermatitis with desquama-
periungual area. tion, vesicles, and fissures (Menné and Hjorth
The vesicles or bullous lesions are often large 1983). The nail matrices may in some recurrent
and deep-seated. cases be damaged which will result in transverse
Causes and aggravating factors include ridging of the nail plates or even discoloration
emotional stress, hyperhidrosis, weather (Menné and Hjorth 1983). Each transverse ridge
changes, atopy, mycosis, irritants, contact aller- indicates an attack of recurrent vesicular hand
gens, and systemic exposure to metals, dermatitis (Menné and Hjorth 1983). Also, in
drugs, and food. However, the cause is often rare cases, lymphedema may develop due to fail-
unknown. ure of small initial lymphatics of the hand to
Treatment includes primarily removal of caus- absorb and drain lymph to regional nodes (Pearce
ative exposures as well as topical corticosteroids, and Mortimer 2009). Dermatologists may benefit
phototherapy, and in some cases systemic from the use of a magnifying glass when
treatment. searching for vesicles in the diagnostic workup
of their patients (Veien 2009). This is of relevance
as vesicular hand dermatitis at causal glance
2 Introduction incorrectly may be diagnosed as other non-
vesicular chronic hand dermatitis (Veien 2009).
Acute and recurrent vesicular hand dermatitis is a The dyshidrotic eczema area and severity index
term used to describe eruptive vesicular dermatitis (DASI) is a commonly used tool that quantifies
reactions that affect the palms, the palmar and clinical signs and symptoms of acute and recur-
lateral aspects of the fingers, and the periungual rent vesicular hand dermatitis based on the num-
area (Veien and Menné 2000; Veien 2009). Itch ber of vesicles, desquamation, erythema, itch, and
and burning sensitization often precede the devel- extension (Vocks et al. 1999).
opment of lesions by 12–24 h. The vesicles or
bullous lesions are deep-seated and are rarely
observed outside the above-defined areas, e.g., 3 Nomenclature
the back of the hands or the forearms (Menné
and Hjorth 1983; Veien 2009). However, similar Over time, acute and recurrent vesicular hand
vesicular lesions may also be observed on the dermatitis has also been known as dyshidrotic
soles and toes. Guillet et al. showed that among eczema, dyshidrosis, pompholyx, and
120 patients with pompholyx, 70% had palmar cheiropompholyx (pompholyx of the hands).
lesions, 10% had plantar lesions, and 20% had Dyshidrosis and pompholyx come from Greek
lesions in both places (Guillet et al. 2007). Similar and mean “bad sweating” and “bubble,” respec-
findings were reported by Castelain (1987) tively. The term dyshidrosis was initially used
whereas Benedek (1974) found that among 1835 since vesicular hand dermatitis was thought to be
military cases with acute and recurrent vesicular associated with occlusion of the sweat glands
palmar or plantar dermatitis, 51% had foot and ducts leading to sweat retention, and as clin-
involvement only. The palmar or plantar skin is ical worsening was often observed during a swift
18 Acute and Recurrent Vesicular Hand Dermatitis 243
to higher temperatures and during the warmer had vesicular morphology (Meding and
summer months (Castelain 1987; Lodi et al. Swanbeck 1989). Thus, the overall estimated
1992). However, studies have rejected an asso- prevalence of vesicular hand dermatitis in the
ciation as histopathological examinations have general population in Sweden was 0.2% in
revealed spongiotic dermatitis with 1964–1965 and 0.3% in 1983–1984 (Meding
intraepidermal vesicles and as the intraepidermal and Swanbeck 1989). Slightly higher preva-
portion of the eccrine sweat duct lences were identified by Latinga et al. (1984),
(acrosyringium) is unaltered by the spongiosis as they showed that the prevalence of vesicular
(Christensen et al. 1981; Kutzner et al. 1986). hand dermatitis was 0.9% in 1979 and 2.8% in
Thus, sweat ducts are mostly pushed aside by 1982 among 1992 adults from the Netherlands.
vesicles or pass between them (Menné and More females than males were affected
Hjorth 1983). A case report described bile- (Lantinga et al. 1984). More recently, Bryld
colored vesicles in a patient with jaundice and et al. found that 300 (5.3%) of 5673 Danish
the authors speculated whether secondary path- twins reported vesicles on the hands without
ological damage to the ducts was driven by other symptoms (Bryld et al. 2000) and Lerbaek
inflammatory spongiosis (Lee et al. 2009). et al. found that among 77 twins with hand der-
Some authors have distinguished between matitis, 20% had vesicular morphology (Lerbaek
dyshidrotic hand eczema and pompholyx as et al. 2008).
they claim these subtypes have different clinical Several reports have estimated the prevalence of
expression patterns (Löfgren and Warshaw vesicular hand dermatitis in patients. Among
2006). Thus, dyshidrotic hand eczema is charac- 425 Swedish patch-tested dermatitis patients, 38%
terized by chronic and recurrent eruptions of had vesicular hand dermatitis (Edman 1988). Lodi
small (1–2 mm) vesicles whereas a severe and et al. (1992) found that among 104 patients with
explosive onset of larger bullae is observed in vesicular hand dermatitis, 56% were men. Like
pompholyx (Löfgren and Warshaw 2006). The other subtypes of hand dermatitis, vesicular hand
above-mentioned terms cover the same disease dermatitis is associated with young age (Guillet et al.
entity and they should all be addressed as (acute 2007). Among 714 Portuguese patients with hand
and) recurrent vesicular hand dermatitis to avoid dermatitis, 20.3% had vesicular hand dermatitis
confusion. (Magina et al. 2003). Recently, Veien et al. found
that 50% of 347 Danish female patients and 31% of
175 Danish male patients seen in private practice
4 Epidemiology had vesicular hand dermatitis (Veien et al. 2008). In
contrast to these high estimates, an older Swedish
The epidemiology of acute and recurrent vesic- study estimated that vesicular hand dermatitis
ular hand dermatitis has been reviewed on sev- accounted for 1% of all hand dermatitis patients
eral occasions (Veien and Menné 2000; Löfgren (Thelin and Agrup 1985). Furthermore, a recent
and Warshaw 2006; Veien 2009). So far, few European multicenter study found that vesicular
studies have investigated the prevalence of hand dermatitis occurred in 9.3% of 319 patients
vesicular hand dermatitis in the general popula- with hand dermatitis (Diepgen et al. 2009), and
tion. Agrup questioned 107,206 subjects about predominately among men (Diepgen et al. 2009).
skin changes on the hands (Agrup 1969): 2499 In a European multicenter study where patients were
(2.3%) gave an affirmative answer and 1659 categorized according to first etiology and then mor-
underwent clinical examination (Agrup 1969). phology, 26 (6%) of 427 patients with hand derma-
In the latter group, 827 had hand dermatitis and titis had the vesicular subtype (Agner et al. 2015).
51 (6.1%) had dermatitis of recurrent vesicular Among 723 patients with occupational hand derma-
morphology (Agrup 1969). In a large epidemio- titis, vesicular dermatitis was more common in
logical study, Meding and Swanbeck also found women (OR 1.44, 95% CI 1.07–1.94) and signifi-
that 6% of 1032 subjects with hand dermatitis cantly associated with hyperhidrosis (OR 1.69, 95%
CI 1.23–2.33), flexural eczema (OR 1.37, 95% CI The accumulation of evidence from the studies
0.99–1.89), and an atopic hand dermatitis compo- discussed below show that recurrent and vesicular
nent (OR 1.93, 95% CI 1.44–2.61) (Brans and John hand dermatitis can be triggered by many different
2015). From the above, it can be appreciated that causes but the clinical expression and morphology
vesicular hand dermatitis is generally a minor sub- is often similar. Thus, vesicular hand dermatitis is
type of hand dermatitis. likely to be a nonspecific reaction pattern in pre-
disposed individuals as previously suggested (Lodi
et al. 1992). In a review, Menné and Hjorth (1983)
5 Causes and Aggravating found that vesicular hand dermatitis was not asso-
Factors ciated with genetic predisposition. However, one
case report described a gene associated with a rare
Several etiological and aggravating factors of acute autosomal dominant form of pompholyx to chro-
and recurrent vesicular hand dermatitis have been mosome 18q22-18q22.3 (Chen et al. 2006). Future
suggested (Table 1). As vesicular hand dermatitis is genetic studies may help to further subdivide this
infrequent in the general population, evidence is disorder into etiological subtypes which will
mainly derived from clinical studies which are increase our understanding markedly.
known to be more biased. Furthermore, it should
be remembered that hand dermatitis is a complex
disorder with many causative factors and that these 5.1 Atopy
may interact differently in different individuals.
According to the American Academy of Allergy,
Immunology and Asthma, atopy refers to the
Table 1 Possible causes and aggravating factors of acute
and recurrent vesicular hand eczema genetic tendency to develop allergic diseases such
as allergic rhinitis, asthma, and atopic dermatitis
Causes and
aggravating factors Comments (eczema). Atopy is typically associated with height-
External factors ened immune responses to common allergens, espe-
Fungal Trichophyton species. cially inhaled allergens and food allergens.
(id-reactions) Convincing association Importantly, atopy has repeatedly been discussed
Irritants For example, water, detergents, as a risk factor for acute and recurrent vesicular
and solvents hand dermatitis. Lodi et al. (1992) found a signifi-
Allergens For example, metals, fragrances, cantly higher prevalence of atopy among 104 sub-
and preservatives
For example, house dust mites jects with vesicular hand dermatitis when they were
Systemic allergic For example, foods, metals, compared with 208 controls (50% vs. 11.5%).
dermatitis reaction implants, and drugs Pitché et al. (2006) found a strong association with
Hyperhidrosis Patients may have a higher atopy in a multivariate analysis performed in a
perspiration volume recent prospective case–control study performed in
Weather and Worsening during a shift to Togo, Africa. In a comparison between 59 workers
temperature changes warmer or colder temperatures
with vesicular hand dermatitis and 160 workers with
Sunlight UVA exposure
other subtypes of hand dermatitis, no significant
Parasites Rare cause
HIV infection One case
difference in the prevalence of atopy was found
Smoking Limited evidence (42.4% vs. 30.6%) (Lehucher-Michel et al. 2000).
Internal factors Also, the authors found no association with contact
Atopy Doubtful association among allergy of occupational relevance (Lehucher-Michel
Caucasians et al. 2000). De Boer et al. (1988), found that only
Emotional or Evidence of improvement 1 (4.7%) of 21 patients with occupational vesicular
general stress following biofeedback therapy hand dermatitis had atopy. Edman et al. investigated
Hormones Worsening during the 425 patients with hand dermatitis of which 92 had
premenstrual period
vesicular hand dermatitis and found no association
with atopy (Edman 1988). Thelin and Agrup (1985) vesicular hand dermatitis when compared to
did not find a higher prevalence of atopy among metals. Bryld et al. (2003) rejected an association
68 patients with vesicular hand dermatitis when they between vesicular hand dermatitis and nickel
were compared to the expected prevalence in the allergy among 398 Danish twins from the general
Swedish general population. Finally, Bryld et al. population. A recent Dutch study showed that
(2003) rejected an association among 398 Danish among 1395 patients, recurrent vesicular hand
twins. The published data suggest that atopy may eczema were significantly more likely to have a
only be weakly associated with vesicular hand der- contact allergy (OR 1.55) (Boonstra et al. 2015).
matitis among European patients whereas a stronger Cutaneous skin contact with irritants as well as
association possibly exists for Africans. A recent contact allergens may elicit vesicular hand derma-
randomized, double-blind, placebo-controlled, titis although study results are diverging and not
cross-over study including 18 patients with vesicu- very convincing. It may be difficult to adequately
lar hand dermatitis and house dust mite allergy study this association by using epidemiological
showed worsening when patients were exposed to tools since vesicular hand dermatitis is relatively
house dust mites compared to placebo (Schuttelaar uncommon and as many other factors may play a
et al. 2013). role. Exposure studies such as those previously
performed for other subtypes of hand dermatitis
seems to be required (Nielsen et al. 1999).
5.2 Cutaneous Contact
with Irritants and Allergens
5.3 Systemic Exposure to Allergens
The possible association between vesicular hand
dermatitis on one hand and contact allergy and Reports have described the development or aggra-
irritant reactions on the other hand, respectively, vation of vesicular hand dermatitis following inser-
has been investigated on several occasions. How- tion of metallic implants such as orthodontic wires
ever, these data are mainly observational and not and dental plates, infusion needles, clips, pace-
generated from exposure studies. De Boer et al. makers, and orthopedic plates and screws (Veien
(1988) showed that among 21 metal workers with and Menné 2000; Veien 2009). On a large scale,
vesicular hand dermatitis, only three had positive such reactions are uncommon as shown by a Dan-
patch test reactions, suggesting that irritancy was ish questionnaire study performed among 1085
associated with vesicular hand dermatitis. In con- girls in active orthodontic treatment or retention
trast, Meneghini et al. found a high prevalence of (Staerkjaer and Menné 1990). Furthermore, there
contact allergy among 364 patients with vesicular is substantial evidence that oral ingestion of food,
hand dermatitis (Meneghini and Angelini 1979). metals, and drugs can result in vesicular hand
Also, Jain et al. (2004) found a high prevalence of dermatitis (Menné and Hjorth 1983; Veien and
contact allergy among 50 patients with vesicular Menné 2000; Löfgren and Warshaw 2006; Thys-
hand dermatitis. Of note, most investigators have sen and Maibach 2008; Veien 2009). However, the
found the strongest association between vesicular contribution of systemic reactivation in the patho-
hand dermatitis and metal allergy (Menné and genesis of vesicular hand dermatitis was recently
Hjorth 1983; Veien and Menné 2000; Veien questioned as Guillet et al. found that only 6.7% of
2009). Crosti and Lodi (1993) speculated that 120 patients had an internal reactivation of their
the higher prevalence of metal allergy among hand dermatitis from food, drugs, or metals
patients with vesicular hand dermatitis could be (Guillet et al. 2007). Oral provocation has repeat-
explained by the high frequency of hyperhidrosis edly been shown to result in vesicular hand derma-
as metal ions are readily released from metallic titis since the pioneering work performed by Flood
items upon contact with sweat. However, Guillet and Perry (Flood and Perry 1946; Veien 2009). In a
et al. (2007) found that cosmetics and personal double-blind, placebo-controlled study with
hygiene products were more often associated with 17 patients sensitized to balsam of Peru and five
patients sensitized to spices, per oral challenge controlled study (Veien et al. 1994). Of note, the
with balsam of Peru and spices resulted in an chromium content in food is much lower (Veien
increased number of palmar vesicles (30–280%) et al. 1994). Taken together, the association
(but not with placebo) in eight patients and an between high metal intake and elicitation of vesic-
increased number of vesicles in three patients ular hand dermatitis is indisputable but it remains
using both the placebo and the active ingredients unclear why nonallergic subjects also may react to
(Niinimaki 1995). Veien et al. found that peroral challenge. The association may have been
28 (60.9%) of 46 patients treated with long-term stronger in the middle of the twentieth century
dietary restriction of balsams in food had improve- than today as cutaneous skin contact with higher
ment in their dermatitis (Veien et al. 1996). metal concentrations occurred more frequently at
Besides foods, there is evidence that the inges- that time. The difficulty of conducting random-
tion of metals may elicit vesicular hand dermatitis ized double-blinded placebo-controlled diet stud-
in predisposed individuals (Veien et al. 1983; ies should be taken into account when one
Veien and Menné 2000; Veien 2009). It is inter- interprets data. Clearly, there is a need for further
esting that vesicular hand dermatitis is observed in research to clarify the exact role of diets in the
both metal sensitized and nonsensitized individ- treatment of vesicular hand dermatitis.
uals (Veien and Kaaber 1979; Veien et al. 1987). The role of systemic drug exposure in the
Whether this is explained by false-negative patch development of vesicular hand dermatitis has
test reactions (Veien 2009), a “placebo” effect, or been reviewed (Thyssen and Maibach 2008).
by direct activation of immunological reactions Briefly, many drugs may be causative and they
caused by metal ingestion is currently unknown should always be suspected (Ekelund and Möller
(Thyssen and Maibach 2008). A study on sys- 1969). Of interest, case reports have described
temic nickel allergy found a dose–response rela- vesicular hand dermatitis following treatment
tionship between nickel ingestion and dermatitis with intravenous immunoglobulin in patients
flare-up. Thus, 0.3, 1, and 4 mg pure nickel as a (Iannaccone et al. 1999).
sulfate hexahydrate gave dermatitis in 40%, 40%,
and 70% of nickel allergic subjects (Jensen et al.
2003). From this study, it can be concluded that a 5.4 Tinea Pedis
single dose of 4 mg nickel will result in wide-
spread dermatitis in most nickel-allergic patients. Tinea pedis is known to result in vesicular erup-
However, normal daily dietary nickel intake has tions on the hands. In temperate climates, they are
been found to vary from 0.02 to 0.48 mg (Jensen most often observed during the summer months
et al. 2006). An open study found an effect of a (Veien and Menné 2000). Most cases are caused
6-week low-nickel diet in 9 of 17 nickel-allergic by Trichophyton mentagrophytes and Tri-
patients that previously had reacted to 2.5 mg chophyton rubrum (Veien and Menné 2000;
nickel exposure (Kaaber et al. 1978). Despite Pitché et al. 2006). The classic example of “id”
disulfiram, therapy may reduce the frequency of reaction is a dermatophytid, a symmetrical vesic-
flares in nickel allergic-patients with vesicular ular eruption on the hands caused by tinea pedis
dermatitis (Kaaber et al. 1983); the risk of severe (Veien and Menné 2000). Veien refers to an early
side effects has prevented their routine use. description by Sulzberger and Baer’s which
Cobalt-allergic patients may experience worsen- among other things requires that the onset of
ing of their vesicular hand dermatitis upon oral eruption on the hands must follow activation or
exposure to 1 mg cobalt (Veien and Kaaber 1979; irritation of the primary focus and that the erup-
Veien et al. 1995). A point-based guide has been tion should disappear or subside within a reason-
published that reduced cobalt intake to <12 μg per able time after the fungal infection has cleared
day (Stuckert and Nedorost 2008). Finally, most (Veien and Menné 2000). In a Danish twin
chromium allergic patients reacted to an oral chal- study, the point prevalence of vesicles on the
lenge with 2.5 mg chromium in a placebo- hands was three times elevated among those
with tinea pedis (Bryld et al. 2003). In a recent 5.6 Other Causes
prospective study performed in Togo, Africa, a
very strong association was found in a multivari- Acute and recurrent vesicular hand dermatitis has
ate analysis (Pitché et al. 2006). Also, Guillet et al. also been associated with psychological stress or
found that 10% of 120 patients with vesicular nervousness (Kellum 1973; Hansen et al. 1981).
hand dermatitis had mycosis (Guillet et al. 2007). Biofeedback training appeared to have a positive
effect in two different patient series (Miller and
Coger 1979; Kodlys and Meyer 1979). Little
5.5 Tobacco Smoking research has been conducted in this field in recent
years. Furthermore, seasonal variation can influence
So far, three studies have investigated the associ- the development of vesicular hand dermatitis and
ation between tobacco smoking and vesicular can lead to aggravation. Lodi et al. found that
hand dermatitis. A positive association was 43 (41%) and 38 (37%) of 104 patients with vesic-
found in these studies but results should be care- ular hand dermatitis reported seasonal variation and
fully interpreted as the studies were not designed worsening due to sweating, respectively (Lodi et al.
optimally to address this question (Edman 1988; 1992). However, Thelin and Agrup rejected an asso-
Guillet et al. 2007). The most recent study showed ciation with hyperhidrosis (Thelin and Agrup 1985).
in 723 patients that vesicular hand dermatitis was In an interesting study, Yokozeki et al. found that
significantly associated with tobacco smoking patients with vesicular hand dermatitis had a 2.5
(OR 1.94, 95% CI 1.40–2.68), whereas hyperker- higher perspiration volume than age- and
atotic hand dermatitis was significantly less com- sex-matched controls indicating an association
mon in smokers (OR 0.38, 95% CI 0.22–0.65) between vesicular hand dermatitis and hyperhidro-
(2016a). Moreover, tobacco smoking was associ- sis (Yokozeki et al. 1992). Also, iontophoresis has
ated with foot dermatitis (OR 1.79, 95% CI: proved successful in the treatment of vesicular hand
1.25–2.57), in particular with the vesicular sub- dermatitis in 20 patients (Odia et al. 1996). Recently,
type (Brans et al. 2016). In addition, other studies it was suggested that UVA exposure could play a
have investigated the association between role in the pathogenesis of vesicular hand dermatitis
smoking and hand dermatitis in general (any sub- as Man et al. showed that UVA provocation on
type) and found diverging results (Montnemery previously affected sites induced vesicular dermati-
et al. 2005; Lerbaek et al. 2007; Meding et al. tis in five patients (Man et al. 2004).
2009). However, there is indirect evidence of an
effect from tobacco smoking on the pathogenesis
of vesicular hand dermatitis as smoking may neg- 6 Differential Diagnoses
atively influence the effect of psoralen UVA
(PUVA) therapy (Douwes et al. 2000). A possible Several differential diagnoses to vesicular hand
positive association between smoking and vesic- dermatitis should be considered (Table 2). In the
ular hand dermatitis may be explained by the fact acute phase, vesicular and bullous disorders (e.g.,
that nickel is found in tobacco plants as a result of pustulosis palmo-plantaris, vesicular tinea manus)
absorption from soil, fertilizing products, or pes- may mimic vesicular hand dermatitis, whereas in
ticides. Furthermore, the nickel content in ciga- the chronic phase, it is rather the scaly and hyper-
rettes and tobacco is high regardless of its kind keratotic disorders that should be excluded (e.g.,
and origin (Stojanovic et al. 2004). One study hyperkeratotic palmar hand eczema, superficial
examined the nickel concentration in 123 blood peeling, and psoriasis). Of note, vesicular hand
samples and 147 urine samples from smokers and dermatitis may be observed in the initial phase
nonsmokers. It revealed a significantly higher or concomitantly with other disorders, e.g., bul-
concentration of nickel in the urine but not in the lous pemphigoid, linear IgA disease, cutaneous
blood of smokers in comparison to nonsmokers T-cell lymphoma, and lichen planus (Veien and
(Stojanovic et al. 2004). Menné 2000).
Table 2 Differential diagnoses of acute and recurrent 1 week) (Veien 2009).Others have recommended
vesicular hand eczema (Veien and Menné 2000; Löfgren higher treatment doses (Löfgren and Warshaw
and Warshaw 2006; Wollina 2008; Veien 2009)
2006; Wollina 2008). Long-term, or repeated
Pustulosis palmo-plantaris short-term, treatment with oral corticosteroids
Superficial peeling (dyshidrosis lamellosa sicca) should be avoided due to the risk of systemic
Infantile acropustulosis
side effects.
Protein contact dermatitis
Bullous pemphigoid
Pustular bacterid
Acrodermatitis continua
7.2 Topical Calcineurin Inhibitors
Hyperkeratotic hand eczema
Palmar psoriasis Topical calcineurin inhibitor treatment may
Vesicular tinea manus and pedis be effective for the treatment of vesicular hand
Scabies dermatitis. In a randomized, single-blind study,
Herpes simplex 16 patients were treated twice daily for
Epidermolysis bullosa hereditaria 4 weeks with either topical tacrolimus or
Herpes gestationis mometasone furoate 0.1% ointment (Schnopp
Friction blisters et al. 2002). The two therapies were equally
efficient (both reduced the DASI score
with 50%) and the authors suggested that the
treatment could be used rotationally to prevent
7 Treatment excessive corticosteroid use (Schnopp et al.
2002). Topical pimecrolimus therapy was used
Treatment modalities for acute and recurrent vesic- twice daily in a 3 week double-blind, random-
ular hand dermatitis has been reviewed (Table 3) ized, placebo-controlled study of 294 patients
(Löfgren and Warshaw 2006; Wollina 2008). Firstly, with chronic hand dermatitis of which some
causative and aggravating exposures should be had vesicular hand dermatitis (Belsito et al.
identified and removed. Low-diet treatment may 2004). A nonsignificant effect was observed in
be necessary in selected cases as described previ- the pimecrolimus group when compared to
ously. Secondly, the use of emollients remains a the vehicle group (p = 0.068). Perhaps
cornerstone of all treatment protocols and should occlusive treatment with pimecrolimus may
be applied liberally. In some cases, supplementary have a better effect as suggested by a case report
use of cool compresses to dry up blisters and to treat (Schurmeyer-Horst et al. 2007). The exact role of
pruritus may be beneficial. In the rare case of lymph- tacrolimus in the treatment of vesicular hand
edema, prophylactic antibiotics together with dermatitis remained to be defined.
aggressive treatment has proven to be efficient
(Pearce and Mortimer 2009).
7.3 Botulinum Toxin-a Therapy
7.1 Corticosteroid Treatment The efficacy of botulinum toxin-A was assessed

among eight adult patients with vesicular hand
First-line therapy of vesicular hand dermatitis dermatitis in an 8-week prospective, side-by-side
includes topical application of corticosteroids controlled study using topical corticosteroid treat-
(Veien et al. 1999; Veien 2009), sometimes ment on both hands in combination with intracu-
applied under occlusion (Volden 1992). Intermit- taneous injections of botulinum toxin-A on the
tent control is necessary to prevent atrophy. It is more severely affected hand (Wollina and
generally perceived that ointments are more effi- Karamfilov 2002). A significant improvement
cient than creams. Short-term oral corticosteroid was observed over an 8-week period (Wollina
treatment is often effective (e.g., 30 mg/day for and Karamfilov 2002). Furthermore, among
Table 3 Treatment options for acute and recurrent vesicular hand eczema
Treatment Comments
Frequently used:
Emollients A mainstay in all therapy regimens but may in some cases
cause irritancy
Cool compresses Typically applied for a few days to dry up blisters
Topical corticosteroids (Veien et al. 1999; Veien 2009) First line; these should often be potent and maintenance
therapy is recommended
Oral corticosteroids (Veien 2009) Only short-term treatment advised, and only when a
concomitant treatment plan is presented
Non-ionizing radiotherapy (Grattan et al. 1991; Schempp UVB/UVA-1/topical and oral PUVA therapy, typically
et al. 1997; Behrens et al. 1999; Petering et al. 2004; 12 weeks
Schiener et al. 2005)
Antibiotics Bacteria should be suspected upon deterioration or when
the skin is broken. A conservative approach is
recommended
Rarely used:
Ionizing radiotherapy (King and Chalmers 1984; Fairris Should be used with caution due to harmful side effects
et al. 1984; Fairris et al. 1985; Stambaugh et al. 2000)
Aluminum chloride Typically applied during night time for prevention of
hyperhidrosis
Iontophoresis (Odia et al. 1996) Rarely used but efficient in some patients
Botulinum toxin (Swartling et al. 2002; Wollina and Two trials; some effect
Karamfilov 2002)
Calcineurin inhibitors (Schnopp et al. 2002; Belsito et al. Two trials; tacrolimus seem to be effective whereas
2004) pimecrolimus may only have a weak effect
Cromoglycate (Cox 1971) One single-blind trial; significant effect
Mycophenolate mofetil (Pickenacker et al. 1998) One case report
Methotrexat (Egan et al. 1999) One case series
Azathioprine (Scerri 1999) One case series
Cyclosporine (Petersen and Menné 1992) One case report
Etanercept (Ogden et al. 2006) One case report
Alitretinoin (Bollag and Ott 1999; Fowler et al. 2014; Several trials performed
Ruzicka et al. 2004; Ruzicka et al. 2008)
10 patients with vesicular hand dermatitis, botuli- hand dermatitis (Odia et al. 1996). Treatment was
num toxin-A therapy resulted in improved self- performed for a total of 20 sessions (15 min each)
assessment of hand dermatitis in the hand treated on one hand for 3 weeks. Seventeen patients had a
with injections in comparison to the untreated significant improvement.
hand (Swartling et al. 2002). Double-blind studies
are warranted but it is unlikely that injection treat-
ment will become routine. 7.5 Alitretinoin
Alitretinoin is a relatively novel treatment option

7.4 Iontophoresis for vesicular hand dermatitis. In a Swiss pilot
study, 34 (89%) of 38 patients with chronic refrac-
Iontophoresis is traditionally used for the treat- tory hand dermatitis (of which seven were diag-
ment of hyperhidrosis. However, a significant nosed as having vesicular hand dermatitis)
effect was demonstrated in a single-blind right- showed a good or very good response to systemic
left study performed in 20 patients with vesicular alitretinoin treatment (20 mg or 40 mg) lasting
1–5 months (Bollag and Ott 1999). “Good” and 7.6 Methotrexate
“very good” were defined as 61–80% and
81–100% reduction of lesions, respectively. All Methotrexate is rarely used for the treatment of
subtypes of hand dermatitis responded in a similar vesicular hand eczema but seemed efficient in an
way. Only mild side effects such as cheilitis, tran- open study with five patients treated with
sient headache, and transient flush to the head 12.5–20 mg per week for up to 20 weeks (Egan
were recorded. The duration of remission after et al. 1999).
discontinuation of successful therapy was
1 month to more than 1 year (Bollag and Ott
1999). The initial findings were only supported 7.7 Azathioprine
to some degree in a double-blind, randomized,
placebo-controlled multicenter study where treat- The efficacy of azathioprine therapy was retro-
ment with oral alitretinoin was performed in spectively evaluated in six patients with vesicular
319 patients, of which 70 had vesicular hand hand dermatitis (Scerri 1999). An oral dose of
dermatitis (Ruzicka et al. 2004). Treatment with 50–100 mg/day was given for a mean duration
either placebo (n = 78), alitretinoin 10 mg (n = of 33.5 months and resulted in excellent response
80), 20 mg (n = 80), or 40 mg (n = 81) was (n = 3), good response (n = 1), and fair response
conducted over a 12-week period. Fifty-three per- (n = 2) (Scerri 1999).
cent of patients who were treated with 40 mg
alitretinoin per day and 27% of those who
received placebo therapy reported complete or 7.8 Mycophenolate Mofetil
nearly complete disappearance of disease signs
and symptoms. Physician’s global assessment One case report showed that treatment with
showed that 12% of patients who received pla- mycophenolate mofetil was efficient in a patient
cebo and 43% of patients who received 40 mg who had tried corticosteroids, iontophoresis,
alitretinoin per day had clearance of their hand PUVA therapy, cyclosporine, dapsone, and topical
dermatitis. However, the response rate was not tar (Pickenacker et al. 1998). Treatment with 1.5 g
significantly different among patients with vesic- mycophenolate mofetil twice a day resulted in
ular hand dermatitis. In a recent randomized, complete recovery after 4 weeks (Pickenacker
double-blind, placebo-controlled multicenter et al. 1998). Of note, mycophenolate mofetil treat-
trial, 1032 patients with hand dermatitis (27% ment following lever transplantation resulted in
with vesicular hand dermatitis) were enrolled vesicular hand dermatitis in one patient
and randomized to treatment with 10 mg (n = (Semhoun-Ducloux et al. 2000).
418) or 30 mg (n = 409) alitretinoin or placebo
therapy (n = 205) for up to 24 weeks (Ruzicka
et al. 2008). This study also found a dose- 7.9 Cyclosporine
dependent effect of alitretinoin therapy as clear
or almost clear hands was observed in 17% of Cyclosporine therapy may be efficient for vesicu-
those who received placebo and in up to 48% of lar hand dermatitis (Petersen and Menné 1992).
those who received alitretinoin. Recurrence of However, no studies have so far been directed at
75% of symptoms was observed after typically evaluating the effect on vesicular hand dermatitis
6 months (Ruzicka et al. 2008). alone but this subtype has probably been a part of
Taken together, alitretinoin represent a treat- larger patient series (Löfgren and Warshaw 2006).
ment modality for vesicular hand eczema but the Granlund et al. found that 3 mg cyclosporine per
results from three trials have not yet convincingly kilogram per day had a similar efficacy as topical
determined its role. A real life report from Ger- betamethasone therapy in a randomized double-
many suggested good effect also in patients with blind study with 41 patients suffering from
hand dermatitis (Diepgen et al. 2012). chronic hand dermatitis (Granlund et al. 1996).
A recent Dutch drug survival study found that x-ray therapy resulted in a significantly better
patients with vesicular hand dermatitis had similar skin condition than Grenz ray therapy (given in
survival as controls (Christoffers et al. 2016). three doses at 21 day intervals) at follow-up after
3, 6, 12, and 18 weeks (Fairris et al. 1985).
Stambaugh et al. reported complete remission of
7.10 Cromoglycate severe vesicular hand dermatitis following
low-dose external beam megavoltage therapy
Cromoglycate therapy was significantly more effi- 1 month after therapy was initiated (Stambaugh
cient at reducing vesicular hand dermatitis than a et al. 2000).
low-nickel diet when used in a randomized, Nonionizing radiotherapy includes the use of
single-blind study including 24 patients with UVB, UVA-1, and topical or oral psoralen in
vesicular hand dermatitis (Cox 1971). combination with UVA irradiation (PUVA). In a
clinical study of seven patients with vesicular
hand dermatitis, oral PUVA therapy was given
7.11 Etanercept three times weekly and resulted in remission on
the maintenance schedule for 2–6 months (LeVine
A patient with atopic dermatitis suffered from et al. 1981). Promising results have also been
chronic vesicular hand dermatitis and was treated found for topical PUVA therapy in small open
with 25 mg etanercept twice weekly (Ogden et al. patient series (Schempp et al. 1997; Davis et al.
2006). Symptoms cleared at 6-week follow-up but 1998; Behrens et al. 1999). There seems to be no
the patient experienced flare-up after 4 months. difference in the efficacy of PUVA-gel versus
When therapy was repeated (in double dose), no PUVA-bath therapy (Schiener et al. 2005). Treat-
effect was observed. ment with UVB irradiation was inferior to oral
PUVA therapy when applied in 35 patients with
chronic hand dermatitis (only one had acute and
7.12 Radiotherapy recurrent vesicular hand dermatitis) (Rosen et al.
1987). However, a recent prospective, compara-
Ionizing radiation techniques include the use of tive study found that local narrowband UVB ther-
superficial x-rays, Grenz rays, and megavoltage apy was as effective as paint-PUVA therapy in
therapy. In some patient series, no information is 15 patients (Sezer and Etikan 2007). In a double-
given about hand dermatitis morphology and blind controlled study including 28 patients with
these articles have been discussed elsewhere vesicular hand dermatitis, UVA-1 versus simu-
(Löfgren and Warshaw 2006). Superficial radio- lated irradiation given five times weekly for
therapy given at 1-week intervals resulted in a 3 weeks resulted in significant improvement
significant better response than simulated therapy after 2–3 weeks in the active treatment group
(placebo) after 1 month, whereas the difference (Polderman et al. 2003). Studies have suggested
was not apparent after 3 and 6 months (King and that UVA-1 therapy is equally efficient with topi-
Chalmers 1984). In a double-blind trial of cal and oral PUVA therapy (Grattan et al. 1991;
24 patients with vesicular hand dermatitis, super- Petering et al. 2004).
ficial x-ray therapy was given on one hand (and
simulated therapy on the other) at intervals of
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Hyperkeratotic Dermatitis
of the Palms 19
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
Keywords • Oral alitretinoin treatment represents an effec-

Hand eczema · Hyperkeratotic · Treatment tive but expensive therapeutic option.
1 Core Messages 2 Introduction
• Hyperkeratotic hand eczema is uncommon. Hyperkeratotic hand eczema is a relatively rare

• It is characterized by volar, often bilateral, and subtype of hand eczema. This hand eczema sub-
symmetric hyperkeratosis of the skin. type is characterized by volar, often bilateral, and
• It is typically located centrally or proximally in symmetric thickening of the skin. The lesions are
the palms. typically located centrally or proximally in the
• The hyperkeratotic skin tends to crack which palms and are less defined than, for example,
may result in painful fissures. psoriatic lesions. The thick skin tends to crack
• First-line treatment options include topical cor- which may result in painful fissures. Pruritus is
ticosteroids, photochemotherapy, and usually weak to moderate. The heels and plantar
retinoids. soles may also be affected. A pioneering study
found no association with psoriatic HLA sub-
types in 32 (21 women and 11 men) patients
with hyperkeratotic hand eczema (Hersle and
J. P. Thyssen (*) · T. Menné
Department of Dermatology and Allergy, Herlev-Gentofte Mobacken 1982). Also, at 10-year follow-up,
University Hospital, Hellerup, Denmark only 1 of 32 patients had developed psoriasis,
e-mail: jacob.pontoppidan.thyssen@regionh.dk; and histological examination of skin biopsies in
jacob.p.thyssen@regionh.dk; tomen@geh.regionh.dk;
9 patients revealed chronic spongiotic dermatitis
Torkil.menne@regionh.dk

https://doi.org/10.1007/978-3-319-68617-2_19
(Hersle and Mobacken 1982). These findings hyperkeratotic hand eczema among a total of
support that hyperkeratotic hand eczema is a 1238 subjects with hand eczema (Meding and
distinct clinical entity different from, for exam- Swanbeck 1989). Two (6.9%) subjects had
ple, psoriasis (Hersle and Mobacken 1982). concomitant allergic contact dermatitis on the
Whether it is associated with manual work or hands. The female/male ratio was 0.8 (Meding
not has not been fully elucidated. When a diag- and Swanbeck 1989). Menné et al. found that
nosis of hyperkeratotic hand eczema is made, 14 (2.5%) of 564 Danish patients under investi-
one needs to exclude allergic and irritant contact gation for permanent disability had hyperkera-
dermatitis as well as dermatomycosis. A recent totic eczema (Menne and Bachmann 1979). The
Dutch study found an inverse association with female/male ratio was 0.8 (Menne and
contact allergy (Boonstra et al. 2015). Also, one Bachmann 1979). Finally, a recent study con-
needs to distinguish this disorder from frictional firmed the low prevalence of hyperkeratotic
contact dermatitis which is caused by frictional hand eczema. Thus, 21 (5.3%) of 319 patients
trauma. Other clinical differential diagnoses in a European multicenter cross-sectional study
include psoriasis, pustulosis palmoplantaris, had hyperkeratotic hand eczema (Diepgen et al.
Bazex syndrome, and lymphoma. In many arti- 2009). The disease was associated with older age
cles, the term “hyperkeratotic hand eczema” is groups and a high hand eczema severity index
used to describe hand eczema with hyperkerato- score (HECSI) and with female gender (Diepgen
sis in general although these morphologically et al. 2009). Hyperkeratotic hand eczema was
associated subtypes may have a different patho- mainly located on the palms and fingers and
genesis. This distinction should be taken into was defined as hyperkeratotic morphology in
account when one interprets the outcome of var- the palms and absence of relevant contact allergy
ious trials. and irritant exposure and exclusion of atopic
dermatitis (Diepgen et al. 2009).
Recently, it was shown that hyperkeratotic
3 Epidemiology hand eczema was inversely associated with
smoking in 723 German patients (Brans and
Only few studies have investigated the preva- John 2016).
lence of hyperkeratotic hand eczema. In
1964–1965, Agrup questioned and examined
107,206 subjects from Southern Sweden and 4 Treatment
found that 33 (2.1%) of 1551 subjects with
inflammatory hand dermatosis had hyperkera- Treatment options for hyperkeratotic hand eczema
totic hand eczema (Agrup 1969). The disorder are plentiful. The use of emollients is a cornerstone
was more prevalent among men than women of all treatment protocols. Topical therapy includes
(the female/male ratio was 0.6) (Agrup 1969). application of corticosteroids (Saeki et al. 2009),
Furthermore, hyperkeratotic hand eczema was often applied under occlusion. Intermittent control
observed in all age groups but seemed to be is necessary to prevent atrophy. Also, the use of
most prevalent among 40–69-year-olds (Agrup topical tar products may be effective. However, no
1969). Among 33 subjects with hyperkeratotic randomized, double-blind, placebo-controlled
hand eczema, 4 (12.1%) had occupational rele- studies have been performed to investigate their
vance, 10 (30.3%) had previously been exam- efficacy. Keratolytic therapy with salicylic acid
ined at the outpatient department of dermatology preparation in combination with corticosteroids
in Lund, Sweden, and 3 (9.1%) had been on sick was excellent at reducing hyperkeratosis and fis-
leave due to their condition (Agrup 1969). sures in seven patients (Baden 1974). Topical vita-
In 1982–1983, Meding et al. investigated the min A acid treatment was investigated in five
epidemiology of hand eczema in Gothenburg, patients with hyperkeratotic hand eczema but
Sweden, and found that 29 (2.3%) subjects had gave severe inflammation (Gunther 1972). Egawa
19 Hyperkeratotic Dermatitis of the Palms 259
applied topical vitamin D3 (calcipotriol 50 μg/g and Ott 1999). “Good” and “very good” were
and maxacalcitol 25 μg/g) in five patients with defined as 61–80% and 81–100% reduction of
hyperkeratotic hand eczema (Egawa 2005). lesions, respectively. All subtypes of hand
Lesions improved and almost disappeared within eczema responded in a similar way. Only mild
2–8 weeks in all patients (Egawa 2005). side effects such as cheilitis, transient headache,
Retreatment was effective at reducing relapses and transient flush to the head were recorded.
(Egawa 2005). Finally, tazarotene has been anec- The duration of remission after discontinuation
dotally reported for treatment of hyperkeratotic of successful therapy was 1 month to more
hand eczema (Warshaw 2004). than 1 year (Bollag and Ott 1999). The above
Topical and oral psoralen photochemotherapy findings were confirmed in a double-blind,
may also be useful treatment modalities randomized, placebo-controlled multicenter
(Mobacken et al. 1983; De Rie et al. 1995; study where treatment with oral alitretinoin was
Schempp et al. 1997). Mobacken et al. showed performed in 319 patients, of which the majority
that oral psoralen and UVA irradiation (PUVA) had hyperkeratotic hand eczema (Ruzicka et al.
was effective in five patients with hyperkeratotic 2004). However, in this study, “hyperkeratotic
hand eczema (Mobacken et al. 1983). Further- hand eczema” was not strictly defined as in the
more, two patients with hyperkeratotic hand first study using alitretinoin. Treatment with either
eczema showed partial remission following topi- placebo (n = 78) or alitretinoin 10 mg (n = 80),
cal PUVA therapy with psoralen in aqueous gel 20 mg (n = 80), or 40 mg (n = 81) was conducted
(De Rie et al. 1995). Among 14 patients with over a 12-week period; 53% of patients who
chronic hyperkeratotic palmar or plantar eczema, were treated with 40 mg alitretinoin per day
local bath-PUVA therapy had a good effect in and 27% of those who received placebo therapy
86% (43% cleared and 43% had substantial reported complete or nearly complete dis-
improvement) and gave no phototoxic effects appearance of disease signs and symptoms.
(Schempp et al. 1997). In a recent study, a better Physician’s global assessment showed that 12%
effect of PUVA-gel than bath-PUVA therapy of patients who received placebo and 43% of
was observed in one of three patients (Schiener patients who received 40 mg alitretinoin per day
et al. 2005). had clearance of their hand eczema. In general,
Systemic treatment options include oral efficacy seemed to be dose dependent. Adverse
acitretin and alitretinoin. In a Danish single- effects also seemed to be dose dependent
blind, placebo-controlled study including and comprised headache, flushing, elevations in
29 patients with hyperkeratotic hand eczema, serum lipid level, decreased hemoglobin level,
14 patients received 30 mg acitretin daily, and decreased free thyroxin level (Ruzicka et al.
whereas 15 patients received daily placebo treat- 2004). In another randomized, double-blind,
ment (Thestrup-Pedersen et al. 2001). Following placebo-controlled multicenter trial, 1032 patients
4 weeks of treatment, symptoms such as hyper- with hand eczema (85% hyperkeratotic) were
keratosis, fissures, scaling, itch, redness, and enrolled and randomized to treatment with
vesicle count were reduced by 51% among 10 mg (n = 418) or 30 mg (n = 409) alitretinoin
patients that received acitretin in comparison or placebo therapy (n = 205) for up to 24 weeks
with 9% in the placebo group (Thestrup- (Ruzicka et al. 2008). Again, hyperkeratotic
Pedersen et al. 2001). No further improvement hand eczema was not defined. This study also
was observed over another 4 weeks. In a Swiss found a dose-dependent effect of alitretinoin
pilot study, 34 (89%) of 38 patients with chronic therapy as clear or almost clear hands were
refractory hand eczema (of which 22 were observed in 17% of those who received placebo
diagnosed as having classic hyperkeratotic and in up to 48% of those who received
hand eczema subtype) showed a good or very alitretinoin. Recurrence of 75% of symptoms
good response to systemic alitretinoin treatment was observed after typically 0.5 year (Ruzicka
(20 mg or 40 mg) lasting 1–5 months (Bollag et al. 2008).
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Atopic Dermatitis
20
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
3 Epidemiology, Pathophysiology, and Clinical Features of
Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
4 Atopic Dermatitis and Filaggrin Mutations Are Risk Factors of
Occupational Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
5 Pathogenesis of Occupational Contact Dermatitis in Patients with Atopic
Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
6 The Role of Allergic Contact Dermatitis in Atopic Dermatitis . . . . . . . . . . . . . . . . . 270
7 Occupational Contact Dermatitis: Clinical Presentations in
Atopic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
8 Management of Occupational Contact Dermatitis in Atopic Dermatitis . . . . . . 273
9 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Abstract
Atopic dermatitis (AD) is a chronic inflamma-
tory skin disease that is associated with a defi-
K. Breuer (*) cient epidermal barrier function. The risk of
Private Practice, Reinbek, Germany developing occupational contact dermatitis is
e-mail: breuer@dermatologie-reinbek.de increased in patients with AD exposed to wet
T. Werfel work. In this chapter, an overview of patho-
Department of Dermatology and Allergy, Klinik für genesis, clinical presentations and manage-
Dermatologie und Venerologie, Hannover Medical School,
Hannover, Germany ment of occupational contact dermatitis in
e-mail: werfel.thomas@mh-hannover.de patients with AD will be presented.
https://doi.org/10.1007/978-3-319-68617-2_20
262 K. Breuer and T. Werfel
Keywords • Since several factors contribute to the develop-

Atopic dermatitis · Atopic skin disposition · ment of occupational contact dermatitis,
Atopy · Transepidermal water loss · Epidermal a general exclusion of persons with atopic
barrier function · Filaggrin · Risk factors · skin disposition or atopic dermatitis from risk
Erlangen atopy score · Flexural eczema · occupations is not effective in terms of primary
Apprenticeship · Irritant contact dermatitis · prevention. Instead, individual advice should
Epidemiology · Epidemiologic studies · rather be given to persons at risk and technical,
Allergic contact dermatitis · Atopic organizational, and personal protection mea-
hand eczema · Post-occupational dermatitis · sures, as well as repeated follow-up examina-
Hand eczema · Primary prevention · Pre- tions have to be considered.
employment examination · Intrinsic
atopic dermatitis · Cornified envelope ·
Ceramides · T cells 2 Introduction
Atopic dermatitis (AD) is a chronic inflam-

1 Core Message matory skin disease that commonly begins
in early infancy, runs a course of relapses and
• Previous atopic hand dermatitis and/or flexural remissions, and is associated with a characteristic
eczema increases the risk of developing irritant distribution and morphology of skin lesions.
contact dermatitis at least twofold in individ- Furthermore, pruritus and consequent sleepless-
uals exposed to irritants and wet work. ness are hallmarks of AD.
• In contrast to allergic contact dermatitis to A complex interaction between susceptibility
haptens, individuals suffering from atopic der- genes, host environments, and specific immuno-
matitis are prone to protein contact dermatitis logic responses is involved into the pathogenesis
and contact urticaria to occupational allergens of atopic dermatitis (AD). AD is associated
like food stuff or latex proteins. with a deficient epidermal barrier function and
• It is often difficult to decide whether occupa- irritants play an important role in the initiation
tional exposure or constitutional factors have and perpetuation of inflammatory lesions. There-
a greater impact for the development of hand fore, AD is often complicated by irritant contact
eczema in atopic individuals. The diagnostic dermatitis in adolescents and adults working in
work-up should therefore lead to a distinct occupations with a continuous exposure to irri-
diagnosis and allow to quantify the impact of tants and wet work.
occupational and nonoccupational factors. An
exposure-independent course and persistence
of eczema after discontinuation of work sug- 3 Epidemiology,
gest a preponderance of atopic skin disposition Pathophysiology, and Clinical
over occupational exposure. Features of Atopic Dermatitis
• With regard to atopy and dependent on
the morphology of skin lesions as well as the The prevalence of AD has at least doubled
course of the disease, hand eczema may be in industrialized countries over the past
classified as chronic irritant contact dermatitis three decades; 15–30% of children and 2–10%
with atopic skin disposition, irritant-induced of adults suffer from AD (Williams and Flohr
atopic hand eczema, or atopic hand eczema. 2006). The 12-months prevalence in 11-year-old
• It is a matter of debate whether “dyshidrotic” children ranged from 1% to 20% in the Global
vesicular hand eczema without a strict expo- International Study of Asthma and Allergies
sure-dependent course and with no relevant in Childhood trial; prevalence was highest in
contact sensitization and normal IgE levels Northern Europe (Anonymus 1998).
represents “intrinsic” atopic hand eczema or a A total of 45% of all cases of AD begin within
distinct entity. the first 6 months of life (Kay et al. 1994). While
20 Atopic Dermatitis 263
in the past, AD was considered to show remis- developing allergic asthma and allergic rhinitis
sion in more than 50% of young patients up to (“atopic march”). Fifty percent of all children
adolescence; more recent epidemiologic data who had AD during the first 2 years of life
suggest that AD is a disease that persists life- developed asthma over the subsequent years. A
long. A large majority of children with early family history of atopy, severe disease, and early
onset AD suffering from mild to moderate sensitization to food allergens were identified as
eczema show persistent AD in the second and risk factors for asthma in children with AD (Illi
even third decade according to data of a large et al. 2004; Warner and Esg 2001). However,
longitudinal cohort study performed in the USA 20% of all adult patients with atopic dermatitis
(Margolis et al. 2014). Individuals with AD may have normal IgE serum levels. This subtype of
develop occupational irritant contact dermatitis AD which has been described as “intrinsic” AD,
and/or various clinical manifestations of atopic often has a late onset (>20 years of life) and a
dermatitis in occupationally exposed skin later lack of IgE sensitization against food and inhal-
on (Belhadjali et al. 2008) (see also paragraph 5 ant allergens (Schmid-Grendelmeier et al.
of this chapter). The clinical presentation of 2001). Variations in cytokine profiles might
atopic dermatitis is dependent on the age (Bieber explain the phenomenon of “extrinsic” and
et al. 2017): In infants, erythematous lesions “intrinsic” subtypes of AD, and rather than two
with oozing and crusting are typically located distinct phenotypes of one disease, extrinsic and
on the cheeks and the scalp. Older children com- intrinsic subtypes may represent opposite parts
monly show more chronic lesions with of a large spectrum of phenotypes.
lichenified papules and plaques involving the A complex interaction between susceptibility
flexural folds, the wrists, and ankles, but may genes encoding skin barrier molecules and
also have eczema on the hands and feet. In ado- markers of the inflammatory response, host
lescence and adulthood, atopic dermatitis is environments, infectious agents, and specific
most frequently located at the face and neck immunologic responses are involved in the
and the flexural folds. Additionally, the hands pathophysiology of AD. Recent genetic associa-
and feet are frequently involved in this age tion studies have identified 31 loci associated
group. In the elderly, skin lesions often have with atopic dermatitis risk (Paternoster
erythrodermic aspects with a strong pruritus et al. 2015).
component. Asymptomatic skin in AD differs from normal
Numerous trigger factors have been identified skin. Lesional but also nonlesional skin of
for AD in recent decades. Besides inhalant patients with atopic dermatitis has a deficient
allergens and food allergens, various nonspecific permeability barrier and barrier function impair-
trigger factors may worsen AD such as irritants ment of uninvolved skin has been related
(e.g., detergents, textiles, and chemicals), climatic to the severity of atopic dermatitis. This is
factors, and colonization with microorganisms reflected by an increased transepidermal water
like Staphylococcus aureus and Malassezia furfur. loss (TEWL), a decrease in the stratum corneum
Moreover, also self-allergens may contribute to hydration, and an increased permeation of irritants
the pathophysiology of AD (Breuer et al. 2006; such as SLS or polyethylene glycol (Jakasa et al.
Tang et al. 2012; Werfel and Kapp 1998; Werfel 2007). Over the last decades, lipid abnormalities
et al. 2015). and an abnormal differentiation process of
Atopic dermatitis, together with allergic keratinocytes have been identified as causes of
asthma, allergic rhinoconjunctivitis, and IgE- epidermal barrier defects in atopic dermatitis
mediated food allergy belongs to the so-called (Cork et al. 2009; Proksch et al. 2009).
atopic diseases. These diseases are commonly Changes in at least three groups of genes
associated with an elevated level of total serum encoding structural proteins, epidermal proteases,
IgE and the presence of specific IgE antibodies and protease inhibitors predispose to a deficient
directed to inhalant or food allergens. Children skin barrier and increase the risk of developing
with atopic dermatitis are at high risk of atopic dermatitis, mutations of the filaggrin gene
being the most relevant. Filaggrin “loss-of-func- De Benedetto et al. 2011): Decreased expres-
tion” mutations (“FLG null mutations”) were sion of tight junction proteins such as claudin-1,
detected in about 30% of patients with atopic decreased levels of ceramides, reduced
dermatitis in European countries. This finding sphingomyelinase activity, impaired metabolism
was first published by Palmer et al. (2006) and of omega-6-unsaturated fatty acids, and elevated
then confirmed by several groups (see reviews cholesterol and phospholipid contents contribute
Brown and Mc Lean (2009), O’Regan et al. to a weakened skin barrier function. In patients
(2009)). According to epidemiological studies, with atopic dermatitis, the skin pH of lesional
the risk of developing atopic dermatitis is signif- and nonlesional skin is higher than in normal
icantly increased for carriers of these mutations – individuals which may inhibit barrier recovery
in a meta-analysis the odds ratio was calculated and facilitate barrier breakdown. The described
with 4.1 in case control studies and 2.1 in family deficiencies leading to disrupted skin barrier
studies (Cork et al. 2009; Proksch et al. 2009). function are thought to be causal for the
Filaggrin aggregates keratin filaments into bun- susceptibility to irritant contact dermatitis in
dles. Due to FLG mutations, several barrier func- patients with atopic dermatitis.
tions are impaired, such as the formation of the Besides barrier dysfunction, dysregu-
cornified envelope, modelling of the corneocyte lation in innate and acquired immunity con-
shape, moisturization through NMF, and lipid tributes to the signs and symptoms of AD.
lamellae synthesis as well as the desquamation The inflammatory mechanisms and immunologi-
process. These mechanisms lead to increased cal aspects which are specific to AD are reviewed
inflammation and higher penetration of allergens in (Werfel et al. 2016).
into the skin: AD patients carrying filaggrin loss- The presence of large numbers of T cells
of-function mutations suffer from severe eczema both in the dermis and the epidermis is a
with chronic courses and multiple sensitizations hallmark of AD. Today, AD is considered as
to inhalant and food allergens. Moreover, the risk a mainly Th2-driven systemic disease. Recent
of developing AD in carriers of FLG mutations research revealed that apart from Th2 cell
exposed to distinct environmental allergens such populations, also Th17 and Th22 cell populations
as cat allergens has been shown to be increased are present in AD skin. Cytokine profiles differ
(Bisgaard et al. 2008). Thus, weakening of the due to dependence on age and ethnic origin:
epidermal barrier function may increase the effect AD in childhood exhibits a Th2, Th9, and
of environmental exposures in the induction and Th17 polarization, while adults show a Th22
perpetuation of skin inflammation. However, skin dominance. In the Asian AD population, the
barrier function is reduced in patients with AD T cell response shows a Th17 dominance (Bieber
who do not carry FLG mutations (Jakasa et al. et al. 2017).
2011) and the majority of heterozygous carriers of Defined subsets of dendritic cells play a
FLG mutations do not develop AD (O’Regan et role in the different phases of inflammation.
al. 2009); in AD skin, high levels of Th22 cyto- Langerhans cells (LHC) expressing the high affin-
kines and IL-22, skin-colonizing microorganisms, ity IgE receptor (FceRI) are critical for uptake and
and environmental factors may induce down- presentation of allergens penetrating the epider-
regulation of filaggrin expression (Thyssen and mis, i.e., pollen allergens. They prime naive
Kezic 2014), but also of other skin barrier proteins T cells to Th2 cells, while inflammatory dendritic
such as involucrin and hornerin, leading to epidermal cells (IDEC) become more prominent
disrupted skin barrier function despite absence of in chronic AD lesions and promote Th1 cytokine
FLG mutations. production from T cells by release of IL-12 and
Besides FLG mutations, further changes IL18. Moreover, eosinophils and mast cells are
of proteins and lipids maintaining the skin involved in cutaneous inflammation.
barrier integrity and function are associated There is a complex interaction between
with AD (Cork et al. 2009; Proksch et al. 2009; cutaneous immune responses and microbes
colonizing the skin. The microbiome of the skin is dermatitis was shown in a previous study, where
altered in patients with AD: most AD patients are 38% of nearly 300 patients with severe occupa-
colonized with Staphylococcus aureus. During tional hand dermatitis suffered from irritant-
acute flares of AD, the microbial diversity of the induced atopic eczema (Skudlik and Schwanitz
skin is decreased, while diversity is restored after 2004). Since atopic hand dermatitis has been
anti-inflammatory treatment (Kong et al. 2012). shown to be associated with longstanding disease
Whether decreased microbial diversity is a cause and long-lasting sick leave as compared to other
or a consequence of cutaneous inflammation is forms of hand eczema (Cvetkovski et al. 2005;
discussed controversely; the Th2 cytokine milieu Veien et al. 2008), preventive measures should
dominating in acute AD lesions may favor specifically consider patients with skin atopy.
deficiencies of antimicrobial peptide expression The definition of “atopy”includes AD, allergic
which in turn may lead to loss of microbial asthma, and allergic rhinoconjunctivitis. The
diversity and growth of S. aureus. The resulting prevalence of atopy in the general population is
predominance of Toll-like receptor (TLR)-2 assumed to be 20–30% (Roberts 1987). Since skin
ligands might then lead to upregulation of Thymic atopy seems to be of higher relevance for a
stromal lymphopoietin (TSLP) in keratinocytes predisposition to occupational irritant contact
and accumulation of type 2 innate lymphoid dermatitis than inhalant atopy and flexural eczema
cells (ILC2s), which in turn influence dendritic may be absent at the time point of the investiga-
cells to promote a Th2 phenotype in T cells. tion, diagnostic criteria for the identification of
However, recently S. aureus strains isolated from patients with atopic skin disposition are helpful.
children with severe AD were used to colonize the For the diagnosis of AD, several major and minor
skin of pathogen-free mice. In this animal model, clinical features based on traditional clinical expe-
colonization with S. aureus induced a cutaneous rience have been proposed by Hanifin and Rajka
inflammation pattern characteristic of AD (Byrd (1980). Accordingly, at least three basic and three
et al. 2017). minor criteria have to be present in a patient
Pruritus is one of the major clinical character- in order to diagnose AD. As major criteria, a
istics of AD. The signal for pruritus is mediated history of flexural eczema, of rhinoconjunctivitis,
by cutaneous nerve fibers (CNF). Recent studies and of allergic asthma and a family history of
suggest that cytokines such as IL-31 derived from atopy as well as itch when sweating were
Th2 cells and TSLP derived from keratinocytes described. In order to develop a scoring system
rather than histamine are critical for the induction to identify patients with atopic skin disposition,
of itch in AD skin. Diepgen et al. have compared the prevalence
of these basic and minor features in patients with
past or present flexural eczema recruited from
4 Atopic Dermatitis and Filaggrin their Department of Dermatology and in a normal
Mutations Are Risk Factors of population (Diepgen et al. 1989). Anamnestic and
Occupational Contact clinical features which had significantly higher
Dermatitis prevalence as compared to the normal population
and were more frequent than 20% in AD were
With respect to occupational trigger factors included in a score system and weighed according
of atopic dermatitis, irritants play a significant to their statistical significance. Past or present
role in the initiation and perpetuation of inflam- flexural eczema was excluded from the score
matory lesions. Dependent on the causative agent, since it was the selection basis. By using this
irritant-induced atopic dermatitis may become “Erlangen atopy score,”patients with past or pre-
manifest at different localizations but most fre- sent flexural eczema and normal individuals could
quently presents as hand eczema. The high probe separated well with minimal overlapping. The
portion of individuals with atopic skin disposition authors propose that patients with more than 10
among patients with occupational contact points should be considered to have an atopic skin
disposition, and patients with 6–10 points should studies, patch tests were not performed; therefore,
be suspected to be atopics. According to this irritant contact dermatitis could not be distin-
study, 7% of the investigated normal population guished clearly from allergic contact dermatitis.
were estimated to have an atopic skin disposition, As a part of the Swiss Prospective Metal Worker
and a further 19% were suspected to be atopics. Eczema Study (PROMETES), Berndt et al. have
The Erlangen atopy score was validated in a fur- followed more than 200 healthy male trainee metal
ther study by Diepgen et al. (1991). In the frame- workers from the beginning of their apprenticeship
work of the POSH study (Prevention of over a period of 2.5 years (Berndt et al. 1999a,
Occupational Skin Disease in Hairdressers), Uter 2000). Nearly 10% of the study population devel-
et al. have applied the Erlangen atopy score in oped signs of hand dermatitis within 6–8 months
a cohort of hairdressing apprentices (Uter et al. after starting the training and the 2.5-year incidence
1999a). Similar to Diepgen et al., the different was 23%. Mechanical work and an insufficient
features of the Erlangen atopy score were associ- amount of skin recovery time increased the risk of
ated significantly with past or present flexural hand eczema significantly. A history of flexural
eczema, but the association was weaker and eczema was reported by 5% of the study population
the discrimination between individuals with past and could be identified as a relevant risk factor for
or present flexural eczema and healthy indivi- the development of hand dermatitis within the
duals was worse, which points to a lesser validity 2.5 year study period (odds ratio, OR 4.2), whereas
of single atopy features. According to the authors, a preexisting metal sensitivity increased the risk for
the differing results may be due to clinical early onset of hand dermatitis within 6 months (OR
distinctions between the investigated cohorts 6.96). Interestingly, the risk of developing hand
with a higher number of patients with pronounced dermatitis was not increased for the 4.5% of
skin lesions and atopic stigmata in the collective trainees who had an Erlangen atopy score indicat-
recruited from a dermatologic unit as compared to ing atopic skin diathesis (score of 10 and above)
a working population. and single minor atopic features did not have a
Employees in occupations involving continu- significant influence on the development of occu-
ous exposure to irritants and wet work are at high pational contact dermatitis.
risk of developing occupational irritant contact The Prospective Audi Cohort (PACO) study
dermatitis. Among others, the hairdressing trade, has investigated the incidence and risk factors of
health-care professions, cleaning occupations, occupational hand dermatitis in more than 2000
and the metal industry have an outstanding rele- trainees of the German Audi AG and also white-
vance as risk occupations. collar workers were included (Funke et al. 1996,
Besides occupational exposure to irritants, 2001). This study takes a variety of work-related
several epidemiological studies have identified factors into account and demonstrates clearly
atopic dermatitis as a relevant risk factor for that irritant exposure at the workplace plays an
the development of occupational contact dermati- important role in the development of occupational
tis, whereas the Erlangen atopy score of Diepgen contact dermatitis. The 1-year and 3-year inci-
et al. (1989, 1991) seems to be less relevant. dence of hand eczema were 8.6% and 14.1%,
However, due to heterogeneous methods applied respectively, and a particularly high rate of der-
in these studies – particularly the definitions of matitis occurred within the first 6 months. More
“morbidity (hand eczema/contact dermatitis),” than 90% of the cases were diagnosed as irritant
“sensitivity (atopy),” “exposure,” and the statisti- contact dermatitis, while allergic contact dermati-
cal measure used to calculate the risk of develop- tis was assumed in about 6%. Within 3 years,
ing occupational contact dermatitis (odds ratio vs. blue-collar workers had a significant twofold ele-
relative risk vs. prevalence ratio) – the comparison vated risk of developing occupational hand der-
and interpretation of the results is difficult. More- matitis compared to white-collar occupations. On
over, some studies have a retrospective design and the basis of the 1-year incidence, previous hand
no physical examination was done. In most of the eczema or flexural eczema increased the risk of
occupational hand eczema significantly (Relative questionnaires, the attributable fraction of hand
Risk, RR 6.0 and 4.8, respectively). Furthermore, eczema from childhood eczema was 9.6% (Lind
private exposure to irritants was identified as et al. 2007). Skin atopy and hairdressing had
a further risk factor. Nearly 1500 subjects were a synergistic effect on the development of
followed up in the PACO II study (mean follow- hand dermatitis. For about half of the females
up period 13.3 years from the beginning of with hand eczema, the onset was before the age
the apprenticeship) (Apfelbacher et al. 2008). of 20 years.
Interestingly, the occurrence of hand eczema Nilsson et al. studied the prevalence and risk
dropped after the end of apprenticeship and the factors of occupational hand eczema in 1613
cumulative incidence of hand eczema was not hospital workers and found a period prevalence
significantly different between white- and blue- of 41% over 20 months. Previous atopic dermati-
collar workers which points to the fact that the tis was identified as a significant risk factor
occupational environment becomes less important (OR 3). Occupational and domestic wet work
in the long run. further increased the risk (Nilsson et al. 1985).
The POSH project (prevention of occupational Few investigators have identified inhalant
skin disease in hairdressers), a large prospective atopic diseases as risk factors of irritant
population-based study, analyzed the risk associated contact dermatitis. In a prospective study on the
with constitutional and exposure-related factors of development of occupational contact dermatitis
occupational hand eczema in >2000 hairdressing in the car manufacturing industry, >1500 new
apprentices (Uter et al. 1995, 1998, 1999b). The employees were followed during the first year
point prevalence of hand eczema at the end of the of employment. Besides previous hand eczema
apprenticeship was 55%. While previous flexural or and atopic dermatitis, wool intolerance and hay
hand dermatitis was associated with an increased fever were significantly associated with the
risk of occupational contact dermatitis in the first occurrence of hand eczema (Kristensen 1992).
year of training (OR 1.7) (Uter et al. 1995), no Since no adjustment for confounders was
association was found at the final follow-up exam- performed in this study, the data have to be
ination and only the rare combination of both factors interpreted cautiously. In a small retrospective
showed a tendency to being a risk factor. The attrib- cohort study which included 111 nurses, Smit et
utable risk for the development of hand eczema was al. identified respiratory atopy as a risk factor for
4% for previous flexural eczema and 13% for pre- the development of hand dermatitis in
vious hand eczema which means that most cases of nurses (Smit and Coenraads 1993). In a cross-
hand eczema were not caused by atopy but by sectional study on 1375 geriatric nurses, a history
exposition to wet work and irritants. While an ele- of allergic rhinitis was associated with an
vated atopy score between 7 and 9.5 points was increased risk of hand eczema (OR 1.5), while
identified as a significant risk factor, the highest no association was found for childhood flexural
score category (10 points and more) was not asso- eczema (Skudlik et al. 2009).
ciated with an increased risk of developing hand Due to the difficulties to define the term
dermatitis. Among the clinical signs of the atopy “atopy” and the failure of the Erlangen atopy
score, only xerosis and Herthoge sign increased score to predict the development of irritant
morbidity. Moreover, unprotected wet work of contact dermatitis, several investigators aimed
more than 2 h duration was shown to be a major to identify predictors of individual susceptibility
risk factor for irritant hand dermatitis while glove by use of cutaneous bioengineering methods.
wearing diminished the risk. Low absolute humidity John et al. followed a cohort of hairdresser
and low outside temperature were identified as sig- apprentices for 3 years (John et al. 2000). Neither
nificant environmental factors doubling the risk the Erlangen atopy score nor basal bioengineering
of irritant contact dermatitis. parameters – such as transepidermal water loss
In a retrospective cohort study on Swedish (TEWL), microcirculation (laser Doppler flow),
female hairdressers using self-administered capacitance (relative skin moisture), pH, sebum,
and temperature measured under standardized hand eczema in apprentice nurses was investigated
circumstances previous to the beginning of the in a prospective cohort study (Visser et al. 2014).
apprenticeship – were indicators for the develop- The prevalence of hand eczema was increased for
ment of occupational contact dermatitis during trainees who had pre-occupational hand eczema,
the follow-up period. Apprentices who later who had a history of atopic dermatitis and for
developed irritant contact dermatitis showed a frequent handwashing at the workplace and
significantly higher increase of TEWL in repeti- at home. Carriers of FLG mutations who had
tive measurements of exposed skin areas com- AD showed the highest risk of hand eczema,
pared to individuals who did not develop skin whereas an increased risk for carriers of FLG
lesions. Furthermore, there was no significant mutations who did not suffer from AD was not
association between any of the bioengineering established.
parameters and the atopy score or preexisting FLG mutation status and atopic diathesis
atopic dermatitis (hand eczema and/or flexural have an influence on the response of occupa-
eczema). tional ICD to therapy, on the recovery rates
In the framework of PROMETES, different and rates of job continuation (Landeck et al.
biophysical tests were performed in metalwork 2012): Patients with atopic diathesis (defined
trainees and none of the single methods were as past or current flexural eczema and /or
appropriate to identify individuals at high risk an Erlangen atopy score of at least 10 points)
of developing irritant contact dermatitis (Berndt showed a worse response to therapy, lower
et al. 1999b). A combination of irritation tests recovery rates, and higher rates of job discontin-
with dimethyl sulfoxid (DMSO) and NaOH uation than nonatopic individuals; the outcome
allowed to identify individuals who developed of therapy was least favorable for atopic carriers
contact dermatitis during their apprenticeship of FLG mutations.
with a high sensitivity of >90% but a low speci- Recently, it was shown that FLG mutations
ficity of <25%. Therefore, the results of cutane- increase the risk of early onset of hand eczema
ous bioengineering methods are not predictive in patients with AD but not in individuals without
for the manifestation of occupational skin diseases a history of AD (Heede et al. 2017). Moreover,
and do not correlate with preexisting atopic der- self-reported hand eczema and AD were associ-
matitis or the Erlangen atopy score. ated with a particularly high risk of disability
The mechanisms by which AD influences the pension among FLG mutation carriers, suggesting
development of ICD were largely unknown for that FLG mutation carriers with a history of AD
a long time. The discovery that 20–30% of and hand eczema should be advised against high-
patients with AD are carriers of FLG null muta- risk occupations.
tions and that decreased epidermal filaggrin In summary, both FLG mutations and AD are
expression contributes to the impaired skin barrier independent risk factors of irritant contact derma-
function shed new light on this question. titis and of a higher resistance to therapy. More-
Visser et al. investigated the contribution of over, the risk is greatest for individuals with AD
current or past AD (defined as flexural eczema) who are carriers of FLG null mutations.
and FLG mutations in German vocational school In conclusion, the studies presented above
apprentices with occupational ICD and controls demonstrate that occupational irritant contact
(Visser et al. 2013). The adjusted OR for subjects dermatitis is a complex disease with a multifac-
with FLG mutations (adjusted for AD) was 1.62, torial pathogenesis involving several constitu-
and the OR for subjects with AD (adjusted for tional and exogenous risk factors. Wet work
FLG mutations) was 2.89. Individuals with FLG performed for at least 2 h daily increases the
mutations who suffered from current or past AD risk of developing irritant contact dermatitis at
were at highest risk of ICD (combined OR 4.7). least twofold. Furthermore, previous atopic der-
The influence of AD, FLG mutations and wet matitis (hand dermatitis and/or flexural eczema)
work exposure on the development of occupational and filaggrin mutations are independent risk
factors which add a further minimum twofold hand eczema should be advised against risk
risk to individuals exposed to irritants and wet occupations; routine determination of the
work. This is a multiplicating effect, which markers of the FLG mutation status/barrier
means that the risk of hand eczema in persons impairment (e.g., NMF) in individuals with AD
with atopic dermatitis and/or filaggrin mutations may be helpful for the identification of indivi-
who are exposed to occupational irritants is duals at high risk of occupational ICD in
increased at least fourfold. No association was the future.
found with the “minor atopic criteria” or the
Erlangen atopy score and only few studies iden-
tified inhalant atopy being a significant risk fac- 5 Pathogenesis of Occupational
tor. On the other hand, private exposure to Contact Dermatitis in Patients
irritants and environmental factors (i.e., climate) with Atopic Dermatitis
has been found to be factor increasing the risk of
occupational contact dermatitis significantly. Patients with altered epidermal barrier function
Importantly, the impact of atopic dermatitis on are prone to developing irritant contact dermatitis,
the development of occupational hand eczema is and existing dermatitis, irrespective of type,
dependent on the intensity of occupational enhances reactivity to irritants in other body loca-
exposure to irritants and wet work; in profes- tions (Slowodnik et al. 2008). This is also the case
sions associated with an intensive exposure in patients with atopic dermatitis since the consti-
to irritants, a smaller proportion of hand eczema tutionally deficient epidermal barrier allows the
cases will be attributed to atopic dermatitis penetration of irritants through the skin. After
than in professions with a low or even no expo- irritation with SLS, the TEWL is significantly
sure to irritants. According to Rystedt et al. increased in patients with atopic dermatitis as
(Rystedt 1985), one-fourth of individuals with compared to normal controls (Cowley and Farr
childhood atopic dermatitis working in high 1992). In contrast, individuals with isolated
risk professions do not develop hand eczema mucosal atopy have a similar barrier function as
and two-third of individuals with childhood normal individuals (Conti et al. 1996). This con-
atopic dermatitis who have no occupational cept is supported by a number of epidemiological
exposure to irritants suffer from atopic hand studies which have been discussed above.
dermatitis. Cutaneous contact with irritants causes a non-
The data above suggest that extrinsic factors, specific reaction of the skin (Slowodnik et al.
i.e., exposure to irritants and wet work, are the 2008): Irritants such as detergents may emulsify
major causative factors for the development of the skin surface lipids which are then washed off.
AD and intrinsic factors like AD and FLG muta- Even more important is the increase of the skin
tion status increase the risk. Therefore, improve- pH, leading to an inhibition of enzymes which
ment of working conditions for all employees exhibit a low acid pH optimum and are critical
in risk occupations, individual advice, and use for the synthesis of epidermal lipids such as β-
of skin protection measures are of fundamental glucocerebrosidase, whereas enzymes with
importance for the prophylaxis of occupational a neutral pH optimum such as the serine proteases
contact dermatitis. Moreover, the relevance KLK5 and KLK7 are activated which play a role
of periodical examinations for the prevention in desquamation (Cork et al. 2009). Besides skin
of occupational contact dermatitis, specifically barrier dysfunction, direct cellular damage and
in early phases of the apprenticeship, is under- induction of pro-inflammatory mediators are
lined by the study results. Individuals with pre- mechanisms which lead to the clinical signs
occupational hand eczema and persons with of irritant contact dermatitis such as red, dry,
atopic dermatitis who are carriers of FLG muta- scaly, and fissured skin. Keratinocytes play a sig-
tions are at a particular high risk of developing nificant role in the elicitation and perpetuation
ICD. Patients with preoccupational atopic of irritant contact dermatitis. Skin barrier damage
is followed by an upregulation of major histo- mutations without dermatitis was only slightly
compatibility complex II antigens and cell increased (Thyssen et al. 2013).
adhesion molecules on keratinocytes. Further- In other studies, the frequency of contact sen-
more, innate pro-inflammatory cytokines such as sitization was not increased in patients with atopic
tumor necrosis factor-alpha (TNF-α), interleukin dermatitis as compared to nonatopic individuals:
(IL)-1α, and IL-1β are released. The chemokine Heine et al. have retrospectively analyzed patch
CCL21 is also upregulated and attracts T lympho- test data of nearly 54,000 patients collected
cytes expressing the CLA antigen to the skin. by the German Information Network of Depart-
As shown by Proksch et al., barrier disruption ments of Dermatology (IVDK) with respect to the
is also followed by an increase of epidermal frequency of contact allergic reactions in atopic
Langerhans cell density (Proksch et al. 1996). individuals as compared to nonatopic controls
On the basis of these findings, it was postulated (Heine et al. 2006). First, occupational allergic
that skin barrier disruption alone leads to cytokine contact dermatitis was diagnosed more often
production and inflammation. in atopic individuals than in control individuals
As FLG polymorphisms affect the skin barrier, without atopy. Second, no significant difference
they may lead to an increase in the susceptibility with regard to the number of positive patch test
to irritants and allergens and to the develop- reactions to allergens of the standard series was
ment of irritant and allergic contact dermatitis. A found between the groups and the frequencies of
reduced threshold to inflammation upon cutane- single, double, or polyvalent sensitization was
ous application of irritants has been demonstrated nearly identical. Third, the frequency of positive
in filaggrin deficient flaky tail mice (Scharschmidt patch test reactions to certain common type-IV
et al. 2009). However, the fact that AD is a greater allergen groups (fragrances, emollients, external
risk factor for developing occupational ICD than drugs, rubbers) were significantly higher in
FLG mutations suggests that other factors than the patients with atopy than in the control group as
impaired barrier function such as immune was the frequency of sensitization to bufexamac,
dysregulation may play a role in the perpetuation compositae mix, thiuram mix, and (chloro)-
of ICD in individuals with AD. methylisothiazolinone (MCI/MI). Patients with
atopy and concomitant allergic contact dermatitis
were more often employed as office workers and
6 The Role of Allergic Contact nurses than patients with allergic contact dermati-
Dermatitis in Atopic Dermatitis tis without atopy. As allergen sources, external
drugs and ointments, fragrances, rubbers and
Irritant allergic contact dermatitis is a risk factor gloves, as well as disinfectants were more often
for the development of allergic contact sensitiza- identified in patients with atopy. This may reflect
tion, and the impaired barrier function in lesional the higher exposure of atopic patients to topical
skin as well as the cutaneous inflammatory milieu emollients and ointments and the higher propor-
have been shown to favor the penetration of tion of employees of the nursing profession
contact allergens and alleviate type IV sensitiza- among the patients with atopy.
tion (Smith et al. 2002). Similarly, Clemmensen et al. found in gen-
The role of atopic dermatitis as a risk factor eral similar frequencies of positive patch test
for the occurrence of type IV sensitization and reactions in patients with and without AD, but
contact allergy is still a matter of debate and multiple sensitizations were detected more fre-
it has been speculated that both the deficient quently in patients with severe AD as compared
barrier function and the cytokine milieu of atopic to mild or moderate AD (Clemmensen et al.
skin may alleviate sensitization; in a Danish study, 2014). Severity of eczema influenced the fre-
carriers of FLG mutations with self-reported quency of patch test reactions in a further
dermatitis had an increased risk of contact sensi- study on ACD in patients with AD (Belhadjali
tization, whereas the risk for carriers of FLG et al. 2008).
However, a recent systematic review and meta- addition of acontact allergic component to the
analysis of the association between AD and disease. However, with regard to occupational
contact sensitization did neither reveal an exposure, the development of irritant contact der-
increased nor a decreased risk of contact sensiti- matitis in patients with atopic dermatitis may
zation between AD and controls (Hamann et al. favor the occurrence of allergic contact dermatitis.
2017). The authors concluded that clinicians Further aspects with regard to occupational
should consider patch testing AD patients when ACD in patients with AD are important to note:
allergic contact dermatitis is suspected. The exposure to volatile occupational allergens
Allergic contact dermatitis and atopic such as fragrances, constituents of glues, plastics
dermatitis are both mediated by skin homing or rubbers, lubricants, wood or metal dust, as well
T lymphocytes and the cutaneous infiltrate is as pharmaceuticals may lead to airborne contact
mainly composed of mononuclear cells. Allergic dermatitis which presents at uncovered skin areas
contact dermatitis is triggered by small allergens and has to be differentiated from head-and-neck
(haptens) and occurs at the sites of contact. atopic dermatitis (Breuer et al. 2009; Santos and
The clinical presentation of both diseases is sim- Goossens 2007).
ilar: acute lesions exhibit papulovesiculae, and Atopic dermatitis is a risk factor for the devel-
chronic lesions present with dry, erythematous, opment of protein contact dermatitis and contact
and lichenified skin. Atopic dermatitis mainly urticaria (von Krogh and Maibach 1981). Protein
occurs in early infancy, and concomitant allergic contact dermatitis usually presents as a chronic
contact dermatitis may also develop in this age eczema with episodic acute exacerbations a few
(Dotterud and Falk 1994, 1995; Giordano- minutes after contact with sources of protein aller-
Labadie et al. 1999) which points to a certain gens, mainly fruits, vegetables, spices, meat, fish,
overlap between these diseases. With regard to flour, or plants. Kitchen personnel, bakers, and
the pathomechanism, TNF-α polymorphisms gardeners are at risk of developing protein contact
were detected in patients with allergic contact dermatitis.
dermatitis but not in patients with atopic dermati- With respect to the reading and interpretation
tis (Reich et al. 2003; Westphal et al. 2003). of patch tests in patients with atopic dermatitis,
In AD, Th2 cytokine production may function irritant reactions which are expected to occur
as an important factor for increased ACD more frequently in patients with atopic dermatitis
reactions: Th2 cytokines may synergize with (Brasch et al. 2003), present as well-demarcated
innate immune cytokines produced in the early areas and show a decrescendo phenomenon, have
phases of ACD such as TNF-(greek alphabet: to be distinguished from “true” allergic reactions.
alpha) and IL-1a to induce TSLP production by
keratinocytes which in turn stimulates migration
of LCs to local lymph nodes. Moreover, the pre- 7 Occupational Contact
existing activation of innate immunity, and the Dermatitis: Clinical
upregulation of Th17 and Th22 in AD skin may Presentations in Atopic
explain the increased prevalence of ACD in Patients
patients with AD (Gittler et al. 2013).
In conclusion, the results of studies on ACD Occupational contact dermatitis is not a homoge-
in AD are conflicting; a generally increased nous entity, but rather a number of eczema types
or decreased risk of atopic dermatitis patients contributing to different clinical presentations.
to be sensitized to contact allergens was not With regard to atopy, hand eczema may be classi-
found in previous studies and the higher fre- fied using the following diagnoses (Skudlik and
quency of positive patch test reactions to certain John 2007):
allergens may rather reflect a higher exposure than
a greater sensitivity. Vice versa, type-IV-sensiti- 1. Chronic irritant contact dermatitis with atopic
zation may trigger atopic dermatitis by the skin disposition becomes manifest as a
consequence of occupational exposure to irri- eczema, further renders the classification of

tants and shows an exposure-dependent course occupational hand eczema difficult.
with fast improvement after discontinuation of Moreover, there are constellations which addi-
exposure. It usually presents with erythema, tionally aggravate the classification of job-related
scaling, and fissures and is located at the back eczema: In patients with previous atopic dermati-
of the hands or the interdigital web spaces. tis, occupational irritant contact dermatitis of the
Patients have a history of atopic dermatitis or hands may precipitate a flare of generalized
show a combination of the atopy minor criteria eczema which appears clinically consistent with
according to Diepgen. Chronic irritant contact atopic dermatitis. Many of these patients
dermatitis commonly develops slowly over a have not had eczema since childhood and the
period of weeks or months and is the result of pathomechanism beyond this phenomenon is
multiple subthreshold insults induced by weak largely unknown (Williams et al. 2007).
irritants (Slowodnik et al. 2008). After discontinuation of occupational expo-
2. Irritant-induced atopic hand eczema becomes sure, hand eczema may persist with no obvious
manifest or is significantly deteriorated due present cutaneous exposure. This phenomenon
to occupational exposure. It often presents is described as “persistent post-occupational der-
at the palmar sides of the hands with itch, matitis” (Sajjachareonpong et al. 2004) and
vesicles, and erythema. The back of the hands the patients often report initial improvement of
and the volar wrists are frequently involved. the skin condition upon removal from exposure
Irritant-induced atopic hand eczema shows an before they develop persistent eczema which
exposure-dependent course, but may also clinically resembles endogenous eczema. The
show deterioration in work-free periods. It pathogenesis of persistent post-occupational
may persist months after discontinuation of dermatitis is poorly understood, severity of pre-
exposure. ceding eczema, cumulative irritation, and atopic
3. Irritant-induced atopic hand eczema shows skin diathesis have been suggested as risk fac-
similar clinical features as in 2 mentioned tors. However, many patients do not exhibit
above, but exacerbations and remissions signs of atopy such as elevated IgE and minor
occur independently from occupational expo- atopic features. It has to be discussed whether
sures. Nonoccupational trigger factors such as post-occupational dermatitis represents a kind of
climate, exposition to inhalant or food aller- “intrinsic” atopic hand eczema. Irrespective of
gens, domestic wet work, and others may lead this aspect, it is difficult to define whether the
to exacerbation. former occupational exposure still has an influ-
ence on the skin condition and skin irritability or
It is a matter of debate, whether “dyshidrotic” whether constitutional factors such as atopic der-
vesicular hand eczema without a strict exposure- matitis or skin atopy are pivotal. Persistent post-
dependent course and with no relevant occupational dermatitis has a substantial impact
contact sensitization and normal IgE levels repre- for the statutory accident insurances, since
sents “intrinsic” atopic hand eczema or a distinct months or even years after the approval as occu-
entity (Diepgen et al. 2009). pational skin disease insurances’ compensation
In longstanding hand eczema, it is often payments are reviewed and suspended if the
difficult to differentiate etiological types of der- disease is believed to be endogenous due to
matitis from each other and from allergic contact lack of improvement after cessation of work.
dermatitis, since with increasing duration, mor- Previous long-lasting occupational exposure, a
phology, localization, and course tend to be sim- long history of occupational hand eczema, and
ilar (Cvetkovski et al. 2005; Diepgen et al. 2009). no evidence of remissions after discontinuation
The fact that different forms of hand eczema of exposure may suggest a predomination of
may occur in parallel, e.g., irritant-induced atopic occupational factors as cause of persistent hand
hand eczema and subsequent allergic contact eczema.
Therefore, it may be difficult to decide whether Eventually, the course of the disease has to
in patients with atopic skin disposition, hand be observed over a longer period in order to quantify
eczema constitutional and exogenous (occupational) factors.
With respect to therapeutic management
1. Has primarily been caused (e.g., become man- of AD, we refer to the recent consensus-based
ifest) due to occupational exposure European guideline for treatment of AD
2. Has been significantly deteriorated due to (Wollenberg et al. 2018a, b).
occupational exposure Avoidance of exposure to irritants and aller-
3. Has been caused primarily by constitutional gens, use of protective equipment, and the use
factors and not by occupational exposure of emollients are basic in the treatment of occupa-
4. Is causally linked to former occupational expo- tional contact dermatitis.
sure in case of persistent lesions upon discon- Topical corticosteroids and calcineurin inhibi-
tinuation of work tors are used for flare management and for
proactive therapy for long-term control.
These aspects are of major importance for the There are studies showing that the application
compensation of patients who have lost their of potent topical corticosteroids (TCS) results in
occupation due to a skin disease. a decrease in the amount of intercellular lipid
Taken together, the classification of occupa- lamellae and a reduced number of membrane
tional hand eczema and the quantification of coated granules at the stratum granulosum –
occupational and constitutional factors in patients stratum corneum interface (Kao et al. 2003;
with atopic dermatitis/atopic skin disposition Sheu et al. 1997). Moreover, potent corticoste-
are difficult and a standardized classification roids induce the expression of serin proteases
system is needed. Clinical studies should address such as KLK7 which are associated with the
this aspect. skin barrier deficiency in atopic dermatitis
(Yousef et al. 2000). Though TCS inhibit cuta-
neous inflammation, they may also cause further
8 Management of Occupational damage to the epidermal barrier and may
Contact Dermatitis in Atopic increase the risk of irritant contact dermatitis in
Dermatitis patients with atopic dermatitis. Therefore, the
long-term use of potent corticosteroids should
When occupational contact dermatitis is suspected be avoided, particularly in adolescents. Topical
in patients with atopic dermatitis, the diagnostic calcineurin inhibitors such as tacrolimus are an
workup should lead to a distinct diagnosis alternative to TCS, since they do not induce skin
(i.e., irritant contact dermatitis, allergic contact atrophy.
dermatitis) and should allow to quantify the impact Since repetitive UV exposure has been
of occupational and nonoccupational factors. shown to elicit hardening of the skin, to sup-
The history taking should particularly focus press cellular proliferation, and to modulate
on occupational exposures and the course of the local immune system by a reduction of
disease, i.e., the relationship between deteriora- the amount of Langerhans cells, phototherapy
tion and occupational exposure. In order to quan- may be considered in adolescents and young
tify competitive factors, private exposure to adults (Simons et al. 1997). However,
irritants or allergens and seasonal variation has according to current guidelines, phototherapy
to be asked for. Clinical investigation should should not be performed in children younger
consider atopic minor criteria and patch testing than 12 years.
helps to detect contact sensitization. Besides Systemic immunomodulating drugs, e.g.,
from commercially available contact allergens, ciclosporine, methotrexate, azathioprine, or
the patient’s own products should be tested mycophenolic acid, are indicated in severe refrac-
whenever possible. tory cases of AD.
Recently, dupilumab, a monoclonal antibody occupational (pre-)employment counselling of per-

antagonizing the Th2 cytokines IL-4 and IL-13, sons with atopic skin disposition which allocates
was approved for moderate to severe AD in persons with distinct symptoms and signs of atopy
the US and in EU countries. However, multiple to certain risk groups (Coenraads and Diepgen
double-blind, randomized clinical trials showing 1998). Preventive measures for individuals belong-
efficacy in AD specifically excluded patients with ing to these risk groups are suggested. According to
AD limited to the hands. In a recent case series on this guide, occupations with wet work or other
three patients with AD limited to the palmar aspects exposure to irritants are not advisable for individ-
of the hands substantial responses to the treatment, uals with atopic dermatitis with hand involvement.
ranging from 80% improvement to complete clear- Technical, organizational, and personal protection
ance, were demonstrated (Zirwas 2018). measures as well as repeated follow-up exam-
Alitretinoin (9-cis retinoid acid) is a novel vitamin inations in the first 2 years of employment have
A derivative which has been licensed for oral treat- to be considered for patients with atopic derma-
ment of chronic hand eczema in several European titis without hand involvement. Similarly, the
countries. Though general dryness of the skin is a German social accident insurance has developed
common side effect of oral retinoids, an improve- guidelines for pre-employment advice to aspirants
ment of eczema by more than 50% as measured with of risk occupations and the frequency of follow-up
the SCORAD was demonstrated in a case series of investigations (G-24) which are, however, not
six adult patients with AD (Grahovac et al. 2010). An obligatory regarding skin diseases. In contrast,
increased general dryness was not observed. since 2005 the German Ordinance on Hazardous
Substances (Gefahrstoffverordnung) stipulates reg-
ular examinations for workers employed in risk
9 Prevention professions involving 4 h wet work.
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Frictional Trauma/Mechanic Skin
Diseases 21
Niels H. Bennike and Klaus E. Andersen
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
3 Individual Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
4 Causes and Frequency of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
5 Hand Eczema Following a Mechanical Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
6 Hand Eczema Following Repeated Friction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Abstract made probable, it has important medical impli-

Normal skin can resist mechanical insults to a cations when job related. Only a minor fraction
certain degree. If not counteracted by protec- of individuals exposed to repetitive mechanical
tive measures, excessive friction or superficial stimuli such as friction develop physical irri-
skin injuries may develop into cutaneous distant contact dermatitis, indicating a probable
ease. Post-traumatic eczema can persist or role of genetic predisposition in addition to
recur for long periods of time, while pre- environmental factors such as temperature
existing dermatoses can be aggravated by and sweat production. Hyperkeratoses, cal-
mechanical trauma. If a dynamic relationship luses, and lichenification are common clinical
between trauma and development of eczema is manifestations of a frictional eczema which
most often involves the hands. Frictional
hand dermatitis can be caused by working in
N. H. Bennike (*) various occupations, from office workers to
National Allergy Research Centre, Department of craftsmen such as carpet installers and
Dermatology and Allergy, Herlev-Gentofte University shoe makers. Time from onset of exposure to
Hospital, Hellerup, Denmark development of frictional dermatitis can vary
e-mail: niels.hoejsager.bennike@regionh.dk
from weeks to years. Post-traumatic eczema
K. E. Andersen following mechanical injury usually occurs
Department of Dermatology and Allergy Centre, Odense
University Hospital, University of Southern Denmark, within weeks. It may occur in association
Odense, Denmark with an underlying endogenous dermatosis
e-mail: keandersen@health.sdu.dk

https://doi.org/10.1007/978-3-319-68617-2_21
280 N. H. Bennike and K. E. Andersen
(isomorphic reaction of Koebner’s phenome- 2014). Furthermore, patients with preexisting skin
non) or occur as an isolated idiopathic reaction. disease may experience localized aggravation of
The clinical features of posttraumatic eczema the disorder as a consequence of mechanical trauma
are indistinguishable from other types of hand to the site. If a dynamic relationship between
eczema. mechanical trauma end the development of hand
eczema is made probable, it has important medical
Keywords implications when the injury is job related. Clinical
Cardboard · Computer dermatitis · Craftsmen · features associated with mechanical insults to the
Hyperkeratosis · Frictional dermatitis · skin include (Samitz 1985):
Koebner’s phenomenon · Lichenification ·
Mechanic dermatoses · Paper · Post-traumatic • Lichenification
eczema · Skin barrier · Skin injury · Skin • Hyperpigmentation
trauma • Hyperkeratosis/calluses
• Fissuring
• Blistering/friction injury
1 Core Messages • Increased susceptibility to infections
• Increased susceptibility to irritants and contact
• A multifactorial etiology is common. allergens
• Posttraumatic eczema may persist and recur for • Development of foreign body reactions
a long time. • Traumatic tattoos
• Friction is the most common cause of physical • Pressure urticaria
irritant contact dermatitis. • Scars and keloids
• Frictional dermatitis can be seen in all trades, • Cutaneous neoplasms
from office workers to craftsmen. • Koebner’s phenomenon (psoriasis) from
• Post-traumatic eczema may be associated with friction
endogenous dermatosis or be idiopathic. • Raynaud’s phenomenon from vibration
This chapter focuses on occupational skin dis-

2 Introduction eases caused by friction and mechanical insults.
Darrell S. Wilkinson has previously reviewed der-
The skin is normally flexible and can resist matitis from repeated trauma in a broader perspec-
mechanical trauma to a certain degree. Excessive tive (Wilkinson 1985).
friction or superficial skin injuries such as abra-
sions, pressure, stretching, compression, and cuts
may affect the integrity of the skin and lead to
symptomatic skin changes. These may, if not 3 Individual Factors
counteracted properly by protective measures
such as use of gloves, develop into disease (Elsner Only a minor fraction of individuals exposed to
2007). Multiple job categories, from office workers repetitive mechanical stimuli develop physical
to craftsmen, carry a risk of mechanical trauma to irritant contact dermatitis. In addition to the ambi-
the skin and subsequent development of physically ent environment, it is likely that genetic factors
induced skin disorders. In the clinic, dermatitis play a role in determining the response of the skin
patients may complain that their eczema appeared to mechanical strain. Exacerbation of atopic der-
after an injury to the skin. Although coincidental in matitis and psoriasis (both partly inheritable skin
some cases, mechanical trauma can precipitate diseases) may occur after mechanical trauma. In
symptomatic skin disease and lead to post- some patients, contact dermatitis resolves in spite
traumatic eczema that persist or recur for long of continued exposure to an irritant, in a phenom-
periods of time (Mathias 1988; Greiling et al. enon known as “hardening” or “accommodation”
21 Frictional Trauma/Mechanic Skin Diseases 281
(Watkins and Maibach 2009). Why these adaptive complications include scar formation, infection,
alterations are only seen in some exposed individ- persistent pain, and contact dermatitis from top-
uals remains unknown. However, physiological ical drugs used for treatment. Further, local
factors such as the hydration of the skin are impor- eczema may also appear and is common, partic-
tant. Moderate sweating hydrates the corneal layer ularly in susceptible individuals such as ampu-
and increases the coefficient of friction, whereas tees (Meulenbelt et al. 2007).
dry or wet skin diminishes the friction of resis-
tance (Pedersen and Jemec 2006; Schürer and
Dickel 2007). Regarding injuries, neurological 5 Hand Eczema Following
diseases may impair the withdrawal response to a Mechanical Injury
mechanical stimuli and lead to increased risk of
injury of the skin. Post-traumatic eczema is a poorly understood
complication of skin injuries caused by thermal
or chemical burns, lacerations, punctures, or abra-
4 Causes and Frequency sions. The interval between the trauma and the
of Disease development of eczema is usually a few weeks.
Mathias (Mathias 1988) divided post-traumatic
By convention, traumatic injuries result from sin- eczema into two types: It may occur in association
gle and brief episodes of cutaneous exposure and with an underlying endogenous dermatosis (iso-
a subsequently rapid onset of skin ailment. This is morphic reaction of Koebner’s phenomenon) or
opposed to irritant cutaneous reactions which occur as an isolated idiopathic reaction, when
most often require multiple and prolonged expo- longtime follow-up shows that no new lesions
sures and show a relatively delayed onset of the develop on nontraumatized skin. “Koebner’s phe-
disorder. Mechanical stress also significantly nomenon” is a term applied when the dermatosis
affects the barrier properties of the skin measured develops at the site of trauma (Weiss et al. 2002).
by transepidermal water loss and capacitance It is well known in relation to psoriasis but also
(Pedersen and Jemec 2006). occurs in other conditions, such as lichen planus,
Figure 1 summarizes the distribution of occu- vitiligo, Darier’s disease, and discoid lupus
pational injury and illness cases in the US private erythematosus. Isomorphic reactions may also be
industry in 2015. Cuts, lacerations, and punc- seen in patients with eczema during its active
tures constituted close to 10% of injuries, while phases. The isomorphic reaction may be the pri-
skin diseases constituted about 15% of all regis- mary manifestation of an endogenous eczema,
tered illnesses. However, several studies have and probably more frequently, it occurs as a sec-
found trends suggesting both an underestimation ondary eczema at the site of trauma. The clinical
of, and regular increase in, the frequency and features of post-traumatic eczema are indistin-
gravity of observed skin diseases (De Craecker guishable from other types of hand eczema.
et al. 2008). Contact dermatitis comprises Often, it presents within a few weeks of the
around 95% of all recognized occupational skin acute injury as a discoid or nummular eczema
diseases. In a Danish study among 1500 cases with or without vesicles around the site of trauma
with recognized occupational contact dermatitis, (Beukers and van der Valk 2006). The trauma
mechanical irritation was ranked as the fifth most itself causes obvious damage accompanied by
common irritant exposure in relation to occupa- inflammation and regeneration. Fissures, pain,
tion (Carøe et al. 2014). Among patients diag- and itching may be pronounced to varying
nosed with physical irritant contact dermatitis, degrees. The post-traumatic eczema may become
friction has been found to be the most common chronic. The differential diagnoses include non-
causal exposure, and the hands are the primary eczematous skin diseases associated with
body site most often affected (Morris-Jones et al. Koebner’s phenomenon, foreign body reactions,
2002). Regarding skin injuries, common bacterial infections, herpes simplex, and
282 N. H. Bennike and K. E. Andersen
Poisoning 1.2%
100
Illnesses 4.8% Respiratory conditions
Total cases: 8.6%
2,905,900
Hearing loss 12.0%
75
Skin diseases 15.6%
Percent
50
Injuries 95.2%
Other illnesses 62.6%

25
0
Injuries and illnesses Illnesses
Fig. 1 Distribution of occupational injury and illness cases Labor Statistics, U.S. Department of Labor, October 2016
in the US private industry in 2015 Source: U.S. Bureau of (https://www.bls.gov/iif/oshwc/osh/os/osch0057.pdf)
secondary allergic contact dermatitis to topical 1983). Although the various materials are often
preparations. handled frequently over longer periods of time,
duration from onset of exposure to development
of frictional dermatitis can be highly variable,
6 Hand Eczema Following ranging from weeks to years (Bennike et al. 2016).
Repeated Friction A Swedish field study among carpet installers
revealed that over years, they develop hyperkera-
Repeated minor mechanical trauma to the skin tosis on their knuckles and dorsal aspects of the
such as friction, pressure, abrasion, puncture, hands as a result of repeated trauma to the skin
and shearing forces can cause a variety of skin from friction and pressure (Wahlberg 1985). Sim-
changes including dermatitis. Dermatitis from ilar clinical findings have been described in shoe-
friction affects only a small proportion of exposed makers (Mancuso et al. 1996). In more recent
individuals, depending on constitutional factors years, frictional hand dermatoses caused by occu-
and special patterns of exposure. However, fric- pational use of personal computers (PCs) have
tional dermatitis may often go unrecognized been reported, often characterized by lichenified
(McMullen and Gawkrodger 2006). The effects lesions (Corazza et al. 2016). In some manual
of mechanical forces may as well be accentuated labor occupations, mechanical injuries may be
by other physical agents such as heat, cold, and an aggravating factor, which together with consti-
vibration. tutional factors and exposure to irritants and aller-
In a few cases, frictional dermatitis may gens intensify the degree of hand eczema.
develop into chronic hand dermatitis. The fric- Meneghini has previously reported that contact
tional dermatitis may be elicited by highly vari- allergy is more prevalent among workers who
able exposures. These include small metal parts, have sustained cuts, abrasions, and other mechan-
paper and cardboard, driving, fabrics, and other ical injuries compared to those who have not
items with a rough surface not immediately visi- (Meneghini 1985). Further, a Swedish study of
ble to the naked eye such as counter tops (Menne 853 hard-metal workers suggested that the
21 Frictional Trauma/Mechanic Skin Diseases 283
traumatic, frictional effect of grinding and etching Mathias CG (1988) Post-traumatic eczema. Dermatol Clin
was an important factor in the development of 6(1):35–42
McMullen E, Gawkrodger DJ (2006) Physical friction is
cobalt allergy (Fischer and Rystedt 1983). under-recognized as an irritant that can cause or con-
tribute to contact dermatitis. Br J Dermatol 154
(1):154–156
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paper and cardboard causing occupational dermatitis in Meulenbelt HEJ et al (2007) Skin problems in lower limb
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Beukers S, van der Valk PGM (2006) Idiopathic post- Dermatol Venereol 21(2):147–155
traumatic eczema. Contact Dermatitis 54(3):178 Morris-Jones R et al (2002) Dermatitis caused by physical
Carøe TK, Ebbehøj N, Agner T (2014) A survey of expo- irritants. Br J Dermatol 147(2):270–275
sures related to recognized occupational contact dermati- Pedersen L, Jemec GBE (2006) Mechanical properties and
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view. Office for Official Publications of the European noxae. Curr Probl Dermatol 34:98–110
Communities 6:1–244. Available at: https://osha. Wahlberg JE (1985) Occupational hyperkeratoses in carpet
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Elsner P (2007) Skin protection in the prevention of skin Watkins SA, Maibach HI (2009) The hardening phenome-
diseases. Curr Probl Dermatol 34:1–10 non in irritant contact dermatitis: an interpretative
Fischer T, Rystedt I (1983) Cobalt allergy in hard metal update. Contact Dermatitis 60(3):123–130
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Contact Urticaria
22
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3 Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3.1 Clinical Features of CUS and PCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
3.2 Physiopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
4 Immunological CU (ICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
5 Non-immunological CU (NICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
6 Protein Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
7 Jobs Exposing to CU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
8 OCU to Protective Items . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
9 Healthcare Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
10 Industry Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
11 Hairdressers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
12 Laboratory Workers and Veterinarians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
13 Food Industry and Catering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
14 Jobs in Contact with Plants and Woods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
15 Physical Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
C. J. Le Coz (*)
Cabinet de Dermatologie, Strasbourg, France
e-mail: christophe.lecoz@wanadoo.fr

https://doi.org/10.1007/978-3-319-68617-2_22
286 C. J. Le Coz
16 Diagnostic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
17 Management and Prognostic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
Keywords non-immunological mechanism. For example,

Aquagenic urticaria · Cold urticaria · Cyclic the well-known allergy to natural rubber latex is
acid anhydrides · Heat urticaria · due to immediate-type hypersensitivity to natural
Immunological contact urticaria (ICU) · latex proteins, but many other substances and
Protein contact dermatitis · Quaternary many jobs involving contact with animal and veg-
ammonium compounds · Symptomatic etal substances or chemicals can cause CUS. Pro-
dermographism · Vibratory urticaria tein contact dermatitis (PCD) was first described
angioedema in 1976 (Hjorth and Roed-Petersen 1976), and
consists in dermatitis due to immediate-type sen-
sitivity, with frequent acute exacerbation a few
1 Core Messages minutes after contact of a proteinaceous causative
agent. Although less frequent than contact derma-
• In occupational contact urticaria, various caus- titis, occupational contact urticaria (OCU) may
ative agents have been described, in particular account for almost 30% of occupational allergic
chemicals or proteins. skin diseases in Finland (Kanerva et al. 1996).
• The mechanism can be an immunological or
non-immunological.
• Natural rubber latex is due to immediatetype. 3 Contact Urticaria
• Immediate type hypersensitivity reactions to
natural latex proteins are well-described causes 3.1 Clinical Features of CUS
of occupational contact urticaria, resulting in and PCD
protein contact dermatitis.
• Identification of occupational contact urticaria, CUS is a heterogeneous group of skin inflamma-
in particular under the clinical picture of tory reactions, realizing a transient, wheal-and-flare
protein contact dermatitis is a diagnostic response at the site of contact with a substance.
challenge. CU mainly occurs within minutes after skin or
mucosal contact with eliciting agent, and disappears
within minutes or hours (<24 h). It consists in ery-
2 Introduction thema and swelling, sometimes angioedema, associ-
ated to itching and/or pain, on the site of the contact
Occupational urticaria (OU) refers to urticaria with the eliciting agent. Spreading of urticarial
occurring in work environment. Physical urticaria lesions, generalized urticaria, or extracutaneous
such as water-induced and cold-induced urticaria symptoms is possible (Von Krogh and Maibach
can be provoked by occupational activities, but in 1981).
most circumstances, occupational urticarial symp- Symptoms can be classified in different stages
toms are those of contact urticaria (CU). The term (Ale and Maibach 2000) and are reported in Table 1.
“contact urticaria” was first used by Fisher in 1973 In the first stage, symptoms are localized to the
(Wakelin 2001) and then defined by Maibach and contact area: They can be specific of urticaria
Johnson in 1975 as contact urticaria syndrome (wheal, flare, itching), consist in early signs of pro-
(CUS) (Maibach and Johnson 1975). Various tein contact dermatitis, or even be strictly subjective
causative agents can be responsible, chemicals or associated to a discrete erythema (invisible CU).
or proteins, with an immunological or Angioedema, extracutaneous reactions (rhinitis,
22 Contact Urticaria 287
Table 1 Stages of CUS according to severity of substances can induce both types of CU and some
symptoms situations remain obscure (Bourrain 2006; Doutre
Stages Symptoms 2005; Lachapelle and Maibach 2003; Ale and
Stage 1 Localized urticaria, dermatitis, nonspecific Maibach 2000).
symptoms (itching, tingling, burning, etc.)
Stage 2 Generalized urticaria. Cutaneous and
extracutaneous reactions
Stage 3 Rhinoconjunctivitis, oro-laryngeal 4 Immunological CU (ICU)
symptoms, asthma, gastrointestinal symptoms
Stage 4 Anaphylaxis ICU or allergic CU is an immediate-type (Type 1)
hypersensitivity reaction, occurring in patients
conjunctivitis, asthma, gastrointestinal symptoms), who have specific IgE against the agent
and even anaphylaxis (and so-called contact ana- (s) eliciting CU. ICU needs sensitization, and
phylaxis) can occur in severe cases. When the prob- will appear after repeated contacts. ICU is more
lematic agents are foods, the ingestion can lead to frequent in people with previous atopic symp-
“food contact hypersensitivity syndrome,” referring toms. The allergen reacts with the IgE at the
to orally induced food intolerance due to mucosal surface of mast cells and basophiles and provokes
contact with allergens, which can be sometimes life release of histamine, except in rare cases in which
threatening (Konstantinou and Grattan 2008). IgG or IgM responsible for activation of comple-
Numerous proteinaceous and nonproteinaceous ment has been incriminated.
sources have been implicated in CU. In such circumstances, symptoms can be
PCD is considered by many authors as a part severe, with spreading of CU beyond the site of
of CUS (Ale and Maibach 2000; Lachapelle and contact, generalized urticaria, and are at higher
Maibach 2003). Patients generally have chronic risk of extracutaneous symptoms and anaphylac-
hand dermatitis, mainly located of the hands tic shock. The commonest agents are food pro-
and the forearms, sometimes on their face. teins (animal or vegetal), animal proteins, and
They complain immediate symptoms, occu- natural rubber latex (Goossens et al. 2007).
rring with minutes after handling the allergen, Some chemicals can also induce immunological
with flare of itching, burning, or stinging, CU, contained in drugs, cosmetics, and industrial
accompanied by erythema, swelling (urticaria), preparations (Basketter and Lahti 2011; Bourrain
or vesicles. Examination after the acute 2006; Doutre 2005).
crisis shows chronic or cured hand dermatitis, Skin tests such as prick tests are positive, neg-
chronic paronychia, or even fingertip dermatitis ative in controls, and determination of specific IgE
(Lachapelle and Maibach 2003). Atopy is more is possible.
frequent, and irritant contacts and wet working
conditions likely enhance the risk of sensitization
and elicitation. PCD is rarely accompanied by ana- 5 Non-immunological CU (NICU)
phylaxis (Willi et al. 2009). Various foods such
as fruits, vegetables, meats, and seafood or NICU occurs in people without sensitization to
non-food proteins have been reported as responsi- the eliciting agent. Since it needs no sensitization,
ble for PCD (Goossens et al. 2007; Amaro and it can appear during the first contact. The skin
Goossens 2008). penetration of the substance will induce non-
specific release of histamine and other mediators
by mast cells, direct effect on dermal vessels by
3.2 Physiopathology leukotrienes, acetylcholine, prostaglandins,
substance P, and other vasoactive amines.
CU can be divided into two main types, immuno- The severity of symptoms, generally restricted to
logical CU and non-immunological CU, but some contact area, depends on the amount of skin
288 C. J. Le Coz
penetration of the agent: duration of exposure, con- Vegetal and animal proteins inducing occupa-
centration of the agent, skin permeability, etc. In this tional CU/PCD are reported in Tables 3 and 4.
situation, severe symptoms like extracutaneous
signs and anaphylaxis are generally not expected.
Among the numerous substances that can provoke 8 OCU to Protective Items
NICU, like plants, animal products, and chemicals,
cinnamaldehyde, benzoic acid, sorbic acid, nicotinic Among OCU, natural rubber latex (NRL)
acid esters are well-known inducers of NICU remains one of the most frequent agents
(Basketter and Lahti 2011). (Kanerva et al. 1996; Doutre 2005), with a sen-
Provocation tests are theoretically positive in sitization prevalence of 1–3% in general popu-
patients and in controls as well. lation and 5–10% in healthcare workers, Europe
(Bourrain 2006). Since the 1980s, the wide use
of NRL gloves among healthcare workers, in
order to prevent blood-borne infections such as
6 Protein Contact Dermatitis viral hepatitis and HIV, has induced the emer-
gence of immediate reactions to NRL protein.
PCD, although clinically presenting as eczema, is NRL gloves are used in various jobs, and nurses,
mainly defined as a type of dermatitis caused by medical or lab technicians, physician’s assis-
type I hypersensitivity to protein or proteinaceous tants, other clinical professionals, and house-
materials. However, some combinations of type I keepers have the highest prevalence of latex
and type IV have been discussed (Beck 1982; glove allergy symptoms (Epling 2011). Other
Matsuo 2010). jobs such as hairdressers and glove and dolls
manufacturers are at risk (Bourrain 2006). NRL
is usually derived from Hevea brasiliensis
Muell. Arg., family Euphorbiaceae. Among
7 Jobs Exposing to CU numerous proteins contained in NRL,
13 (named Hev b1 to b13) have been recognized
There are extensive lists of proteins and (Doutre 2005, 1987). The risk of sensitization to
chemicals reported as causing immunological NRL proteins is highly enhanced by the use of
CU (Ale and Maibach 2000; Bourrain 2006; powdered medical gloves, atopy, and a history of
Goossens et al. 2007; Amaro and Goossens hand dermatitis (Taylor and Praditsuwan 1996;
2008; Basketter and Lahti 2011), only a part of Ale and Maibach 2000). Airborne transmission
them being reported as occupational. Most of the latex allergens is enhanced by their
publications about CU concern case reports or adsorption onto the cornstarch (derived from
little series and epidemiological studies are Zea mays L.) used as glove powder (Le Coz
scarce. However, some data indicate that CU et al. 2011). Airborne CU can be associated
and PCD are not rare, although frequently with rhinitis, conjunctivitis, or asthma. Cross-
underestimated. CU may account for around reactions between NRL proteins and vegetables
30% of occupational allergic skin diseases in and fruits or plants have been recognized,
Finland (Kanerva et al. 1996), and almost 10% mainly tropical fruits, banana, avocado, and
of the total number of patients with occupational chestnuts. The reduction of use of powdered
skin disease (Williams et al. 2008a). The most NRL gloves is associated with a decrease in
frequently affected occupations are farmers, suspected and proved cases of OCU (Allmers
healthcare workers (nurses and dental assis- et al. 2004).
tants), veterinarians and domestic animals atten- CU to NRL gloves is exceptionally due to
dants, bakers and food handlers, and another allergen that latex proteins. A nurse
hairdressers. Chemicals (nonproteinaceous with persistent hand dermatitis strongly reacted
allergens) inducing OCU are listed in Table 2. to corn, with relevance to cornstarch powder
Table 2 Chemicals reported as causing occupational CU immunological (I) type or non-immunological (NI) type
(Basketter 2001; Ale and Maibach 2000)
Cosmetic ingredients Ammonium persulfate (NI, I)
Basic Blue 99 (I)
Lawsonia inermis (Henna) (I)
Myroxylon pereirae (balsam of Peru) (NI, I?)
Protein hydrolysates (I)
Para-phenylenediamine (I)
Ammonium thioglycolate (Shelley et al. 1998)
Industrial and chemical Benzonitrile (I) (Li et al. 2004)
products Cyclic acid anhydrides (I) (Helaskoski et al. 2009) such as phthalic,
methylhexahydrophthalic, and hexahydrophthalic anhydrides
di(2-ethylhexyl) phthalate and dibutylphthalate (I) (Sugiura et al. 2002a)
Diphenylmethane-4-40 -diisocyanate (I) (Valks et al. 2003)
HATU, HBTU (I) (Yung et al. 2003)
Methyl ethyl ketone (MEK)
Xylene (I) (Palmer and Rycroft 1993; Weiss and Mowad 1998)
Antibiotics Cephalosporins: Cefotiam (I)
Penicillins (I): Penicillin, amoxicillin, mezlocillin, piperacillin
Streptomycin (I)
Beta-lactamase inhibitors: Sulbactam (I)
Macrolides: Azithromycin (I)
Fungicides Albendazole (I) (Macedo et al. 1991)
Chlorothalonil (I)
Antineoplastic drugs Cisplatin (I)
Antiparasitic drugs Pentamidine isethionate (I)
Analgesic antipyretic Methamizole (I)
drugs
Neurop-psychiatric Levopromazine (I)
drugs Donepezil (I) (Galvez Lozano et al. 2009)
Biocides and Chloramine T (I) (Kanerva et al. 1997)
disinfectants Chlorhexidine (I)
Chlorocresol (I, NI)
Ethanol (NI)
Formaldehyde (NI, I)
Phenylmercuric acetate (I)
Sodium benzoate (NI)
Didecyl methyl polyoxyethyl ammonium propionate (I)
Didecyl dimethyl ammonium chloride (I)
Metals and metallic salts Aluminum (Helgesen and Austad 1997), chromium, cobalt (Krecisz et al. 2009), iridium
salts (Bergman et al. 1995), nickel (Estlander et al. 1993; Helgesen and Austad 1997),
platinum salts and rhodium (Ale and Maibach 2000), zinc (Farrell 1987)
present in many medical examination gloves (Liu 2000) and was present in work clothes of the same
and Nixon 2007). patient, which induced CU as well. He did react to
CU to polyethylene gloves was reported in a prick tests with DOP and di(2-n-butyl)phthalate
cook, perhaps due to an antioxidant such as di (Sugiura et al. 2002a).
(2-ethylhexyl) phthalate (DOP) (Sugiura et al. CU from nitrile gloves was described in
2002b). DOP used as a plasticizer was implicated a nurse, with a positive short contact test
in CU from gloves with PVC dots (Sugiura et al. positive to 2,20 -methylene-bis-(4-methyl-6-
290 C. J. Le Coz
Table 3 Animal or vegetal products that have caused occupational CU or PCD. (Adapted from Ale and Maibach 2000,
Basketter and Lahti 2011, and Goossens et al. 2007)
Meat Beef
Chicken
Pork
Horse
Calf
Frog (Goossens et al. 2007)
Roe deer (Geyer et al. 1998)
Seafood Crab
(fishes excepted) Cuttlefish
Large prawns
Lobster
Mussel
Oysters
Scallops
Shrimp
Squid
Fish Cod
Conger eel
Haddock
Herring
Mackerel
Monkfish
Perch
Plaice
Red mullet
Salmon
Sea bream
Sea perch
Sole
Trout
Tuna
Whiting
Worms, insects and Anisakis simplex (Scala et al. 2001)
parasites Cockroaches: Blaberus giganteus (Kanerva et al. 1995a) Periplaneta americana (Zschunke
1978)
Chironomus thummi thummi (midge) larvae
Calliphora vomitoria (maggot)
Locusta migratoria (African migratory grasshopper) (Lopata et al. 2005)
Lumbrinereis impatientis
Scleroderma domesticum (Lembo and Panariello 2008)
Tetranychus urticae (spider mite) (Reunala et al. 1983; Jeebhay et al. 2007)
Tribolium confusum (confused flour beetle) (Alanko et al. 2000)
Thaumetopoea pityocampa, T. processionea (Ducombs 2007)
Euproctis chrysorrhoea (Ducombs 2007)
(continued)
Table 3 (continued)
Other animal products Amniotic fluid
Blood (calf, pork, cow)
Cheese (Cheddar, Emmenthal, Parmesan) (Williams et al. 2007a)
Dander and hair (cow, giraffe, roe deer) (Kanerva and Estlander 1997; Kanerva et al. 1997;
Geyer et al. 1998)
Eggs
Gut (pork)
Hair (human, rat, mice)
Liver (lamb, beef, chicken)
Mesenteric fat (pork)
Milk (cow, dog) (Foti et al. 2007)
Placenta (cow)
Saliva (calf, cow, rat)
Serum (amphibian)
Silk
Skin (chicken, Turkey)
Sperm (dog) (Krakowiak et al. 2004)
Urine
Wools (calf)
Vegetables Artichoke (Quirce et al. 1996)
Asparagus (Tabar et al. 2003)
Beans
Cabbage
Carrot
Castor bean
Celery
Chicory (Willi et al. 2009)
Chive (Alikhan et al. 2009)
Coffee been (green)
Cucumber pickles (Weltfriend et al. 1995)
Endive
Garlic (Alikhan et al. 2009)
Leek (Alikhan et al. 2009)
Lettuce
Mustard
Onion (Alikhan et al. 2009)
Olives (Williams et al. 2007b)
Parsley
Parsnip
Pepper (red bell p., green bell p., Serrano p., Jalapeno, Pasilla P.) (Alikhan et al. 2009)
Potato
Soybean
Tomato
Winged bean
(continued)
292 C. J. Le Coz
Table 3 (continued)
Fruits Apple
Apricot stone
Lemon
Lemon peel
Lime
Strawberry (Weltfriend et al. 1995)
Watermelon
Mushrooms and fungi Shiitake
Salami casing molds
Nuts and seeds Almonds
Hazelnuts
Nuts
Pecan
Sesam (Keskinen et al. 1991)
Grains and derivatives Oak
Corn starch (Fisher 1987)
Protein hydrolysates
Barley
Maize
Rice
Rye
Wheat
Food additives and Beer (Gutgesell and Fuchs 1995)
varia Benzaldehyde (Seite-Bellezza et al. 1994)
Cinnamic aldehyde (Seite-Bellezza et al. 1994)
Coriander (Ebo et al. 2006)
Curry
Paprika (Foti et al. 1997)
Enzymes Alpha-amylase
Cellulase (Tarvainen et al. 1991; Kanerva et al. 1998b)
Glucoamylase
Papain (Quiñones et al. 1999)
Protease (Kanerva and Vanhanen 2001)
Xylanase (Tarvainen et al. 1991)
tert-butylphenol) used as antioxidant (Horn and drugs, disinfectants, etc. The use of gloves does not
Aldridge 2003). Another case of CU induced by always protect from chemicals, and many substances
nitrile gloves was due to morpholinyl have been reported as inducers of CU.
mercaptobenzothiazole (Brehler 1996). Antibiotics include penicillins such as penicillin
(Rudzki and Rebandel 1985), amoxicillin (Cond-
é-Salazar et al. 2001), mezlocillin, piperacillin
9 Healthcare Workers (Kim et al. 2011), cephalosporins such as cefotiam
(Shimizu et al. 1996; Miyake et al. 2000), and beta-
CU from NRL has been largely reported as an occu- lactamase inhibitors such as sulbatam (Kwon et al.
pational problem in health workers with hypersensi- 2006) streptomycin ().
tivity to latex proteins. Healthcare personnel handle a Cisplatin (Schena et al. 1996), donepezil (Galvez
lot of other sensitizers like antibiotics, antineoplastic Lozano et al. 2009), pentamidine (Belsito 1993),
Table 4 Plants and derivatives inducers of OCU/PCD (Ale and Maibach 2000; Goossens et al. 2007; Basketter 2001)
Plants and derivatives Ammi majus (bishop’s weed) (Kiistala et al. 1999)
Camomille (Rudzki et al. 2003)
Cannabis sativa L. (Williams et al. 2008b)
Chrysanthemum (Fischer et al. 1999)
Cinchona (Dooms-Goossens et al. 1986)
Colophony
Dianthus caryophillus L.b (carnation) (Vidal and Polo 1998)
Ficus benjamina (weeping fig) (Kanerva et al. 2001)
Ficus pumila (creeping fig) (Paulsen et al. 1998)
Gerbera-Barberton daisy (Gerbera) (Estlander et al. 1998; Paulsen et al. 1998)
Gypsophila paniculata L (Baby’s breath) (Vidal and Polo 1998)
Ivy (Thormann and Paulsen 2008)
Lilies: Lilium longiflorum L. (Vidal and Polo 1998)
Lime flowers (Rudzki et al. 2003)
Limonium tataricum (German statice) dried flowers (Quirce et al. 1993)
Madagascar jasmine (Stephanotis floribunda) (Paulsen et al. 1998)
Mahogany
Mentha pulegium (pennyroyal) (Pérez-Calderón et al. 2007)
Obeche (Triplochiton scleroxylon) (Kanerva et al. 1998a)
Pollens (Uter et al. 2001)
Poinsettia (Euphorbia pulcherrima) (Paulsen et al. 1998)
Schlumbergera (Christmas cactus) (Paulsen et al. 1997)
Spathiphyllum wallisii (spathe flower) (Kanerva et al. 2001)
Tobacco (Tosti et al. 1987)
Tropical woods (Garcés Sotillos et al. 1995)
Tulips
Verbena
Yucca aloifolia (yucca) (Kanerva et al. 2001)
levopromazine, and methamizole have been reported described as occupational IgE-mediated allergen
as well (Warner et al. 1997; Ale and Maibach 2000). (Nagendran et al. 2009).
Among disinfectants, quaternary ammonium
compounds, a frequent cause of (irritant rather than
allergic) contact dermatitis (Lepoittevin 2009), are a
rare cause of OCU: didecyl dimethyl ammonium 10 Industry Workers
chloride in a catering school (Houtappel et al. 2008)
or didecyl methyl polyoxyethyl ammonium propio- In plastic industry, workers are in contact with
nate in a nurse with a positive prick test at a highly reacting chemicals, that can be strong sen-
1:0.5 104 dilution (Raison-Peyron et al. 2009). sitizers: epoxy resins (Jolanki et al. 1987; Kanerva
Alcohols, and especially ethyl alcohol, can provoke et al. 2002), polyfunctional aziridine hardener
OCU by an immunological or non-immunological (Kanerva et al. 1995b; Sartorelli et al.
mechanism (Ophaswongse and Maibach 1994). 2003), diphenylmethane-4,40 -diisocyanate (MDI)
Chlorhexidine, widely reported to cause (Kanerva 1999; Stingeni et al. 2008), (meth)acry-
IgE-mediated allergic reactions (from urticaria and lates such as 2-ethylhexyl acrylate (Kanerva et al.
angioedema to anaphylaxis) among patients under- 1996). Other chemicals include triphenyl phos-
going surgery/invasive procedures, was recently phite (Torresani et al. 2003).
294 C. J. Le Coz
Cyclic cid anhydrides are low-molecular-weight Formaldehyde was responsible for CU due to
chemicals which cause respiratory irritancy and leather (Helander 1977).
allergy. Phthalic anhydride, methylhexahy-
drophthalic anhydride, methyltetrahydrophthalic
anhydride, and hexahydrophthalic anhydride were 11 Hairdressers
responsible for airborne rhinitis and airborne CU in
workers (Tarvainen et al. 1995; Kanerva 1999; Hairdressers are exposed to numerous products
Yokota et al. 2001; Gutiérrez-Fernández et al. causing irritant and allergic contact dermatitis.
2007; Helaskoski et al. 2009). Specific IgE were Occupational CU, although infrequently
demonstrated to cause them (Helaskoski et al. 2009). reported, may occur due to various substances.
Metals and metallic salts can cause OCU, and Ammonium persulfate and other persulfates are
aluminum (Helgesen and Austad 1997), chro- used as bleaching agents. They can induce irri-
mium, cobalt (Krecisz et al. 2009), iridium salts tant or allergic contact dermatitis, and CU that
(Bergman et al. 1995), nickel (Estlander et al. are most often NICU (Lepoittevin 2009). Gener-
1993; Helgesen and Austad 1997), platinum alized CU, rhinitis, asthma, and anaphylactoid
salts, and rhodium have been occupationally reactions have been reported (Ale 2003;
reported (Ale and Maibach 2000). Among them, Poltronieri et al. 2010) and specific anti-
platinum salts are important allergens in the cata- persulfate IgEs have been documented (Aalto-
lyst industry and the clinical manifestations may Korte and Mäkinen-Kiljunen 2003).
involve both the respiratory system and the skin CU to permanent hair dyes, although rarely
(Cristaudo et al. 2005). Angioedema and urticaria and almost exclusively reported in consumers
as acute and late phase reactions to zinc fume (Le Coz 2007), has been described in a beauti-
exposure were described in a patient who welded cian and was due to PPD (Edwards and Edwards
zinc at his job (Farrell 1987). In some cases, an 1984).
immunological mechanism with specific IgE is Protein hydrolysates, formerly collagen or ker-
demonstrated (Estlander et al. 1993). atin, and recently wheat protein hydrolysates,
In pharmaceutical industry (Sherertz 1994), the were responsible from CU in consumers, hair-
higher risk of OCU due to the increasing number of dressers, and beauticians (Niinimäki et al. 1998;
sensitizing substances is counterbalanced by the Ale and Maibach 2000; Olaiwan et al. 2010).
advances of manufacturing technology and primary Some other rare cases have been reported, like
prevention. OCU has been reported from latex and immediate hypersensitivity to the acid permanent
medicaments, particularly antibiotics such as wave agent glyceryl monothioglycolate (Shelley
piperacillin (Moscato et al. 1995) or azithromycin et al. 1998), to Lawsonia inermis – henna
(Milković-Kraus et al. 2007) or to antineoplastic (Majoie and Bruynzeel 1996) – or to even
agents such as cisplatin (Warner et al. 1997). The human hair and dandruffs (Mikkelsen and
use of volatile or powdered substances can induce Thomsen 1978).
airborne CU, as did sodium benzoate (Nethercott
et al. 1984) or the antihelminthic drug albendazole
(Macedo et al. 1991). In chemistry industry, workers 12 Laboratory Workers
are in contact with highly reactive substances used and Veterinarians
for synthesis. HBTU (o-(benzotriazol-1-yl)-N,N,N0 ,
N0 -tetramethyluronium hexafluorophosphate) and People working with animals (laboratory workers,
HATU widely used for peptide synthesis induced scientists, veterinarians, breeders, etc.) have a high
CU and anaphylaxis (Hannu et al. 2006; Yung et al. risk of allergy to such animals, which was estimated
2003). at 20–30% (Ale and Maibach 2000; Aoyama et al.
Among dyes, para-phenylenediamine was the 1992). Other risks concern medicaments and gloves.
suspected cause of OCU in a doll worker with Veterinarians are frequently in contact with
immediate-type reaction to both PPD and her animal proteins contained in amniotic liquid, pla-
own black cotton thread (Temesvari 1984). centa, saliva, blood, and animal hair. Obstetric
procedures give the higher risk of CU and PCD • Pisces phylum (subphylum Chordata), Osteich-
that is likely enhanced by the repeated hand wash- thyes (bony fish) class: Salmon, plaice, tuna,
ing and occlusion due to gloves (Bulcke and hake, cod, herring, sardine, trout, anchovy,etc.
Devos 2007; Valsecchi et al. 2003).
Among the numerous animals used for biolog- Among vegetal proteins, numerous fruits, veg-
ical research, rat (the most frequently responsible etables, plants and plant products, and food addi-
for skin symptoms), mouse, guinea pig, rabbit, tives can induce OCU/PCD. Wheat proteins cause
hamster, monkey, frog, toads, cats, sheep, and CU and PCD mainly in bakers. Suspected aller-
cockroaches have been reported to cause CU, gens are 27-kD allergen, peroxidase, purple acid
PCD, or extracutaneous symptoms like conjunc- phosphatase (Matsuo 2010), and the additive
tivitis, rhinitis, asthma, or even anaphylaxis alpha-amylase (Morren et al. 1993).
(Rudzki 1975; Agrup and Sjöstedt 1985; Aoyama Some cases are more anecdotal: olives in a
et al. 1992; Hesford et al. 1995; Ale and Maibach pizza worker (Williams et al. 2007b), menthe in
2000; Goossens et al. 2007). a cook (Pérez-Calderón et al. 2007), beer (Garcés
Sotillos et al. 1995).
In rare instances, CU/PCD can be due to con-
taminants such as Tyrophagus putrescentiae a
13 Food Industry and Catering storage mite present in ham (Estévez 2006).
Food allergy (food contact hypersensitivity syn-
Food industry comprises many activities including drome) after ingestion is possible after occupational
farming, food processing, wholesale, and distribu- sensitization but seems to be rare. Oral syndrome,
tion. Workers in food industry and catering are due to, for example, seafood (Yamaguchi et al.
highly exposed to food and food-additives. Such 2007), is a benign situation, but anaphylaxis was
substances are frequently able to induce irritant, reported, for example, in a patient working in a
allergic dermatitis, contact urticaria, and protein spice factory, who developed urticaria, angioedema,
contact dermatitis as well. Moreover, people work- rhinoconjunctivitis, and bronchospasm during han-
ing in wet environmental conditions are more prone dling coriander and fenugreek, and had anaphylaxis
to develop hand eczema. A lot of proteinaceous from coriander in a meal (Ebo et al. 2006), or gener-
substances have been reported as inducers of CU alized urticaria in anaphylaxis in a patient sensitized
and/or PCD. These are listed in Table 3. to Solanaceae and Alliaceae (Alikhan et al. 2009).
Epidemiological data are rare, and if the bakers
seem to be the most frequently affected by OCU/
PCD (Kanerva et al. 1996), cow’s dander is the
first cause of OCU in Finland (Kanerva and
14 Jobs in Contact with Plants
Susitaival 1996; Kanerva et al. 1997).
and Woods
Chefs, cooks, cold buffet managers, butchers, and
A lot of workers are concerned by a job with more
sausage makers are in contact with animal proteins in
or less direct contacts with plants: farmers, horti-
meat, milk, eggs, blood, liver, etc. (Goossens et al.
culturists, florists, gardeners, forestry workers, or
2007).
people in the wood industry.
Occupational seafood allergy manifests as rhi-
Numerous plants have been reported as inducers
nitis, conjunctivitis, asthma, CU, and PCD
of CU and/or PCD. Some induce CU by an irritant
(Jeebhay et al. 2001). In the fish industry, preva-
mechanism, while some others lead to immunolog-
lence of CU/PCD is 3–11%. One can discern three
ical CU. Both reactions are possible, as described
main groups of causative agents:
for tulip (Piirilä et al. 1999).
• Arthropoda phylum, Crustacea class: Crabs, Probably, the best-known urticant plants are the
lobsters, prawns, shrimp. nettles belonging to family Urticaceae, like Urtica
• Mollusca phylum, Gastropoda (abalone), dioica L., U. urens L., and U. pilulifera L. The
Bivalvia (clams, oysters, mussels), and stinging hairs are disposed on the ventral faces of
Cephalopoda (squid or cuttlefish) classes. the leaves, permitting skin penetration of histamine,
296 C. J. Le Coz
acetylcholine, and 5-hydroxytryptamine after only a in environment: fungicides or pesticides, wood’s

very slight touch (Le Coz et al. 2011). Among other parasites, and stinging insects, mainly Lepidop-
nonprotein substances, plant-derived pharmacolog- tera with butterflies and caterpillars.
ical elicitors of urticaria are numerous and include Chlorothalonil, a fungicide used for agricultural
Myroxylon pereirae (balsam of Peru) and the and horticultural purposes, has been implicated
cinnamic acid derivatives contained therein, in OCU and anaphylactic symptoms (Dannaker
thapsigargin from Thapsia garganica L. (family et al. 1993). People in contact with pine pro-
Apiaceae), and capsaicin from different species of cessionary moth (Thaumetopoea pityocampa)
capsicum, such as paprika and cayenne (Capsicum can develop contact urticaria. The larva caterpil-
spp., family Solanaceae). The mechanism by which lar lives usually in pines but also in cedars or
non-immunological urticant agents elicit their effect larches in Southern Europe and North Africa.
(at least for those agents listed above) appears to CU, frequently associated to airborne and then
involve the release of histamine from mast cells. generalized dermatitis and conjunctivitis, occurs
Most plant and plant products inducing immu- due to urticating hairs containing thaumetopein
nological OCU and PCD are listed in Table 4. CU which induces histamine release, but an immu-
and particularly ICU among workers in contact nological mechanism is possible (Ducombs
with plant seem underestimated, since in Danish 2007; Vega et al. 2011). Thaumetopoea pro-
gardeners and greenhouse workers with immedi- cessionea lives in oaks and induces similar man-
ate skin or mucosal reactions to plants, 35 out of ifestation. Euproctis chrysorrhoea (browntail
105 people had at least 1 positive reaction likely moth), present in Europe, North Africa, and
immunologic to Schlumbergera cacti, Stephano- Asia, can induce CU as well (Ducombs 2007).
tis floribunda, Euphorbia pulcherrima and Ger- Spider mite (Tetranychus urticae) can cause CU,
bera, Ficus pumila, Gardenia jasminoides, and mucosal symptoms and asthma (Reunala
Hibiscus rosasinensis, Campanula, Columnea, et al. 1983; Jeebhay et al. 2007). Scleroderma
Epipremnum aureum, Pelargonium, and Primula domestica has been implicated in papular CU
vulgaris (Paulsen et al. 1998). A case of OCU (although persisting for months) in antique
with proved sensitization attributable to a gerbera dealers and restorers (Lembo and Panariello
(probably Gerbera jamesonii Bolus, family 2008). Substances Reported in Occupational
Asteraceae) was published. Conjunctivitis and CU (Ale and Maibach 2000; Basketter and
respiratory symptoms are possible (Estlander Lahti 2011; Bourrain 2006).
et al. 1998). Rhinoconjunctivitis, CU, and derma-
titis may occur after handling Gypsophila
paniculata, Dianthus caryophillus, and Lilium 15 Physical Urticaria
longiflorum and were described in a flower sup-
plier with specific IgE (Vidal and Polo 1998). Whatever their mechanism is not occupational,
Other plants include Alstroemeria (Chan and physical urticaria can occur wholly or partly in
Oppenheimer 2002). Recently, Cannabis sativa the workplace (Engel and Lipsker 2009). On can
has been reported in workers exposed to the distinguish several syndromes: symptomatic
plant at work (Williams et al. 2008b). dermographism, delayed pressure urticaria, vibra-
In general, pollens can induce, in addition to tory, heat, cold, solar and aquagenic urticaria.
rhinitis, conjunctivitis, and asthma, airborne CU in Every physical urticaria can have occupational
workers exposed to them, such as florists (Uter et al. consequences.
2001). Airborne contact urticaria was reported in a Symptomatic dermographism is the
warehouseman as well, resulting from exposure to commonest form of physical urticaria. It com-
dust derived from cinchona bark (Cinchona spp., bines the triad of erythema, edema, and pruritus,
family Rubiaceae) (Dooms-Goossens et al. 1986). occurring in areas of scratching or friction.
In some instances, CU is provoked not by Delayed pressure urticaria is a solid swelling,
plant themselves, but by several factors present usually painful, occurring in a several hours delay
after heavy and prolonged pressure. Areas most 16 Diagnostic

commonly affected are the palms, soles, and but-
tocks. Systemic manifestations and inflammatory Diagnosis of OCU is based on the patient’s previ-
syndrome are possible. ous medical history, chronology, and description
Vibratory urticaria angioedema appears as of skin symptoms, skin prick tests, and blood
itchy erythema followed by edema after a vibra- determination of specific IgE whenever possible
tory stimulus (e.g., jackhammers). in contact urticaria. In physical urticaria, tests will
In heat urticaria, hives appears on areas realize the trauma that induces urticaria
exposed to heat. It optionally includes mucosal (Lachapelle and Maibach 2003).
during ingestion of hot foods. This rare situation Patient’s past history will focus on atopic
can be an occupational skin disease as it was in a symptoms and atypical (invisible CU with subjec-
churros-maker (Miranda-Romero et al. 1998). tive signs only, airborne CU) or extracutaneous
Cholinergic urticaria consists in numerous symptoms.
pruritic papules, often surrounded by an erythem- With exception to substances inducing
atous halo, appearing during or after exercise with NICU, skin tests are generally necessary for
sweating, stress, taking a bath or hot shower, diagnosis. In suspected ICU, particularly when
entering a warm store after being in a cold atmo- standardized allergens are not commercially
sphere, etc. Systemic manifestations are possible. available, and moreover when the patient had
Aquagenic urticaria occurs at the site of con- severe symptoms (stages 2–4), in vivo tests
tact with water, with generally follicular papules. have to be performed with caution, the resusci-
The electrolyte composition and temperature of tation facilities being immediately available. An
water can influence the occurrence of lesions. order of skin investigations for evaluation of
Solar urticaria appears within minutes of sun immediate-type responses has been suggested
exposure. Events may extend to the areas covered (Ale and Maibach 2000; Lachapelle and
and accompanied by general signs. A refractory Maibach 2003). Each application is done for
period is generally observed. It may be confounded 15–30 min, and evaluated after removal and
with photoallergic contact urticaria (Basketter and further 30 and 60 min. In case of a positive
Lahti 2011). reaction, further evaluation should be
Cold urticaria is divided into three main sources: discontinued. Positive (histamine) and negative
familial, acquired idiopathic, and acquired second- (saline) controls are recommended, in a patient
ary. In familial, autosomal dominant, eruption not treated by antihistaminic drug.
occurs as erythematous papules and macules, some-
times cyanotic, associated with burning sensations. 1. Open application on unaffected skin
There are systemic signs such as fever, conjunctivi- 2. Open application on slightly (or previously)
tis, arthralgia, myalgia, and inflammation. The most affected skin
frequent, idiopathic acquired form consists of super- 3. Occlusive application on unaffected skin
ficial or deep lesions after exposure to cold stimuli: 4. Occlusive application on slightly
water, air, and objects such as ice, cold rain, cold (or previously) affected skin
wind, cold water – for example, swimming in sea 5. Intraepidermal administration (prick test,
water or river – ingestion or contact with cold food scratch test, scratch chamber test)
or drinks. There is a risk of deep edema after inges- 6. Intradermal injection
tion of cold foods, or even shock after swimming in
cold water (sometimes only <20 ). In the acquired Actually, the choice of test depends on symp-
secondary form, the manifestations are the same, toms and suspected allergen: dilution according to
sometimes associated with necrotic purpura in guidelines and case reports, higher dilution when
areas exposed to cold. CU is associated to proteins there are serious symptoms, adequate vehicle
that precipitate: cryoglobulin, cryofibrinogen, cold (water, saline, petrolatum (?)). Prick tests and
agglutinins. prick by prick (with raw material such as foods)
298 C. J. Le Coz
will be carefully carried out and interpreted. Rub • Take from worker with CU full occupational
tests and scratch tests. history about job, materials used at work, loca-
Determination of specific IgE by RAST will tion of the rash, and temporal relationship with
confirm type I hypersensitivity, but their ordinary work
detection is restricted to some allergens, particularly • Confirm objectively (prick test) for a diagnos-
when they are nonproteinaceous (e.g., formalde- tic of OCU, because of future employment
hyde) or necessitate specific laboratory. Basophile
activation tests are not routinely performed.
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Biologic Causes of Occupational
Dermatoses 23
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
3 Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
3.1 Parapoxvirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
3.2 Orthopoxvirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
3.3 Butchers’ Warts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
3.4 Herpes Simplex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
3.5 Hepatitis B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
4 Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
4.1 Staphylococcal and Streptococcal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
4.2 The Problem of MRSA and CA-MRSA Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
4.3 Bacterial Athlete’s Foot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
4.4 Erysipeloid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
4.5 Anthrax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
4.6 Brucellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
4.7 Tularemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
4.8 Pseudomonas aeruginosa Folliculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
4.9 Warty Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
4.10 BCG: Skin Complications of Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
4.11 Mycobacterium marinum Mycobacteriosis: Fish Tank Granuloma . . . . . . . . . . . . . 312
5 Mycotic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
5.1 Dermatophytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
5.2 Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
5.3 Candida Paronychia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
5.4 Subcutaneous Mycoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
5.5 Systemic Mycoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
6 Skin Protothecosis: A Unique Dermatosis Provoked by Algae . . . . . . . . . . . . . 318
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Keywords
J.-M. Lachapelle (*) Anthrax · Brucellocis · Butcher’s warts ·
Erysipeloid · Hepatitis B · Herpes simplex ·
e-mail: Jean-marie.Lachapelle@uclouvain.be MRSA and CA-MRSA · Mycobacteriosis ·

https://doi.org/10.1007/978-3-319-68617-2_23
Mycoses · Orf · Protothecosis · Warty 3.1 Parapoxvirus Infections

tuberculosis
Three parapoxviruses of domestic animals occa-
sionally cause infections in humans: orf virus,
1 Core Messages normally causing a disease of sheep, pseudo-
cowpox (syn. milkers’ nodule, paravaccinia),
• Many virus skin infections may be of occupa- and bovine pustular stomatitis viruses, normally
tional origin: the most classical are orf, causing diseases of cattle.
milkers’ node, herpes simplex, butchers’ Parapoxviruses (DNA viruses) are ovoid parti-
warts, and hepatitis B. cles that vary from about 260 nm long by 160 nm
• Bacterial skin infections of occupational origin wide for orf virus to 300 nm long by 190 nm wide
are manifold: staphylococcal, streptococcal, for pseudocowpox virus. A tubular, threadlike
erysipeloid, brucellosis, warty tuberculosis, structure 10–20 nm wide and perhaps 1000 nm
BCG vaccination complications, anthrax, tula- long forms a crisscross pattern on the surface of
remia, and fish tank granuloma negatively stained parapoxvirus virions.
(mycobacteriosis).
• MRSA and CA-MRSA are an emerging prob- 3.1.1 Orf
lem of prime importance. It has been recently demonstrated that orf virus
• A large variety of mycoses are related to occu- infection provides a vigorous skin immune
pational and/or recreational activities. They response. However, the virus has acquired a range
include most kinds of dermatophytoses, candi- of immunomodulatory/pathogenesis-related genes
diasis, and subcutaneous and deep mycoses, that function to limit (at least transiently) the effec-
the latter being predominantly imported skin tiveness of host immunity. With the advent of the
diseases. orf virus genome sequence, the study of this
• Protothecosis is the only occupational skin dis- dynamic process will provide important insights
ease due to an algae, Prototheca, mainly in into virus pathogenesis and the host skin immune
tropical and subtropical countries. response to infection (Haig 2006).
The orf virus may infect sheep (more rarely
goats) throughout the world. It affects mainly
2 Introduction young lambs, who contract the infection from one
another. Ewes that are suckling affected lambs may
Strictly speaking, the biologic agents that cause develop lesions on their udders. Healing occurs in
occupational dermatoses comprise the infections about a month, without scarring. Orf virus remains
and infestations. It is not always easy to define viable for a long period in dried scabs, and this is
when a natural hazard becomes an occupational or important in maintaining enzootic infection in
recreational (e.g., sport activities) hazard. Among sheep under field conditions. Orf (sometimes called
infections, it is classical to consider viral, micro- “contagious ecthyma among sheep and goats”)
bial, and mycotic infections (and exceptionally remains an economically most important disease
due to algae). (Büttner and Rziha 2002).
Human lesions are caused by direct inoculation
of infected material. Various occupations are at
3 Virus Infections risk: shepherds, farmers, and veterinarians are in
the first line. Orf is a frequent occupational disease
Some virus infections are undoubtedly related to among shearers, of considerable industrial impor-
occupational activities. The most important ones tance in Australia and New Zealand. More occa-
have been selected, excluding AIDS, the occur- sionally, butchers and meat porters can be affected
rence of which in occupational life is discussed in from infected carcasses. In Western countries, it is
another chapter. not rare among immigrants from Muslim countries,
23 Biologic Causes of Occupational Dermatoses 305
who work as sheep slaughtermen in unofficial painless, are hemispherical, cherry-red papules
slaughterhouses (Lachapelle et al. 1992). This sit- which appear 5–7 days after exposure and gradu-
uation is partly under control in Belgium. ally enlarge into firm, elastic, purple, smooth
The lesions of orf occurring mainly on the hemispherical nodules (Fig. 2) varying in size up
fingers (Fig. 1) are rather large, painful nodules to 2 cm in diameter and, when fully developed,
(1–2 cm in diameter), which may be multiple with may be umbilicated. They are highly vascular,
a vesiculopustular roof; the surrounding skin is which explains the purple color. The lesions dis-
inflamed. There may be a low fever and swelling appear after 4–6 weeks (Groves et al. 1991). Neg-
of the draining lymph nodes. More rarely, “giant” ative electron microscopy examination of biopsy
lesions (as large as 5 cm in diameter) may occur. fragments is most useful to confirm diagnosis.
Secondary infection is not uncommon (Groves There is no treatment available. Milkers’ node is
et al. 1991). Spontaneous recovery occurs in 3–6 considered nowadays less frequent than orf.
weeks. Second attacks are quite common. Ery-
thema multiforme occasionally develops, typi- 3.1.3 Bovine Papular Stomatitis
cally 10–14 days after the onset of orf (Sterling Human infections with bovine papular stomatitis
2010). Diagnosis is confirmed by examination of virus are less common than with the other two
collected material (from a vesiculopustule or a parapoxviruses, probably because contacts
scab) by negative electron microscopy, which between animal handlers and lesions of bovine
reveals the presence of characteristic virions. papular stomatitis, clinically similar to milkers’
Treatment is limited to prevention and/or cure node, are less common than those of shearers
of secondary infection. and shepherds with orf and milkers with pseudo-
cowpox lesions.
3.1.2 Milkers’ Node
Milkers’ node (pseudocowpox; paravaccinia). In
cattle, two forms of parapox manifestations are 3.2 Orthopoxvirus Infections
commonly observed: the bovine papular stomati-
tis in young calves and the occurrence of lesions at Two orthopoxviruses may be very occasionally
the udder of cows (Büttner and Rziha 2002). involved as human offenders in occupational
Man may be occasionally infected. Lesions life: the vaccinia virus and the cowpox virus.
occur on the hands of milkers or veterinarians Orthopoxviruses are DNA viruses; virions have
who examine the mouths of animals. Human an ovoid structure, 300 250 nm, and are readily
infection is considered accidental, and human-to- identified by negative electron microscopy.
human spread does not appear to have been
recorded. Clinically, the lesions, relatively 3.2.1 Vaccinia
Vaccinia has barely limited interest in occupational
life nowadays. Vaccinia virus can potentially be
used as a carrier of genes for protective antigens
Fig. 1 Orf Fig. 2 Milkers’ node

of other pathogenic microorganisms (recombinant This is not a case of transmission of an animal

vaccinia viruses), and it is used in some specialized papillomavirus to man (it has never been men-
laboratory research. Vaccination has ceased except tioned in the literature) but of interhuman trans-
for investigators at special risk (Sterling 2010). mission, favored by a combination of
Buffalopox is considered to be a strain of vaccinia environmental circumstances. Indeed, several fac-
virus. It is found in buffalo herds in certain areas in tors acting concomitantly seem to be important for
India and may cause bullous or crusted lesions in explaining such an occurrence of the disease
buffalo farmers (Ramanan et al. 1996). among selected groups: (a) work at relatively
The geopolitical situation has changed during low temperature, (b) constant humidity of the
the last 10 years, and this renewed the need for hands, and (c) presence of cuttings and/or
improved vaccinia vaccines. ACAM 2000 is one repeated minor trauma to the skin (De Peuter
of the new generations of smallpox vaccines et al. 1977; Jablonska et al. 1988). According to
(Handley et al. 2009). our current knowledge, two types of human pap-
illomaviruses (HPV) are preferentially involved.
HPV-2 (the cause of common warts) is frequently
3.2.2 Cowpox
found in butchers’ warts, but HPV-7 is present in
Cowpox is traditionally considered to be a disease
up to a third of lesions (Keefe et al. 1994). The
of cattle; yet despite the name, it appears that cattle
clinical features are the following: (a) on the pal-
are only infected by chance, as are the cat and
mar aspect of both fingers and hands, butchers’
human (Sterling 2010). Cowpox appears to occur
warts resemble the myrmecia of HPV-1 infection,
only in Europe; it is uncommon and sporadic.
endophytic lesions surrounded by a small ring of
An occupational source is probable, when pro-
keratosis with central black dots representing
fessional activities involve contact with infected
thrombosed capillaries, and (b) on the dorsal
animals, such as cattle or cats (in the latter case,
and/or lateral aspects of fingers and on the backs
when skin has been broken by a scratch).
of the hands, virus warts are either of the common
Clinical symptoms can be reported as fol-
type or may become very exophytic, showing far
lows: after an incubation period of 5–7 days, a
advanced craggy keratosis (Fig. 3).
papule appears and rapidly becomes vesiculo-
Classical treatments of common warts can be
pustular, hemorrhagic, and later ulcerated. Later
applied to butchers’ warts: it is our experience that
on ulceration is covered by a hard black crust,
injections of a bleomycin solution at a proper
surrounded by a zone of erythema and edema.
concentration using a Dermo-Jet ® do offer better
Lymphangitis and lymphadenitis are usual.
results than liquid nitrogen applications
Healing takes place in 3 or 4 weeks. Treatment
(Lachapelle et al. 1992).
is limited to prevention and/or care of secondary
infection.
An epidemic of monkeypox has been reported
in the United States (Lewis-Jones 2004) in 2003
from the importation of exotic animal species
(occupational cases).
3.3 Butchers’ Warts
Virus warts are very common on the hands and/or

fingers in some occupational groups: meat or
poultry handlers (primarily slaughtermen). Fish
handlers (fishermen and fishmongers) are another
group at risk. Fig. 3 Butchers’ warts
There is no proof that wearing gloves is an occurred in wrestlers and rugby or soccer players.
efficacious individual preventive method. Recur- On the face of the adult male, the appearance of
rence of older lesions and outcome of new lesions herpes may be deceptive; it may take the form of a
are not rare and may represent a real hindrance in folliculitis, but satellite umbilicated vesicles soon
terms of quality of life. suggest the correct diagnosis. Facial contact during
rugby is another recognized means of acquiring
herpes simplex virus infection (Johnson 2004;
3.4 Herpes Simplex Turbeville et al. 2006).
Herpes simplex, caused by Herpes virus hominis, is 3.4.3 Recurrent Herpes Simplex
one of the commonest infections of humans Triggered by Ultraviolet
throughout the world. There are two major antigenic Radiation
types: type 1 (HSV 1) which is classically associated Recurrent facial herpes simplex (and, in particular,
with facial infection and type 2 (HSV 2), which is herpes labialis) can be triggered by sun exposure.
typically genital, although there is considerable UVB (290–320 nm) seem to play a major role, the
overlap in disease manifestations. In some circum- mechanisms involved being related to an inhibitory
stances, an occupational origin can be advocated. effect on Langerhans cells.
Seasonal workers suffering from recurrent her-
3.4.1 Herpes Simplex in Healthcare pes simplex are prone to present reactivation at the
Workers beginning of each sun exposure period (Fig. 4).
It is well-known that trauma facilitates transfer of Skiing, sailing, or swimming instructors are good
the virus to fully keratinized skin. Doctors, nurses, examples of professions at risk.
dentists, and dental assistants can be infected Prevention of recurrences is achieved by the
by contaminated saliva and pharyngeal or use of acyclovir, starting treatment a few days
laryngotracheal secretions. Primary infection before exposure.
occurs on the extremity of one finger (Gill et al. The use of sunscreens is of prime importance
1990). Inoculation of the fingertips results in a during the period of exposure.
“herpetic whitlow” in which pruritic and painful
deep vesicles coalesce to form a honeycombed
appearance or to form a large bulla. The condition 3.5 Hepatitis B
is easily confused with pyogenic infection, but
virological identification from collected material The risk of becoming infected with blood-borne
can be easily achieved nowadays. pathogens (e.g., hepatitis B) during surgery is real.
Recurrent herpes may occur, presenting as coa-
lescent vesicles gradually transforming to pus-
tules on a very painful erythemato-edematous
plaque. Common use of protective gloves has
dramatically decreased the occurrence of this
occupational disease and represents the best pre-
ventive measure.
3.4.2 Herpes Simplex in Sport Practice

Inoculation herpes simplex may be favored by the
practice of some particular sport activities (the
so-called herpes gladiatorum). Multiple crops of
vesicles and pustules on plaques or erythema and
edema on the face, scalp, and upper trunk, simulat- Fig. 4 Recurrent herpes simplex in a ski instructor after
ing impetigo and lasting some 10–12 days, have sun exposure
The degree of risk for perioperative personnel is

related to factors that include participating in large
numbers of surgical procedures each year, the
nature of perioperative work (e.g., use of different
types of sharp instruments), exposure to large
amounts of blood and body fluids, the prevalence
of blood-borne pathogens in the surgical popula-
tion, the variation in different organisms’ ability to
be transmitted, the existence of vaccines and the
level of vaccination, the availability of postexposure
treatment, and the consequences of acquiring the
disease. Controlling risks to perioperative personnel Fig. 5 Staphylococcal folliculitis
can be accomplished by using the Occupational
Safety and Health Administration’s three methods is ecthyma, mainly but not exclusively observed
of control-redesigning surgical equipment and pro- in tropical countries: it consists of a slow
cedures, changing work practices, and enhancing and gradually deepening ulceration surmounted
the personal protection equipment of perioperative by a thick crust. After healing there is a
personnel (Stringer et al. 2001). permanent scar.
Since hepatitis B vaccination becomes gener- Workers in contact with industrial mineral oils,
alized among healthcare personnel in many for example, in the metallurgic industry can
European countries, some skin side effects may develop lesions of folliculitis due to Staphylococ-
be expected (Grézard et al. 1995). Apart from cus spp. (Fig. 5). Bacteria that may contaminate
short-lived local reactions, generalized granuloma used oil are not responsible for the infection. In
annulare has been described (Wolf et al. 1998). fact, occlusion of hair follicles by cutting,
lubrification, and cooling mineral oils may lead
to a secondary infection by Staphylococci present
4 Bacterial Infections on the skin of patients. Industrial Staphylococcal
folliculitis is less frequent nowadays, due to an
Some occupational bacterial infections are distrib- increased use of soluble oils in industry, which
uted worldwide, whereas others are nowadays have replaced mineral oils, in relationship with
limited to certain countries where prevention mea- more advanced technologies.
sures have not been applied. In those conditions, conventional therapy is
applied, i.e., multiple applications of a 10%
povidone-iodine solution, either aqueous or
4.1 Staphylococcal hydro-alcoholic in the daytime and an antibiotic
and Streptococcal Infections cream (sodium fusidate or mupirocin) in the eve-
ning. But secondary prevention of infection is
The most common staphylococcal and/or strep- mandatory, requiring in many cases a change of
tococcal infections are consecutive to cuttings, working habits.
abrasions, burns, and/or puncture wounds.
Beta-hemolytic Streptococcus of group A and
Staphylococcus aureus or both are the usual 4.2 The Problem of MRSA and CA-
bacteria cultured from lesions (Barnham and MRSA Infections
Neilson 1987). Some occupations are at partic-
ular risk: butchers, meat-packers, fish handlers, Methicillin-resistant Staphylococcus aureus
slaughtermen, etc. The commonest clinical pic- (MRSA) infections have been confirmed to
ture is impetigo characterized by erythematous healthcare centers for decades. However, MRSA
patches covered by a yellowish crust. A variant infections are increasingly seen in young healthy
individuals with no exposure to healthcare cen- Prevention is of prime importance to avoid

ters. These community-acquired MRSA recurrences; the wearing of shoes provoking min-
(CA-MRSA) differ from healthcare-associated imal occlusion is highly recommended.
MRSA by the presence of the toxin Panton-
Valentine leukocidin. The number of CA-MRSA
infections increases in most European countries. 4.4 Erysipeloid
Outbreaks with CA-MRSA have occurred in
day-care centers, athletic teams, and prisons (i.e., Erysipeloid is an acute infection due to
groups whose common characteristics appear to Erysipelothrix rhusiopathiae, which colonizes a
be close person-to-person contact). It is therefore wide variety of animals worldwide, including
a major environmental problem and is considered mammals, birds, fowl, fish, and shellfish. It is a
occupational in pig farmers (or more rarely other pathogen for many of them, especially for pigs
farm animals). (high prevalence and economic importance).
The management and control strategies Human infection is contracted by direct contact,
are between the hands of the medical and most commonly from carcasses; it is the reason why
paramedical staff: nurses, kinesiotherapists, occupations mainly affected by the disease are
pharmacists, etc. slaughtermen, butchers, cooks, fishermen (Diaz
In order to reduce the prevalence of such infec- 2014), farmers, veterinarians, and housewives.
tions, a more limited use of topical antibiotics Scratches or pricks are the usual mode of incubation.
such as mupirocin, fusidic acid, and retapamulin More anecdotally, it has been mentioned among
is encouraged. They can be replaced advanta- dolphinarium attendants or, in the United States,
geously by antiseptics. among crab fishermen (crab dermatitis).
The general rules of personal hygiene are of The clinical symptoms are usually obvious: about
course of prime importance. Information of the 3 days after inoculation, a hot violaceous and tender
care personnel is mandatory (Kieffer et al. 2008; erythema develops around the inoculation site and
Mempel et al. 2008; Lorette et al. 2009). extends centrifugally but irregularly, with a sharp and
sometimes gyrate border, which may be vesicular.
Erysipeloid is in fact a true cellulitis. Most lesions are
4.3 Bacterial Athlete’s Foot on the fingers, hands, and forearms. Some lesions
have a violaceous hue. Fever and mild general symp-
The commonest cause of this purely bacterial var- toms such as arthralgia or tenosynovitis (Tolis et al.
iant is a mixture of flora comprising both Gram +ve 2015) are present in only 10% of cases. Without
and –ve bacteria. The clinical presentation can be treatment, healing normally occurs spontaneously
florid, with the entire interdigital web and neigh- in 2 weeks without desquamation or suppuration.
boring skin subject to extensive ulceration with Other rare clinical forms have been described: a
raised, whitish, and macerated margins. It may be generalized cutaneous form and a septicemic form
associated with small fissures in the clefts provid- associated with endocarditis.
ing a portal of entry for erysipelas of the leg. Recommended treatment refers to antibiotics:
Athlete’s foot is a misnomer, as both water sports penicillin IM, ciprofloxacin, or cephalosporins.
and occlusive (maceration-promoting) high-ankled Prevention is, as far as pigs are concerned, under
trainers also contribute to this environmental der- the responsibility of the veterinarian: systematic
matosis. It is encountered in occupational life and slaughtering of infected animals is mandatory.
is considered to be a common problem in sport Reduction of trauma (e.g., in fish processors) can
medicine (Lachapelle et al. 1997). Topical treat- be obtained by constant use of protective gloves.
ment includes potassium permanganate (1/10,000) Two recent reviews (Veraldi et al. 2009; Wang
baths and antibiotic creams (sodium fusidate or et al. 2010) have been dedicated to erysipeloid,
mupirocin). Systemic antibiotics are needed when despite the fact that the disease is nowadays less
secondary erysipelas does occur. frequent throughout the world.
4.5 Anthrax 4.6 Brucellosis
Anthrax is a specific infection with Bacillus Some years ago brucellosis was a common dis-
anthracis, a Gram-positive, encapsulated organism ease in farm animals, due to three Brucella organ-
which can survive as spores for over 20 years in isms: B. suis (pigs), B. abortus (cattle), and
soil. Herbivores are primarily affected. In endemic B. melitensis (sheep and goats). In recent years,
countries (some parts of Africa, Pakistan, India, the incidence of the disease has dramatically
Iran, the Middle East, and parts of Russia), decreased, due to extensive animal prophylaxis
human infections remain a serious problem. In programs, including elimination of infected ani-
Western Europe or the United States, anthrax mals and vaccination of healthy ones; it is well
often follows occupational exposure during care controlled in many European countries but is still
of livestock or the handling of products. Therefore, common in some parts of the world.
most cases occur in the wool, hair (Szablewski Farmers, shepherds, veterinarians, and
et al. 2017), or bristle industries. Unsterilized slaughtermen are at risk in endemic areas.
imported bone meal, or sacks contaminated with Human infection is related to handling of contam-
it, or even straw remains a potential hazard. inated animals or ingesting milk and cheese that is
Cutaneous inoculation is favored by minor contaminated and unpasteurized. Occupational
trauma or preexisting skin lesions. The lesion of injuries are another mode of entry. The skin man-
cutaneous anthrax, called “the malignant pustule,” ifestations are nonspecific and range from a
commonly occurs on exposed skin and is usually maculopapular eruption to petechiae, which
single. One to 5 days after infection, a papule occur in less than 5% of patients. A chronic
develops at the site of inoculation. A bulla on a red ulcer may develop at the site of inoculation or
edematous zone soon follows. The bulla ruptures injury. Systemic symptoms include chills, high
and forms a hemorrhagic crust. General symptoms fever, headache, and extreme weakness.
of great severity appear and may be life-threatening, Treatment of choice is a combination of doxy-
particularly anthrax meningoencephalitis. cycline (100 mg 2/day) and rifampicin (300 mg
Diagnosis is confirmed by bacteriological 3/day) for 6 weeks.
examination. “Contact brucellosis” refers to urticarial and/or
The prevalence of anthrax is decreasing eczematous lesions on the skin sites in contact
steadily in industrialized countries, but the disease with infected animals. It is considered to be a
is still endemic in some parts of the world, most protein contact dermatitis to Brucella antigens
always related with agricultural activities. (Lachapelle et al. 1992).
In recent years, cases of anthrax have been
reported from Peru (Maguina et al. 2005), Turkey
(Karahocagil et al. 2008), and India (Narayan 4.7 Tularemia
et al. 2009).
For cutaneous anthrax, oral ciprofloxacin, doxy- Tularemia is encountered in the United States,
cycline, or amoxicillin may suffice for 7–10 days. Northern Europe, Central Europe (Hubalek and
For systemic disease, the treatment of choice is Rudolf 2017), and Japan. It results from systemic
intravenous penicillin G for 7–10 days. Tetracy- infection with the Gram-negative bacteria,
cline or erythromycin can be given in the presence Francisella tularensis. Wild rodent (in particular,
of allergy to penicillin. Very recently, obilto- hares) and other small animal populations are the
xaximab has been recommended as a new poten- main reservoir of infection. In humans, most cases
tial treatment (Hou and Morrill 2017). are sporadic, related to tick bites (Dermacentor), or
Vaccination gives some protection, but preven- direct contact with infected animals. Shooters are at
tion should be directed primarily at control of the greatest risk, but the disease also affects butchers,
disease in animals and disinfection of animal farmers, landscapers, foresters, laboratory workers,
products (Hay and Adriaans 2010). and veterinarians (Evans et al. 1985).
An epidemiologic survey has been conducted in

France (Vaissaire et al. 2005). The authors have
demonstrated that the prevalence of the disease is
underestimated. They conclude that it is necessary
to be increasingly vigilant, for animal cases and
human contamination. It is advised to strengthen
medical and veterinary supervision especially since
Francisella tularensis may be used for bioterrorism.
The incubation period varies from 1 to 10 days.
The clinical manifestation is usually an ulcerated
nodule at the point of inoculation (Sateia et al.
2017) associated with enlargement and later
Fig. 6 Pseudomonas aeruginosa folliculitis
breakdown of lymph nodes. Systemic symptoms
(e.g., meningitis) and toxemia may be severe
(Hofinger et al. 2009). Minocycline is considered superinfection from extraneous sources: physi-
to be efficacious in most cases (100 mg 2/day cians, pathologists, and postmortem attendants
during 4 weeks). are traditionally at risk. This explains the classical
terms used in the past: “anatomist’s warts” and
“prosector’s warts” (Lundgren et al. 1987). At the
4.8 Pseudomonas aeruginosa present time, it is an extremely rare disease in
Folliculitis Western countries.
The lesion starts as a small, symptomless, indu-
Epidemics of Pseudomonas aeruginosa are now rated warty papule with a slight inflammatory are-
commonly associated with aquatic activities, par- ola. By gradual extension, a verrucose plaque is
ticularly public Jacuzzis (pH >8 and only 2–3 g formed. Its color is purplish, red, or brown. Usual
free chlorine, which is inadequate at this pH) or localizations are the hands and fingers. Treatment
inadequately chlorinated swimming pools. refers to antibiotic schedules used in other forms of
P. aeruginosa is an organism universally present tuberculosis. Wearing of appropriate gloves (resis-
in humid environments. Sports instructors are of tant to cuttings) is highly recommended in terms of
course at risk, but most cases are linked with rec- primary prevention.
reational activities (Lachapelle et al. 1997). The
clinical manifestations consist of a papulopustular
eruption of fulminant onset on the trunk (Fig. 6). 4.10 BCG: Skin Complications
Diagnosis is confirmed by microbiology. of Vaccination
Treatment of first choice is oral ciprofloxacin
(500 mg 2/day). Prevention of epidemics is BCG vaccination is still compulsory for some
related to usual recommendations in terms of occupational groups, according to the current leg-
water maintenance (pH between 7.2 and 7.8; ade- islation applied in each individual country. It is an
quate chlorination). occasional source of complications that can be
summarized as follows: (a) nonspecific reactions
including urticaria and erythema multiforme,
4.9 Warty Tuberculosis (b) nonspecific abscess formation generally
resulting from an injection made too deeply, and
This variety of tuberculosis occurs as a result of (c) BCGitis that is considered as an attenuated
the inoculation of organisms into the skin of a form of tuberculosis (Bellet and Prose 2005).
previously infected patient who usually has a Treatment is adapted to each individual situation;
moderate or high degree of immunity. In occupa- when BCGitis is confirmed, the use of isoniazid for
tional life, the disease occurs by accidental a period of 6 months is classically prescribed.
4.11 Mycobacterium marinum The portal of entry is a minor wound which

Mycobacteriosis: Fish Tank may go unnoticed. The lesion presents either as a
Granuloma light-red single nodule (Fig. 7) which is mildly
keratotic or as coalescent purplish red plaques of
Mycobacterium marinum is the agent of a cosmo- the fingers or dorsum of the hand (fish tank gran-
politan atypical mycobacteriosis, often mentioned uloma). A fairly common clinical variant is the
in the literature under the name of fish tank gran- sporotrichoid form (Fig. 8), in which one or
uloma. Its natural habitat is water, particularly several satellite nodules appear at successive
enclosures of water that are not often replenished. intervals on the forearm along the line of the
It is especially prevalent in heated water in tem- lymph drainage sometimes in association with
perate climates and in the sea and natural pools in locoregional lymphadenopathy. Diagnosis seems
warmer regions. obvious when considering both anamnestic data
It can be isolated from diseased fish. Patho- and clinical symptoms and is confirmed in 70% of
genic only on abraded skin, it has been called a cases by culture obtained from a skin biopsy
“leisure-time pathogen”; in fact, it is mainly (Streit et al. 2008).
observed among people keeping tropical fish. Treatment schedules are still debated: combin-
Apart from fish fanciers, pet shop helpers (tropical ing rifampicin (15 mg/kg/day) and ethambutol
aquariums) can also be infected, and this repre- (25 mg/kg/day) for 6 months is a classical
sents a true occupational disease. approach; minocycline (100 mg 2/day) is some-
times but not always efficacious. Excision of the
nodule has also been proposed as a reasonable
approach.
Simple prevention measures such as the use of
gloves could reduce the incidence of infections
considerably. Minocycline can be added to fish
tank water to eradicate fish infection.
5 Mycotic Infections
Many fungi are able to infect man, provoking

common superficial mycoses or subcutaneous
Fig. 7 Aquarium granuloma due to Mycobacterium and systemic infections. Dermatophytoses,
marinum candidosis, and pityriasis versicolor are the most
Fig. 8 Sporotrichoid form

of Mycobacterium marinum
mycobacteriosis
common cutaneous mycoses; systemic mycoses 5.1.1 Tinea Corporis

such as cryptococcosis are also of prime impor- All known dermatophytes can produce lesions of
tance in some parts of the world. In the following the glabrous skin. These are perfectly circular
sections, we refer only to mycotic infections that erythemato-squamous lesions usually sharply
are provoked or significantly worsened by the demarcated with a raised edge; in some cases, the
work environment. center of the lesions is the same color as the normal
skin, with a few squames, which means that spon-
taneous regression is underway. The degree of
5.1 Dermatophytoses inflammation is highly variable. This feature
depends not only on the species of the fungus and
Dermatophytes are related fungi capable of caus- the immune status of the host but is also roughly
ing skin changes of the type known as ringworm proportional to the extent of follicular invasion. In
or dermatophytosis (Hay and Ashbee 2010). Thus the latter case, ringworm appears as a large, round,
defined, the ringworm species are all molds infiltrated erythemato-squamous plaque dotted
belonging to three asexual genera: Microsporum, with multiple follicular pustules (Fig. 9).
Trichophyton, and Epidermophyton. It is also tra- The occupational origin of many cases of tinea
ditional to group dermatophytes according to their corporis is obvious and is closely related to the
ecological niche: geophilic species originating in species of the dermatophyte. Among others,
the soil, zoophilic species having animal origins, the commonest species are Microsporum canis
and anthropophilic species, which are largely (major hosts, cat, dog), Trichophyton
restricted to the human skin. However, these mentagrophytes (major host, small rodents), Micro-
three groups are not always sharply demarcated. sporum persicolor (major host, voles), Trichophyton
It remains classical to describe clinical forms of verrucosum (major host, cattle), and Trichophyton
dermatophytosis, according to the skin sites that equinum (major host, horses). Microsporum
are invaded; such a division is useful for epidemi- praecox, living in the horse environment, is a path-
ological studies and also for treatment strategies. ogen for the human skin. Extensive forms of
Diagnostic procedures include (a) direct micros- dermatophytosis, occurring mainly on the trunk
copy of the squames that shows dermatophyte and/or buttocks, may be due to Trichophyton
filaments and (b) culture on Sabouraud’s medium rubrum, an anthropophilic species of dermatophyte.
for the identification of the species involved. The Not only workers normally in contact with
epidemiology of dermatophyte infections has domestic and farm animals but also explorers,
been updated recently (Seebacher et al. 2008). surveyors, zoo attendants, and laboratory
Fig. 9 Tinea corporis with

follicular pustules
technicians are at risk. Particular examples 10% of the total population is considered to be
include T. verrucosum among farmers infected; some subjects can be almost asymptom-
(or veterinarians) and their families and atic. Living in an institution, especially where
T. mentagrophytes among laboratory workers. washing facilities are shared, is likely to increase
Pet shop and kennel workers are at risk from the chances of infection (English 1969). Preva-
M. canis. Sportsmen and various categories of lence as high as 80% has been reported in some
workers (e.g., miners) may contract T. rubrum factories or sport institutes. On the other hand,
infection. tinea pedis may be equally well transmitted within
the family bathroom. Reinfection from the
5.1.2 Tinea Cruris environment is usual (with the same or another
Tinea cruris is due mainly to Trichophyton species or with combined species). Maceration of
rubrum, Trichophyton mentagrophytes var. the toe clefts plays an important role. A simulta-
interdigitale, and Epidermophyton floccosum. It neous increase in the bacterial flora may also
is probably more prevalent in tropical zones and play a part. Resident bacteria, such as large-
particularly among migrants from temperate colony coryneforms, may be acting as important
countries (Hay and Ashbee 2010). It is also more copathogens. In adolescents and children, attend-
common in men than in women. The most impor- ing swimming baths is the major source of
tant feature is the fact that tinea cruris is often infection.
combined with tinea pedis: this means that all The commonest form of tinea pedis is located
professional circumstances which favor the onset in the toe webs. The fourth interdigital web is
of tinea pedis can also be of importance for tinea preferentially infected, but the other webs can
cruris. also be infected, on one or both feet. The clinical
Clinically, lesions of tinea cruris are sharply symptoms are characterized by a whitish diffuse
marginated infiltrated erythemato-squamous maceration in the cleft marginated by a collarette
plaques in the groin. Vesiculation is rare, but of continuous desquamation (Fig. 10). In some
dermal nodules forming beading along the edge cases, there is a small painful fissure running
are commonly found in older lesions. Minute along the line of the cleft. The entire area
pustules are often present. is ulcerative and macerated from microbial
superinfection. Itching is usually present. In Tri-
5.1.3 Tinea Pedis chophyton rubrum infections, a squamous
Tinea pedis corresponds to an infection of the feet hyperkeratotic variety, which is particularly
or toes with a dermatophyte. The term athlete’s chronic and resistant to treatment and which
foot, used to imply any form of toe-cleft intertrigo affects the soles, heels, and sides of the
(see Sect. 4.3), is preferably banned from the feet (“moccasin foot”), is often found (Hay
dermatologic literature. and Ashbee 2010). The dorsal surfaces of the
Two anthropophilic species, Trichophyton toes and feet are not often affected, but associ-
rubrum and Trichophyton mentagrophytes var. ated onychomycosis is common. Tinea pedis is
interdigitale, are together responsible for the vast sometimes associated with reactive plantar
majority of cases of foot ringworm in Central and pompholyx: extremely pruritic coalescent
Northern Europe. In contrast, in Southern Europe vesicular eczema is observed. Microscopic
and in Arabic countries, zoophilic dermatophytes examination reveals sometimes the presence
such as Microsporum canis or Trichophyton of dermatophytic filaments in these “id”
verrucosum are the most frequently isolated. reactions.
It is important to say that tinea pedis is the
commonest form of dermatophytosis in most 5.1.4 Tinea Manuum
countries. The wearing of shoes and the resultant Infections of the dorsal aspect of the hands
maceration of toe-cleft predisposes to this condi- resemble ringworm of the glabrous skin. Ring-
tion, usually involving the lateral toe clefts. About worm of the palmar skin (the palm and palmar
Fig. 10 Tinea pedis
aspect of the fingers) presents a particular clini-

cal picture. There is dusty desquamation on an
erythematous background with pearl-white
accentuation of the palmar flexor folds. The
appearance is similar to that of some cases of
hyperkeratotic palmar eczema, but in tinea
manuum, scraping yields a flurry of
disintegrating scabs. In most cases, the organ-
isms concerned are the two anthropophilic spe-
cies involved in tinea pedis. Zoophilic
dermatophytes can also be incriminated. Apart
from animal infections, there is preexisting foot Fig. 11 Dermatophyte onychomycosis
infection with or without toenail involvement. In
this respect, the occupational origin of tinea
manuum can be ascertained in some cases. The Onychomycosis may have different clinical char-
“two feet-one hand syndrome” is not uncommon acteristics: in some cases, leukonychia affecting
(Daniel et al. 1979). An extensive study of this part of the distal nail extremity but also extending
clinical entity has been carried out (Daniel et al. along a nail fold toward the cuticle is the major
1979). From the results, it can be assessed that symptom. Full thickness, including the superficial
patients with a high intensity of hand use in their plate, accounts for the pearly mat appearance of
jobs are significantly more likely to develop the infected area. In other cases, massive destruc-
tinea pedis/onychomycosis and tinea manuum tion of the nail does occur, spicules of which being
at an earlier age. Tinea pedis precedes in most detached all along the free border (Fig. 11). When
cases the development of tinea manuum. irregular pigmentation – whitish at some points
and bright yellow at others – does occur, it sug-
5.1.5 Dermatophyte Onychomycosis gests mixed infection with dermatophytes and
This is a frequent condition which may be isolated opportunistic yeasts, such as Scopulariopsis
or associated with tinea pedis and/or tinea brevicaulis.
manuum. The role of occupational activities is
therefore similar to that evoked in tinea pedis. It 5.1.6 Kerion Celsi
affects one or more toenails; it is less common on Kerion Celsi (or tinea barbae) is a particular form
the hands. The infection begins at the distal of ringworm, affecting the beard and moustache
extremity of the nail bed or nail fold. areas of the face with invasion of coarse hairs. The
affected men are commonly farm workers in cases and terbinafine have been more extensively stud-
caused by the two main species: Trichophyton ied for these indications than fluconazole.
verrucosum and Trichophyton mentagrophytes In tinea corporis and tinea cruris, the scheme of
var. mentagrophytes. treatment is as follows: terbinafine, 250 mg/day
The infection is traditionally acquired from for 2 weeks; itraconazole, 100 mg/day for
contact with cattle, mainly during winter months 2 weeks; and fluconazole, 150 mg once weekly
when keeping cattle in sheds does occur. Veteri- or 50 mg/day for 2–4 weeks.
narians are also at risk. The clinical picture is that Tinea manuum and tinea pedis require a longer
of a highly inflammatory pustular folliculitis. period of treatment: terbinafine, 250 mg/day for
Hairs of the beard or moustache regions are 4 weeks; itraconazole, 100 mg/day for 4 weeks;
surrounded by red, inflammatory papules or pus- and fluconazole, 150 mg once weekly or
tules, usually with exudation or crusting (Fig. 12). 50 mg/day for 4 weeks.
Many hairs within the affected areas are loose and The treatment of dermatophyte
easily removed with the forceps without causing onychomycosis has been studied extensively in
pain. It is noteworthy that, without treatment, the last years. The schedules proposed are as
lesions tend to settle spontaneously but may per- follows: terbinafine 250 mg/day for 3–4 months
sist for some months (Hay and Ashbee 2010). according to the severity of the disease and the
response to the treatment; itraconazole is more
5.1.7 Treatment and Management efficient when a “pulse therapy” is conducted as
of Dermatophytoses follows – 100 mg 4/day during 1 week,
Treatment of dermatophytoses is nowadays followed by 3 weeks of no treatment. Three or
straightforward. The topical agents, including var- four consecutive waves are prescribed following
ious imidazoles (miconazole, econazole, the same schedule (Degreef et al. 1987).
tioconazole, isoconazole, bifonazole, Kerion Celsi also requires a well-defined
sulconazole, etc.) and/or terbinafine is equally schedule of treatment: terbinafine 250 mg/day
efficient and can be used in all forms of for 6 weeks or itraconazole 100 mg/day for the
dermatophytosis, except onychomycosis (due to same period. Fairly long-term follow-up is
a lack of penetration). One daily application is recommended, and late recurrences undoubtedly
considered to be adequate for 2–4 weeks. There occur.
is a current tendency to use simultaneously sys- In addition to treatment, some other manage-
temic antimycotics, even in tinea corporis when ment measures are generally helpful. The identi-
multiple lesions are present. fication of the causative agent is useful,
Each type of dermatomycosis requires an particularly where treatment of infected animals
adapted schedule of administration. Itraconazole is important, in order to prevent other infections.
5.1.8 Prevention of Dermatophytoses

Specific measures of prevention can be applied to
tinea pedis. They include the following:
(a) Frequent washing of changing room floors

and walkways; it will remove infective mate-
rial in skin scales.
(b) Use of imidazole powders to reduce levels of
toe-cleft tinea pedis.
(c) Prompt treatment of infected people com-
bined with simple hygienic measures such as
washing shower room floors with an antisep-
Fig. 12 Kerion Celsi tic solution.
5.2 Candidiasis Proteins of foods could induce a protein contact

dermatitis (Tosti et al. 1992) and secondarily an
Candidiasis refers to various forms of infection infection by Candida albicans. When consider-
caused by the yeast Candida albicans or occa- ing this new concept, the primary role of the
sionally by other species of Candida. A limited yeast is therefore minimized. Professions at risk
number of Candida infections can be directly apart from those already quoted as prone to
related to the work environment. develop Candida intertrigo of the interdigital
folds include all categories of workers handling
5.2.1 Candida Intertrigo food, including cooks and housewives. Clinical
of the Toe Webs symptoms are obvious. Several fingers are usu-
Candidiasis may affect the web spaces of the toes. ally infected, but one or all may be involved. The
Marked maceration with a thick, white horny nail fold is red and swollen; there is loss of the
layer is the usual clinical symptom. Gram- cuticle, and detachment of the nail fold from the
negative bacteria are often copathogens. Work dorsal surface of the nail plate, leading to
circumstances that favor tinea pedis can also pocketing (Fig. 13). Occasionally, thick, white
play a role in the occurrence of candidiasis of the pus may discharge; often force is needed to
toe webs. express it. In more advanced cases, nail dystro-
phy and onycholysis do occur.
5.2.2 Candida Intertrigo
of the Interdigital Folds 5.3.1 Treatment and Management
An erythematous, glazed, “velvety” maceration of Candidiasis
area of one or more folds is the usual clinical Candida intertrigo requires specific therapy.
picture. There is often a collarette of desquama- Topical imidazoles are commonly used for a
tion at the periphery (Fig. 13). Similar lesions can period of 2 weeks, but a longer period of treat-
also develop under the rings. In those cases, it is ment is sometimes needed. When the toe webs
often considered that candidiasis is triggered by a
previous skin irritation, mainly due to detergents
and/or to sugar; this could explain the occurrence
of the disease in bakeries, confectioner’s shops,
chocolate factories or fruit packing trade, etc.
Minor trauma (such as superficial abrasions)
could initiate the infection. We may consider that
the problem has decreased considerably. A steady
decline is related to the introduction of automation
in most factories.
5.3 Candida Paronychia
Candida albicans can be isolated in the majority

of cases of chronic paronychia. The yeast has
traditionally been considered to play an etiolog-
ical role in the condition, but bacteria and irritant
or allergic contact dermatitis also play a role,
although the contribution of each varies from
patient to patient. In recent years, a more recent
approach is to envisage the primary role of a Fig. 13 Candida intertrigo of an interdigital fold with
repeated contact with various kinds of foods. paronychia
are involved, attention should be given to 5.5 Systemic Mycoses

treating concomitant bacteria; potassium per-
manganate soaks (1/10,000) were used in many The systemic mycoses are fungal infections that
European countries, but they tend to be replaced involve deep structures and disseminate, usually
nowadays by povidone-iodine or chlorhexidine. via the bloodstream, from the original site of
In general, systemic treatment is not considered infection to different organs, including the skin
for this indication. (for details see Hay 2006). We have summarized
Candida paronychia is often difficult to treat. in Table 2 some of the features of the most impor-
Topical treatment is insufficient; the best thera- tant systemic mycoses, including occupational
peutic approach is intermittent (pulsed) sources of infection.
itraconazole or fluconazole, following the sched-
ules indicated in the treatment of dermatophyte
onychomycosis. Prevention of candidiasis is 6 Skin Protothecosis: A Unique
straightforward. It implies the avoidance of mac- Dermatosis Provoked by Algae
eration at work. Chronic paronychia is best pre-
vented by the use of appropriate gloves. The Protothecosis is unique in the world of dermatol-
avoidance of contact with foods incriminated in ogy. It is provoked by Prototheca, a saprophyte
the initiating protein contact dermatitis (assessed algae that can be cultivated on Sabouraud’s
by positive prick tests) is mandatory. medium. Skin protothecosis is a rare disease,
ubiquitous, but mainly encountered in tropical
countries, particularly in Southeast Asia (Viet-
5.4 Subcutaneous Mycoses nam, Cambodge, etc.). It is observed mainly, but
not exclusively, in immunocompromised patients.
Subcutaneous mycoses, or mycoses of “implanta- Skin lesions are provoked by an inoculation due to
tion,” are sporadically occurring infections caused microtraumas (work in the rice plantations,
by fungi present in the natural environment, mudbanks, drainage systems, and waste products
which are directly inoculated into the dermis or of nutrition). In these countries, it can be consid-
subcutaneous tissue through a penetrating injury. ered an occupational disease. For our European
They are not common even in endemic countries countries, it is a good example of “imported skin
and are mainly seen in the tropics (for details see disease” (Arrese et al. 2003; Laurent 2008).
Hay 2006). We have summarized in Table 1 some Three types of clinical manifestations are
of the features of the most important subcutaneous described: papules and squamo-crusted plaques
mycoses, including occupational sources of (mimicking pyodermatitis), olecranon bursitis
infection. (25% of cases), and systemic protothecosis.
Table 1 Main subcutaneous mycoses implying occupational sources of infection (After Hay 2006)
Mycosis Fungus Endemic areas Occupational sources of infection
Sporotrichosis Sporothrix Cosmopolitan; more frequent Inoculation by trauma (thorns,
schenckii in the Americas and splinters, etc.); common among
South Africa than in Europe South African miners; sporadic among
foresting workers, florists, or
gardeners
Mycetoma Various species Tropical and subtropical Inoculation by trauma (thorns,
of fungi or countries splinters, etc.)
actinomycetes Agricultural workers
Chromoblastomycosis Various species Various countries throughout Inoculation by trauma
of fungi the world; rare in Europe Agricultural workers
(imported cases mostly)
Table 2 Main systemic mycoses implying occupational sources of infection (After Hay 2006)
Occupational sources of
Mycosis Fungus Endemic areas infection
Histoplasmosis Histoplasma Cosmopolitan but very rare in Soil contaminated with chicken
capsulatum Europe feathers or dippings
(occasionally bats)
Airborne conidia
Cleaners, laboratory workers,
speleologists
Blastomycosis Blastomyces North and Central America, the Wood debris and soil close to
dermatitidis Middle East, India, Poland, rivers
Zimbabwe Agricultural workers
Coccidioidomycosis Coccidioides Southwestern states of the Inhalation of airborne spores
immitis United States, Central and South Travellers in endemic areas
America Agricultural workers
Paracoccidioidomycosis Paracoccidioides Latin American countries Inhalation of airborne spores
brasiliensis Agricultural workers
The histopathological features are characteris- Diaz JH (2014) Skin and soft tissue infections following
tic: spherulated PAS + organites (4–15 μm in marine injuries and exposures in travelers. J Travel
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Occupation-Induced Skin Cancer
24
M. L. Lam, A. N. Patel, and John S. C. English
Contents
1 Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
2 Polycyclic Aromatic Hydrocarbons (PAHs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
3 Tar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
4 Welding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
5 UV and Ionizing Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
6 Pilots and Aircrew . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
7 Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
8 The p53 Tumor Suppressor Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Abstract • Common carcinogens include polycyclic

• Occupational skin cancer occurs years after aromatic hydrocarbons, ionizing radiation,
exposure and may be underreported. and arsenic.
• Due to improvements in the safety of indus- • Skin malignancy induction is usually due to
trial processes, there has been a decline in mutation of the p53 gene by the carcinogen.
occupational skin cancers. • There is an increased frequency of mela-
noma among aviation crews.
Keywords
Arsenic · Carcinogen · Coal tar · Ionizing
M. L. Lam (*) · A. N. Patel radiation · Occupation · Outdoorworker ·
Department of Dermatology, Nottingham NHS Treatment Polycyclic hydrocarbons · Skin cancer ·
Centre, Nottingham, UK
Ultraviolet radiation
e-mail: minhlam9@yahoo.com; Anand.Patel2@nuh.nhs.uk
J. S. C. English Nonmelanoma skin cancers, namely, basal cell
Department of Dermatology, Nottingham Circle Treatment
Centre, Nottingham University Hospital, Nottingham, UK carcinoma (BCC) and squamous cell carcinoma
e-mail: john.english@nhs.net (SCC), are the most common forms of skin

https://doi.org/10.1007/978-3-319-68617-2_24
322 M. L. Lam et al.
cancers that occur worldwide. They are also an Determining the true incidence of skin cancer
important category of skin disease caused due to is difficult because health registries exclude non-
occupation. The link between skin cancer and occu- melanoma skin cancer (including SCC) from their
pation was first made in 1775 when a London databases, due to the high number of cases and
surgeon, Sir Percival Pott, made an affiliation limited resources to collect data and also because
between skin cancer and chimney sweeps. The the rate of squamous cell carcinoma varies based
industrial revolution increased exposure to tar and on geographic locations. Determining skin cancer
pitch and thus an increase in cutaneous malignan- rates related to occupation is even more challeng-
cies. Now in the twenty-first century, the culprits of ing because the most common risk factor of UVR
occupation-induced skin cancer include: ultraviolet may overlap with recreational exposure, and spe-
radiation (UVR), chemicals such as arsenic and cific occupational risk factors may be omitted or
shale oil, ionizing radiation, and X-rays used in unrecorded in medical records. Carøe et al. (2013)
medicine and dentistry (Adams et al. 1999). Rogers investigated the prevalence of and exposures lead-
et al. (2015) estimated that there were 5.4 million ing to occupationally induced skin cancers in
nonmelanoma skin cancers in the USA in 2012; this Denmark during a ten-year period. Data were
outweighed the total number of cancers reported in obtained from The National Board of Industrial
all other organs of the body. Injuries and comprised of information about diag-
The diagnosis and treatment of nonmelanoma nosis, occupational and domestic exposure, ana-
skin cancers in the USA increased by 77% between tomic localization, occupation, degree of
1994 and 2014 (Mohan and Chang 2014). The permanent disability, age, and sex. A total of
annual cost of treating skin cancers in the USA is 36 patients were recognized as occupational skin
estimated at $8.1 billion: about $4.8 billion for cancer cases, though underreporting was
nonmelanoma skin cancers and $3.3 billion for suspected. The most frequent diagnosis was
melanoma (Guy et al. 2014). An estimated 4.3 basal cell carcinoma followed by squamous cell
million cases of BCC are diagnosed in the USA carcinoma. No cases of malignant melanoma were
each year, resulting in more than 3,000 deaths. The recognized.
current annual incidence of SCC in the USA is Malignant melanoma makes up 5–10% of all
more than one million new cases per year (www. reported skin cancer and 95% of deaths from skin
skincancer.org), with an age-adjusted procedure cancer. Approximately 14,500 people in the UK
rate per 100,000 beneficiaries of 3278 (Rogers are diagnosed with melanoma each year (www.
et al. 2015). Organ transplant patients are approx- macmillan.org.uk). The number of cases has dou-
imately 100 times more likely than the general bled in the last 20 years or so (www.patient.co.
public to develop squamous cell carcinoma uk). It is rather unlikely that chemical carcinogens
(Lindelöf et al. 2000). In the UK, 131,772 non- are a major contributor in the development of
melanoma skin cancers were registered in 2014, malignant melanoma. However, an association
20% of which were SCCs (Cancer Research UK). with pesticides is reported (Mackie et al. 2009).
Prevalence rates of SCC vary in different coun- A strong association is held with UV exposure. A
tries. The highest incidence occurs in Australia, progressive change from predominantly occupa-
where the age-adjusted incidence has been calcu- tional to predominantly recreational patterns of
lated to be 1,332 cases per 100,000 population for sun exposure is the most likely cause of increasing
men and 755 cases per 100,000 population for real incidence of melanoma in populations over
women. Again, this is likely due to large numbers the last few decades (Armstrong and Kricker
of fair-skinned people in this region who have had 1994). In the past, few studies have demonstrated
extensive sun exposure (Buettner and Raasch a correlation between nonsolar UVR and a signif-
1998). It has been difficult to determine the exact icantly increased risk of melanoma. Examples of
role of chemical carcinogens on those patients this are workers exposed to printing lights,
with SCC due to the fact that these patients also welding torchlights (Elwood et al. 1986), and
have experienced UV light exposure daily. fluorescent lights (Walter et al. 1992). However,
24 Occupation-Induced Skin Cancer 323
more recently, there are more studies looking at the advancing age of the population, earlier and
nonsolar radiation and its association with mela- more frequent diagnosis of skin malignancies due
noma. A study from Spain in 2004 showed risk to enhanced public awareness of skin cancer, and
ratios of melanoma and its site with occupation. more frequent skin examinations by physicians
Apart from UV exposure and artificial sources, and public health drive. In addition, the number
risk excesses were seen in fur tailors/tanners/ of patients on immunosuppressive therapy, used
dressers, patternmakers/cutters, electric fitters/ in solid organ transplantation and various rheu-
wiremen, telephone/telegraph installers/repair- matologic, gastrointestinal, and dermatologic
men, and some glass/pottery/tile workers. Specific conditions, is increasing. Mainly SCC formation
risk excesses were seen with rolling mill workers has been associated with immunosuppressive
in head and neck melanoma, for chimney drug therapy in solid organ transplantation
sweepers in the upper limbs, and for aircraft patients, who have a markedly elevated risk.
pilots/navigators/flight engineers in the lower Metastasis also may be more common in this
limbs. It was also found that artificial UV sources group (Hampton 2005). It is thought that skin
did not confine melanoma to exposed sites and cancers are the result of carcinogens inducing
that the trunk was most affected in these cases mutations to genes, including the p53 gene. The
(Perez-Gomez et al. 2004). p53 gene is a tumor suppressor gene and it is
A study carried out in 2009 examined the rela- found to be mutated in more than 50% of all
tionship between occupational physical activity tumors (Hollstein et al. 1996).
and the risk of melanoma with adjustment for In this chapter, occupational skin cancer will be
occupational and recreational sun exposure. The defined as skin cancers induced by chemical car-
data showed an elevated risk of cutaneous malig- cinogens and radiation in the workplace. There
nant melanoma among those with higher levels of have been numerous studies that have probed the
physical activity (Lee et al. 2009). relationship between sunlight-induced skin malig-
Rushton and Hutchings (2017) estimated the nancy and outdoor occupation, with much debate
burden of cutaneous melanoma in Britain due to concerning the relationship between cumulative
occupational solar radiation exposure. Attributable work-related UV exposure and skin cancers. Lear
fractions and numbers were estimated for mela- et al. showed a strong correlation between outdoor
noma mortality and incidence using risk estimates work and skin cancer in the UK (Lear et al. 1998),
from the published literature and national data whereas other studies by Green et al. (1996) and
sources for proportions exposed. The study esti- Freedman et al. (1997) showed the opposite.
mated 241 cases of melanoma with 48 deaths from Recent meta-analyses (Bauer et al. 2011; Schmitt
occupational solar radiation exposure in 2011. et al. 2011) have demonstrated a significantly
In the UK, over a period of 6 years, 1,608 cases positive association between occupational UVR
of skin cancer thought to be occupation related exposure and BCC and SCC risks, respectively.
were reported to a surveillance scheme (Cherry Recent population-based case-control studies
et al. 2000). In the current era, the relationship have highlighted the importance of occupational
between skin cancer and occupation is usually UVR exposure in the increased development of
linked with sun exposure from leisure activity, as both BCC and SCC (Schmitt et al. 2018a, b).
more people have more leisure time available Skin tumors can result from exposure to sub-
to them. stances such as polycyclic hydrocarbons, inor-
Alongside this is the fashion for having a sun- ganic metals, and arsenicals (Nixon 1998; Alam
tan or working outdoors. The rising incidence of and Ratner 2001). These lesions can also develop
cutaneous carcinoma may be due to an increase in because of trauma, burns, and exposure to ultra-
sun exposure of the general population. Some violet light or ionizing radiation, particularly in
postulate that ozone depletion may be intensifying developing countries (Nixon 1998; Alam and
UV exposure (Gray et al. 1997). Other factors that Ratner 2001). Co-carcinogenesis, such as the
may contribute to the increased incidence include interaction of sunlight and tar, is often implicated.
Frequently, skin tumors do not appear until two or Slovakia. Exposures were evaluated by local
three decades after the exposure (Jerant et al. experts using occupational histories. The lifetime
2000). prevalence of exposure to work-related arsenic is
The results of a case-control study, looking at 23.9% for cases and 15.5% for controls. No sig-
occupation and skin cancer published in 2007, nificant association between arsenic exposure in
showed that the frequency of BCC proved higher the workplace and NMSC was detected, although
among railway engine drivers, firemen, salesmen, an increased adjusted odd ratio was observed for
and specialized farmers in addition to miners, participants with higher cumulative lifetime
quarrymen, and secondary education teachers. A workplace exposure to arsenic in dust and fumes
study from Greece (Apalla et al. 2016) suggested compared to referents.
that farmers were more likely to develop histolog- Industries which may use arsenic include glass
ically aggressive subtypes of BCC compared to production and manufacture of semiconductors; it
non-farmers. The occupations that showed a may be found in some pesticides and herbicides
higher risk of SCC were those involving contact (with potential risk for farmers) (Blair and Free-
with livestock, construction workers, stationary man 2009), and may occur as a by-product in the
engine and related equipment operators, and smelting of copper, lead, and zinc (Gawkrodger
masons (Saurez et al. 2007). 2004). The workforce may also come into
Establishment of an occupational etiology for contact with arsenic when mining and smelting
skin tumors is complicated because of the mobile it. Arsenical keratoses are clinical signs of expo-
work force, numerous job changes by individual sure, and they may progress to basal cell cancers
workers, and exposures that occur both at work or squamous cell cancers (Gou et al. 2001).
and away from the job. All patients should be Arsenic is a puzzling carcinogen as it does not
provided with information on how to prevent cause cancer in laboratory animals. A series of
skin cancer (John et al. 2016). studies has associated arsenic with the induction
of gene amplification; p62 expression to regulate
the Nrf2 pathway; the inhibition of DNA repair;
1 Arsenic the cessation of cells in mitosis; and the expres-
sion of heme oxygenase, the oxidative stress
Chronic exposure to inorganic arsenic increases the protein, and the c-fos gene (Lee et al. 1988;
risk of developing arsenical keratoses, Bowen’s Keyse et al. 1990; Vega et al. 1995; Shah et al.
disease (SCC in situ), BCC, and SCC (Yu et al. 2017). A report in 1998 by Hei et al.
2006). Arsenic enhances ultraviolet carcinogenesis (1998) found that arsenic is in fact a strong
(Burns et al. 2004). It is a co-carcinogen with UVR mutagen that causes large chromosomal
and is able to induce large chromosomal mutations mutations.
by this means (Hei et al. 1998). Chronic liver
disease and malnutrition (Hsueh et al. 1995) may
increase the risk of skin cancer in arsenic-exposed 2 Polycyclic Aromatic
individuals. Contaminated drinking water is the Hydrocarbons (PAHs)
most common source of arsenic exposure
(Knobeloch et al. 2006) and this exposure is usu- PAHs are made up of two or more benzene rings
ally via gastrointestinal absorption rather than a and comprise a large group of chemical carcino-
transdermal means. gens found in the work environment. They are
A study by Surdu et al. (2013) assessed air- formed by a pyrolytic process such as the com-
borne arsenic exposures at the workplace and bustion of organic compounds. Exposure is
quantified associations with nonmelanoma skin mainly by inhalation or skin contact (Bofetta
cancer (NMSC). The study sample consisted of et al. 1997). PAHs are the main carcinogens
618 incident cases of NMSC and 527 hospital- found in coal tar products, including tar, pitch,
based controls from Hungary, Romania, and soot, and raw paraffin.
Exposure to polycyclic aromatic hydrocarbons The main carcinogen in tar is PAH. However, it
may result from the gas production from coal, coke is also thought that tar-induced skin cancer is also
plants, aluminum production, and steel and iron affected by UV exposure (Millard 1986).
foundries and from the exposure to diesel engine Tar-induced skin cancers are most commonly
exhaust fumes, for example, in mechanics or street found on sun-exposed sites, with the exception of
vendors. As well as this, PAH in shale oil, creosote, a high incidence of cancers on the scrotum
asphalt, coal tar products, and chimney soot have Korting (1981).
been associated with an increased risk of tar kera- A case-controlled study in 2005 showed a
tosis, BCC, SCC, and keratoacanthomas (Letzel slight increased risk of SCC with the use of coal
and Drexler 1998). tar and dandruff shampoos (Mitropoulos and Nor-
UVR may work in tandem with PAH to man 2005). However, a large cohort study of over
increase the risk of skin cancer (Millard 1986). 13,000 eczema and psoriasis patients failed to
Its effect on the p53 tumor suppressor gene for demonstrate any increased risk of cancer after
the causation of skin cancer remains unknown. coal tar treatments (Roelofzen et al. 2010).
PAHs are complicated in the fact that they may
be found in mixtures with other carcinogens. To
add to this, much of the data previously used 4 Welding
were mortality data. These data underestimate
the potency of PAHs as a carcinogen due to Even in the twenty-first century, welding is still a
low mortality rates for BCC and SCC (Bofetta common occupation (Meo and Al-Khlaiwi 2003).
et al. 1997). The hazardous agents associated with the welding
processes are acetylene, carbon monoxide, oxides
of nitrogen, ozone, phosgene, tungsten, arsenic,
3 Tar beryllium, cadmium, chromium, cobalt, copper,
iron, lead, manganese, nickel, silver, tin, and zinc.
In 1990, the German social accident insurance Inhalation of these chemicals may lead to respira-
reported 13 accepted cases of skin cancer due to tory disease as well as nonmelanocytic skin cancer
tar, soot, raw paraffin, hard coal, pitch, and similar and melanoma (Meo and Al-Khlaiwi 2003).
materials. These numbers are most likely Arc welding can also produce a full spectrum
underreported, as the recent development in Ger- of UVR which in turn can increase risk of skin
many reveals. In 2015, the number of legally malignancy, especially in workplaces with sub-
accepted cases had considerably risen to 88, the optimal health and safety standards (Dixon and
number of suspicious cases in that year was Dixon 2004).
256 (German social accident insurance [DGUV],
Referat Statistik 2018). The reason for this increase
is that in January 2015, a new occupational disease 5 UV and Ionizing Radiation
had been introduced (occupational skin cancer by
UV exposure at the workplace), which moved the Ultraviolet radiation is usually encountered in the
common focus in history taking more specifically form of sunrays; however, occupational exposure
toward occupational carcinogens. In Germany, could occur from ultraviolet tubes. UV exposure
there are now almost 9,000 notifications annually was believed to be the main causative agent in
of certain forms of occupational skin cancer by UV skin cancer. A study carried out by Cherry et al. in
exposure at the workplace (only multiple actinic 2000 showed that UVexposure was believed to be
keratosis or squamous cell carcinoma is the cause of 96% of skin cancers from a popula-
acknowledgeable); this is already the third most tion of 1,608 over 6 years (Cherry et al. 2000).
frequently reported occupational disease (German Epidemiological studies over recent years have
social accident insurance [DGUV], Referat found circumstantial evidence on the causative role
Statistik 2018). of the sun in the induction of skin cancer (Turner
et al. 2007). Studies confirming the relationship as had proportionately elevated relative risks of mel-
well as determining the dose responses, energy anoma, suggesting that ionizing radiation is
requirements, relationship to chemical stimuli, indeed a risk factor for melanoma (Fink and
immune responsiveness, oncogene expression, Bates 2005).
and tumor suppressor gene inactivity have been UV radiation is known to induce mutations into
solely down to experiments using animal models, the p53 tumor suppressor gene (Ziegler et al.
due to impropriety of such experimentation on 1993) and this is one of the mechanisms by
humans and practicality. Such tumor induction which it may be carcinogenic.
would need roughly 20 years of recurrent, closely
monitored exposures. A study published in 2009
looked at a population in Bavaria from 2001 to 6 Pilots and Aircrew
2005 and data provided by the cancer registry of
this district confirmed previous reports of and Skin cancers among commercial airline pilots
increased risk of BCC and SCC in outdoor workers have been reported to occur at increased rates in
compared to indoor workers (Radespiel-Troger pilot populations worldwide. The reasoning
et al. 2009). Natural and artificial ultraviolet radia- behind this is unclear, but postulated factors
tion exposure has been shown to be a risk factor for include ionizing radiation, leisure sun exposure,
the development of invasive cutaneous melanoma and circadian disruption (Nicholas et al. 2009). A
(Mackie et al. 2009). study undertaken in the USA in 2009 showed that
Ionizing radiation is well-recognized to poten- pilots who had been working for less than 20 years
tially cause skin cancer, especially squamous cell had similar risk factors to developing skin cancer
cancer of the skin and premalignant changes. The as the normal population, i.e., skin type, family
time period elapsing between exposure and occur- history, and childhood skin burns. Among pilots
rence of skin malignancy maybe several decades. who had greater than 20 years flight time, the
This phenomenon was discovered from previous same risk factors were present with the addition
physicians and physicists who used X-rays and of flight time at high latitude (Nicholas et al.
radiation (Pie’rard et al. 2009). Thus, this is now 2009), which increased the risk of skin cancer.
well-controlled and supervised. Occupations Another study in 2006 performed a Medline data-
including radiography are not thought to yield an base search looking at cosmic radiation in aviation
excess of skin malignancy due to appropriate and found that seven out of eight studies showed
safety measures being adopted. However, a report an increased risk for aviators to develop malignant
in 2003 showed a higher risk of malignant mela- melanoma, BCC, and other kinds of skin cancer
noma in radiological technicians who had first (Ott and Huber 2006). However, there is some
worked before 1950 and in those who did not controversy with this and other studies due to the
use the standard lead protection regularly when lack of scientific evidence to support the hypoth-
they first started (Freedman et al. 1997). A review eses solely as well as due to other factors like
in 2005 looked at seven categories of exposure to lifestyle not being incorporated. One study from
ionizing radiation and its link with melanoma. Iceland in 2003 concluded that there was no sub-
These categories included: (1) The Canadian radi- stantial correlation between commercial pilots
ation dose registry, (2) nuclear industry workers, and the general population with respect to preva-
(3) subjects near nuclear test blasts, (4) survivors lence of risk factors for malignant melanoma.
of atomic bombings of Japan, (5) airline pilots and Thus, they concluded that it is unlikely that the
cabin attendants, (6) recipients of medical radia- increased incidence of malignant melanoma
tion, and (7) radiological technicians. Relative found in previous studies of aircrew can be solely
risk for leukemia in each of these studies was explained by excessive sun exposure at high alti-
used to confirm the likelihood of exposure to tude (Rafnsson et al. 2003). Buja et al. (2005)
ionizing radiation. Generally, it was found that believed that as well as the cosmic ionizing radi-
groups with elevated relative risks of leukemia ation that was inflicted upon pilots and air-crew,
other factors such as chemicals (jet fuel, engine A summary of occupations at risk of skin can-
exhausts, cabin air pollutants), electromagnetic cers based on causative agents is summarized in
fields from cockpit instruments and disrupted Table 1 below.
sleep patterns may play a role in the development
of skin cancer in this profession. A meta-analysis
by Sanlorenzo et al. (2015) included 19 studies 8 The p53 Tumor
with over 266,431 participants and found that Suppressor Gene
pilots and cabin crew have approximately twice
the incidence of melanoma compared with the The p53 gene controls cell growth and metastasis
general population. A large cohort study from from malignant cells. It has also been associated
10 countries by Hammer et al. (2014) showed with several cellular functions including DNA
that despite an increased mortality from mela- repair, programmed cell death, cell cycle control,
noma, especially in male cockpit crew, overall differentiation, and genomic plasticity (Trappey
mortality among commercial airline crews was et al. 2010).
reduced compared to the general population. Molecular epidemiology will allow scientists to
investigate cancer risk factors at a more specific
level. This has already been achieved in this for
7 Trauma cigarette smoke in lung cancer and UV radiation in
skin cancer. Carcinogens like tar and UV light can
Skin cancer may occasionally follow an injury damage DNA and cause specific genetic mutations
caused in industry such as burns from hot metal in the type and location in cancer-related genes.
or from welding. Such trauma, may lead to skin Reports have identified the p53 genetic marker for
cancers developing within the scar (Dix 1960) UV-induced skin cancer (Moles et al. 1993). DNA
and usually take several years to develop with mutations encountered from UV exposure occur
Kowal-Vern and Criswell (2005) reporting a when UV radiation is absorbed by the DNA and
mean latency of 31 years after reviewing when pyrimidine photoproducts. The misrepair of
412 cases of burn scar neoplasms reported the the photoproducts causes transition mutations
literature. They found SCCs to be most com- (Mitchell et al. 1992). CC to TT transition muta-
monly developing, followed by BCCs. A report tions in the p53 gene have been identified as the
in 2009 describes a spindle cell melanoma devel- unique marker for UV-light-induced skin cancer
oping in an old scar caused by a burn (Sheff and (Brash et al. 1996). It was reported that 90% of
Pane 2009). SCCs contained the genetic marker for UV light
Table 1 Occupations at risk for occupational skin cancers based on causative agents
ta:1 Arsenic Polycyclic hydrocarbons Ultraviolet radiation Ionizing Burn
radiation
ta:2 Manufacture of Distillation of coal tar Outdoor work, e.g., Nuclear Welding
insecticide or agriculture, driving, fishing, plant
herbicide and construction operations
ta:3 Agricultural Manufacture of coal gas Welding Diagnostic
exposure to X-ray work
pesticide
ta:4 Mining of arsenic Working with shale oil, Laser exposure Uranium
creosote, asphalt, and mining
chimney soot
ta:5 Certain printing processes Airline
staff
ta:6 Airline staff
compared to 50% of BCCs being found to have Apalla Z, Lallas A, Sotiriou E, Lazaridou E, Vakirlis E,
specific UV-induced mutations of p53 (Rass and Trakatelli M, Kyrgidis A, Ioannides D (2016) Farmers
develop more aggressive histologic subtypes of basal
Reichrath 2008). This is most likely due to the cell carcinoma. Experience from a Tertiary Hospital in
difference in biology between the two tumors. Northern Greece. J Eur Acad Dermatol Venereol 30
Mutations in p53 have only been found in 5% of (Suppl 3):17–20
melanomas (Brash et al. 1996). There is a major Armstrong BK, Kricker A (1994) Cutaneous melanoma.
Cancer Surv 20:219–240
gap in our current knowledge of how UV initiates Bauer A, Diepgen TL, Schmitt J (2011) Is occupational
melanoma. However, the components of the reti- solar ultraviolet irradiation a relevant risk factor for
noblastoma (Rb) pathway and the p53 and p16 basal cell carcinoma? A systematic review and meta-
pathways are considered the major targets of analysis of the epidemiological literature. Br J
Dermatol 165:612–625
UV-induced NMSC and melanoma, respectively Blair A, Freeman LB (2009) Epidemiologic studies in
(Trappey et al. 2010). agricultural populations: observations and future direc-
tions. J Agromedicine 20:219–240
Bofetta P, Jourenkova N, Gustavsson P (1997) Cancer risk
from occupational and environmental exposure to
9 Conclusions polycyclic aromatic hydrocar bons. Cancer Causes
Control 8:444–472
Improvements in industrial processes alongside a Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S,
decrease in the amount of distilling of coal tar Leffell DJ (1996) Sunlight and sunburn in human skin
cancer: p53, apoptosis and tumour promotion. J Invest
and its products have resulted in a reduction in Dermatol Symp Proc 1:136–142
risk of occupation-induced cutaneous neo- Buettner PG, Raasch BA (1998) Incidence rates of skin
plasms. Increased care in handling sources of cancer in Townsville, Australia. Int J Cancer
ionizing radiation and a better understanding of 78:587–593
Buja A, Lange JH, Perissinotto E, Rausa G, Grigoletto F,
the risks has also augmented this decrease. The Canova C, Mastrangelo G (2005) Cancer incidence
risk from exposure of natural solar UV radiation among male military and civil pilots and flight atten-
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Occupational Nail Disorders
25
Robert Baran and An Goossens
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
1.2 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
2 Clinical Reaction Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
3 Occupational Traumatic Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.1 Major Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.2 Variations in Color . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
3.3 Sports-Related Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
3.4 Musician-Related Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
3.5 Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
3.6 Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
3.7 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
4 Final Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Abstract observed as well as distal bony phalanx

Clinical reaction patterns mainly include var- anomalies.
iation in the contour of the nail, modification
of the shape and alteration of the surface. Keywords
Changes in the nail plate and soft tissue Trauma · Paronychia · Chromonychia ·
attachment may happen. Variation in the Bacterial infections · Viral infections · Fungal
color of the nail or subungual tissue can be infections
R. Baran (*) 1 Introduction

Nail Disease Center, Cannes, France
e-mail: BARAN.R@club-internet.fr; 1.1 Anatomy
BARAN.R@wanadoo.fr
A. Goossens The nail plate is the product of constantly
Contact Allergy Unit, Department of Dermatology,
differentiating ectodermal tissue. Its normal appear-
University Hospital K.U. Leuven, Leuven, Belgium
e-mail: An.goossens@uzleuven.be ance and growth depend on the integrity of (1) the

https://doi.org/10.1007/978-3-319-68617-2_25
332 R. Baran and A. Goossens
four epidermal structures (matrix, nail bed, hypo- 1.2 Definition

nychium, and proximal nail fold) and (2) the bony
phalanx that forms part of the nail apparatus. The Occupational nail diseases are abnormalities of
nail is set into proximal and lateral nail grooves one or more of the structures of the nail apparatus,
formed by invaginations in the corresponding nail produced or aggravated by the working
folds. The periungual tissue and, above environment.
all, the distal bony phalanx determine its gross In assessing a nail condition suspected of being
form. occupational, one should:
Study of the local anatomy reveals four
areas which are particularly vulnerable to 1. Rule out nail involvement produced by derma-
trauma. The nail plate emerges from an invag- toses, such as psoriasis, atopic dermatitis,
ination beneath the proximal nail fold, which onychomycosis, and lichen planus, which
adheres closely to the nail for a short distance may present with an isolated symptom and
and forms a transverse strip of desquamating lead to a “false-positive” diagnosis (Bennet
tissue, the cuticle (first area of weakness), 1975) in the absence of a thorough history
which seals the cul-de-sac. The matrix from and laboratory tests.
which the nail is derived extends approxi- 2. Determine whether it may be exacerbated, pre-
mately 6 mm under the proximal nail fold, but cipitated, or revealed by occupational trauma
its most distal part is visible as the white semi- (Baran and Levy 1992; Fisher and Baran
circular lunula. For most of its length, the nail 1992).
plate, which has a loose attachment to 3. Visualize what the hands do at work.
the matrix, lies distally on a firmly adherent 4. Look for functional distribution of the lesions;
nail bed of highly vascular connective tissue for example, the first three fingers of the dom-
containing glomus organs. It is colorless but inant hand are commonly involved in occupa-
translucent, transmitting the pink color tional disease.
of the underlying nail bed. The nail bed 5. Look for occupational stigmata on the nails
epithelium presents with parallel longitudinal (Ronchese 1962a).
rete ridges. The subepithelial capillaries run 6. Examine the whole skin surface and mucous
longitudinally at different but parallel levels. membranes.
Distally adjacent to the nail bed, the hypo-
nychium, which is an extension of the epider-
mis under the nail plate, ends at the distal 2 Clinical Reaction Patterns
groove. The hyponychium (second area of
weakness of the nail apparatus) marks the Clinical reaction patterns mainly include:
point at which the nail plate separates from
the underlying tissue. There is very little 1. Variations in the contour or micro-contour of
space between the nail and the bone of the distal the nail including modification of the shape,
phalanx, and this space is solely occupied by such as clubbing and koilonychia, and alter-
the non-keratinizing nail epidermis and mes- ation of the surface, such as longitudinal or
enchyme. There is no subcutaneous tissue. transverse ridging, brittleness, and pitting.
The functions of the nail are multiple: (1) to 2. Modifications of the nail plate and soft tissue
protect the normal nail bed, (2) to act as a attachments. This may give rise to paronychia
weapon or as a tool for scraping or gripping with disappearance of the cuticle and the crea-
small objects, and (3) to provide counter-pres- tion of a pocket between the ventral aspect of
sure for the pulp, which is essential to the tactile the proximal nail fold and the dorsum of the
sensation involving the fingers. Fingernails grow nail plate. Spontaneous separation of the nail
at a rate of 0.1 mm/day; toenails grow much plate from the matrix, called onychomadesis,
more slowly. may appear. Acute trauma may result in dorsal
25 Occupational Nail Disorders 333
or even ventral (distal) pterygium. various levels at which fingertip injuries are
Onycholysis refers to the detachment of the sustained, e.g., distal to the bony phalanx, distal
nail from its bed at its distal and lateral to the lunula, and proximal to the distal end of the
end. Sometimes, epithelial hyperplasia of lunula. The plane of injury will determine the
the subungual tissues may result from most suitable approach to the reconstruction of
exudative skin diseases and produce subungual the pedicle. The level of nail bed injury is the
hyperkeratosis. critical factor in deciding the requirement for
3. Variations in the color of the nail or subungual nail bed management. Nail stability requires at
tissue. least 5 mm of healthy nail bed distal to the lunula
4. Distal bony phalanx anomalies. Some physical for nail adherence (Rosenthal 1983) (Tables 2, 3,
hazards are mentioned in Table 1. 4, 5, 6, 7, 8, and 9).
3.2 Variations in Color

3 Occupational Traumatic
Abnormalities The term chromonychia indicates an abnormality
in color of the substance and surface of the nail
Occupational traumatic abnormalities in the nail plate and/or subungual tissues. Abnormalities of
area represent one of the most important chapters color depend on the transparency of the nail, its
in this field. This includes major trauma, repeated attachment to the underlying tissues, and the char-
microtrauma, and foreign body injury. acter of the latter. Examination of the abnormal
Table 3 Delayed post-acute traumatic deformities

3.1 Major Trauma Onycholysis
Split nail deformity
The impairment of the normal functional anatomy Pterygium
of the tip and perionychium will depend on the Various nail dystrophies
Hooked nail
Table 1 Physical hazards

Burns (onycholysis, pterygium)
Cold (Beau’s line, nail shedding, koilonychia) (Dolma Table 4 Repeated microtrauma associated with
et al. 1990) koilonychia. In time, nail changes may become irreversible
Dishwashers using heavy rubber gloves (subungual Automotive workers (Dawber 1974)
hemorrhages) (Long 1958)
Cabinet makers
Foreign bodies
Cement workers
Ionizing radiation (Dulanto and Camacho 1979)
Chimney sweeps
Trauma
Coil winders (Smith et al. 1980)
Vibrating power tools (discoloration, ridging, nail
Glass workers
shedding, carpal tunnel syndrome, and Raynaud’s
phenomenon, also observed in typists, violinists, and Hairdressers (thioglycolates) (Alanko et al. 1997)
pianists (Boyle et al. 1988) Homemakers
Mushroom growers (Schubert et al. 1977)
Oil burner repairers (Meyer-Hamme and Quadripur
Table 2 Acute injuries
1983)
May be associated with: Organic chemist (organic solvents) (Ancona-Alayon
Partial or total hematoma 1975)
Lacerating wounds Pin threaders
Fractures of the terminal phalanx Rickshaw puller (feet) (Bentley-Philips and Bayles 1971)
Denudation of the terminal phalanx Slaughterhouse workers (Forck and Kästner 1967)
Table 5 Repeated microtrauma often associated with fin- Table 6 Repeated microtrauma associated with toenail
gernail fragility. This leads to a gradual destruction of the dystrophy
nail plate, which becomes brittle and atrophic. Nail fragil-
Dancers (exostosis) (Sebastian 1977)
ity may also occur in isolation or associated with
paronychia and/or onycholysis Rickshaw pullers (koilonychia) (Bentley-Philips and
Bayles 1971)
Bean shellers and potato peelers (paronychia) Miners (onychomycosis) (Gugnani and Oyeka 1989)
Butchers Sportsmen (hematoma, nail shedding)
Cement workers Athletes
Chemical depilatory product (Pancar and Kalkan 2014) Joggers
Chemists and laboratory workers (paronychia) Walkers
Dentist (onycholysis, subungual hyperkeratosis, Squash players
dermatitis)
Soccer players
Engravers (paronychia)
Tennis players
Etchers (paronychia)
File makers
Glaziers (paronychia) Table 7 Repeated microtrauma associated with
Hat cleaners (paronychia) onycholysis of mechanical origin (Ronchese 1962b;
Housewife (onycholysis) Sharquie et al. (2005) Forck and Kästner 1967; Somov et al. 1976)
Manicure (oncyolysis) Chiriac et al. (2014) Chicken processing plant workers
Mechanical forces (Sano et al. 2014) Cropping
Multiple myxoid cysts (pushing a garment into an Fur workers
embroidery mold) (Connolly and de Berker 2006) Housewife (chemical and physical problems)
Nurses Isocyanate-resin-induced onycholysis with secondary
Optical glass handlers Pseudomonas infection was held responsible for
Packers occurrence of dark-green nails in a chemical mixer
Painters (paronychia) (Leung and Hardin 2015)
Photographers (paronychia, discoloration) Milking
Plasterers (corroded nails) Nut cracking
Porcelain workers (serrated nails) Poultry plucking
Pottery workers Separating meat from bone
Radio workers (paronychia and nail loss) Scraping
Removing the plastic corners from patch tests strip Shell casing
(indentations of thumb nails) (Oranges et al. 2016) Destalking mushrooms
Rope workers
Shoe shiners
Shoemakers (onycholysis and paronychia)
nails should be studied with the fingers
Silk weavers (Ronchese 1955) completely relaxed and not pressed against any
Slot machine (digital corns and calluses (Chaudhry and surface. The fingertips should be blanched to see
McGibbon 2005) whether the pigmented abnormality is grossly
Tea-picker (thumbnail lamellar splitting) (Tan 2006) altered; this may help to differentiate between
Triangular worn-down nails (Piraccini et al. 2005) discoloration of the nail plate itself and discolor-
Weeder thumb. Bilateral distal subungual hematoma ation of the vascular nail bed. If the abnormality
(Uter and Uter 2005) lies in the latter, it usually disappears. Further
Wet work (paronychia)
information may be gleaned by transillumination
Wine grower (subungual splinter hemorrhages) (Doutre
et al. 2008)
of the nail using a pen torch (light) placed against
Woodworkers (paronychia and stains)
the pulp. If the discoloration is in the subungual
Workers exposed to microwave radiation (onycholysis) soft tissues, its exact position can more easily be
Workers handling small instruments identified.
Workers lifting repeatedly heavy plastic bags (Schubert When discoloration results from abnormalities
et al. 1977) at the nail plate-nail bed attachment, leading to
onycholysis and/or subungual hyperkeratosis, the
Table 8 Repeated microtrauma associated with Table 9 Occupational paronychia

onycholysis caused by foreign bodies. This may be associ-
Agricultural workers
ated with an acute trauma (metal) or repeated microtrauma
(hairdressers, e.g.). Occupational onycholysis is most fre- Automotive workers (sulfuric acid exposure from
quently due to chemical irritants or sensitizers. In addition, batteries)
there are infective causes, which tend to be limited to Bakers and pastry cooks
medical personnel and occupations which entail prolonged Barbers and hairdressers (onycholysis)
soaking of the hands (Candida and Pseudomonas) Bartenders
Animal (bristles, sea urchin, oyster shell) Bean shellers
Metal, glass, fiber glass (Roga et al. 1975), plastic. They Book binders (paste)
may also produce paronychia Bricklayers (limes, cement, mortar)
Splinters of hair (Buendia-Eisman and Serrano-Ortegas Builders and carpenters (including glass fiber)
1997; de Berker et al. 1994) in a female hairdresser with Button makers
chronic paronychia (Allouni et al. 2014) and bacterial
Cement workers
infection sometimes associated with subungual
manifestation of barber hair signs (Nagtzaam et al. 2007) Chemists and laboratory workers
Vegetable (thorn, splinter, hyacinth, and narcissus bulbs Chicken factory workers
raphide cells with crystals of calcium oxalate) (Hjorth and Cooks
Wilkinson 1968) Cosmetic workers
Dentists (Kanerva et al. 1997b)
Dyers (aniline dyes, producing stains and necrosis)
history of the condition will help in diagnosis. Engravers, glass etchers (brittle nail)
Chemicals, wet occupation, trauma, or infection Fishermen
may be implicated. Thus, history of the condition Fishmongers
may, for example, confirm the traumatic origin of Florist and gardeners (onycholysis) (hyacinth, narcissus
a hematoma. However, the possibility of malig- bulbs, tulip fingers) (fungal infection)
nant melanoma following trauma to a nail as a Glaziers (brittle nail)
coincidental or causal event should be kept in Groundkeepers
mind (Roberts 1984). When the discoloration is Hairdressers
confined to the nail plate, neither the fingertip Janitorial and domestic workers
Meat handlers
pressure producing blanching nor the pen torch
Mechanics
placed against the pulp will alter the pigmentation.
Milkers (onycholysis from bristle)
When there is nail contact with occupationally
Oil-rig workers
derived agents, or topical application of therapeu-
Painters
tic agents, the discoloration often follows the Photographic developers (brittle nail, discoloration)
shape of the proximal nail fold, and it can be Pianists
removed by scraping the nail plate or cleaning it Physicians, dentists, nurses
with a solvent such as acetone. To determine Potato peelers
whether the color is within the nail plate, a piece Radio workers (methanol, causing pigmentation and nail
of nail should be cut off and examined while loss)
immersed in water. When specimens are allowed Salt plant workers (ulcers)
to dry, their true color may be obscured by the Shoes workers (brittle nails)
scattering of the transmitted light. When the pig- Tanners (whitlow)
mentation involves all the digits, it results from Textile workers (threads of fabric)
the systemic absorption of a chemical. Violinists (nail dystrophy)
Woodworkers (brittle nails, stains)
Wool workers (wool thread)
1. When the route of systemic absorption is oral,
the discoloration is more likely to correspond
to the shape of the lunula. Transverse 2. When systemic absorption of a chemical
leukonychia might occur, for example, in arse- through the lung or the skin produces
nic or thallium poisoning. dyschromia, there are two possibilities:
(a) Disappearance of the pigmentation on the 3.4 Musician-Related Trauma

nail bed blanching test means that the pig-
ment originates from the blood vessels. Met- The piano can produce a vasospastic white finger
hemoglobinemia, as an example, manifests disease as well as paronychia. The harp can also
as a bluish discoloration of the terminal digits be responsible for paronychia associated with
and should be looked for in an otherwise onycholysis and subungual hemorrhages (Harvell
asymptomatic worker, i.e., following expo- and Maibach 1992). The violin may induce
sure to aromatic nitro and amino compounds paronychia.
that can penetrate all glove materials. The Friction as a cause of irritant contact dermatitis
color disappears within 16 h of leaving may be observed in guitar players whose fingers
work, as opposed to sulfhemoglobinemia, are used to pluck the strings. Acroosteolysis asso-
which presents with the same distal discolor- ciated with pain in the distal fingers has
ation as an early warning sign of intoxication been reported (Baran and Tosti 1993). To play
(Pinkus et al. 1963) but which disappears the viola, one must make a repetitive compression
only with the normal life span of the red and pluck the strings (Freeman and Rosen 1990),
blood cell, i.e., 4 months (Kern 1990). with the distal portion of the fingers, especially the
(b) If the pigmentation is not altered on the nails, presenting brittleness and worn-down
nail blanching test, it may be obliterated appearance (Piraccini et al. 2004). Worn-out
by the pen torch pressed against the pulp. thumbnail may be a stigma in guitar players. The
This means that the pigment is deposited in right thumbnail may show onychodystrophy
the nail bed, as observed in the blue nails of mediana canaliformis in professional guitarists
silver refinery workers (Bleehen et al. or changes similar to the habit tic deformities
1981) (Tables 10, 11, and 12). (Wu 2009).
3.5 Bacterial Infections
3.3 Sports-Related Trauma The usual microorganisms that may develop in

abrasions or lacerations of the nail area are coag-
Sports-related trauma occurs frequently. In ulase-positive staphylococci and various strepto-
golfer’s nails, distal splinter hemorrhages are cocci (Barnham et al. 1980; Barnham and
seen, especially in the fingers used most strongly Kerby 1984). Pseudomonas infection is responsi-
in the golf grip hand (Ryan and Goldsmith 1995). ble for the green nail syndrome. Such infected
Judo can be responsible for trachyonychia nails, in health-care personnel, may then be a
(sandpapered nails). The frequent grabbing of source of nosocomial infections, especially from
the opponent’s jacket accounts for the rough nurses with artificial nails in whom Serratia,
“judo” nails (Shelley and Shelley 1995). Karate Acinetobacter, and Pseudomonas have been
may produce clubbing; in addition, professional found.
and recreational karate enthusiasts’ sharp, strong Acute paronychia occurs frequently enough in
blows to which their fingernails and toenails are meat handlers (Barnham and Kerby 1984).
prone may also cause clubbing. Clinically, this Erysipeloid infection is rare and can be observed
presents as leukonychia, usually in transverse in meat and fish handlers. Prosector’s wart [tuber-
bands (Scher 1988). culosis verruca cutis (Goette et al. 1978)] has its
Tennis and squash players, in whom sudden, source in a tuberculous-infected cadaver. It may
abrupt changes in foot direction occur, develop be seen in pathologists, morgue attendants, and
tennis toe and may exhibit subungual hemor- other hospital personnel.
rhages. Soccer players and joggers can suffer the Mycobacterium marinum infection (Califano
same complications. et al. 1998), called fish-tank granuloma or
Table 10 Variations in color of the nail plate

Sign Workers affected
Leukonychia Arsenic workers
Butchers
Keypunchers (Honda et al. 1976)
Salt plant workers and contact with salted intestines (Frenk and Leu 1966)
Swimming pool employees (Shemer et al. 2016)
Weed killers (paraquat) (Botella et al. 1985; Dobbelaere and
Bouffioux 1974)
Workers manufacturing thallium rodenticides
Flytier’s finger (apparent leukonychia) (MacAulay 1990)
Blue Anodisers (aluminum)
Local argyria (Bergfeld and McMahon 1987; Sarsfield et al. 1992)
Auto mechanics (oxalic acid in radiators)
Cyanosis from methemoglobinemia or sulfhemoglobinemia
Dye makers
Electroplaters
Gold plasters
Metal cleaners, metal patina solution
Ink makers
Paint removers
Photographers
Rust removers
Silver protein as a disinfection medicine (generalized argyria)
Silver workers (presenting generalized argyria) (Bleehen et al. 1981)
Textile workers
Brown/black Cigar makers
Cobblers
Coffee bean workers
Cooks and bakers (burnt sugar)
Electric bulb cleaners (hydrochloric acid)
Gunsmith
Hairdressers
Pecan nuts (Garcia-Garcia et al. 2015)
Photographers
Roadway pavers
Shoe shiners
Vintners (red wine)
Woodworkers (varnish)
Woodworkers (ebony, mahogany) (Harris and Rosen 1989)
Green (usually caused by
Pseudomonas infection) Bartenders
Dishwashers
Electricians
Fruit handlers
Laundry workers
Metallurgists
Restaurant workers
Sugar factory workers
(continued)
Table 10 (continued)
Sign Workers affected
Yellow Epoxy system handlers
Metaphenylenediamine and 4,40 -methylenedianiline (Cohen 1985)
Flower handlers
Pesticide workers: diquat (Samman 1961; Clark and Hurst 1970), paraquat
(Samman 1961; Hearn and Keir 1971), dinitro-orthocresol (Baran 1974),
dinobuton (Wahlberg 1974)
Workers handling chromium salts
Workers handling dyestuffs: dinitro-salicylic acid (Fregert and Trulson 1980),
dinitrobenzene, dinitrotoluene, and trinitrotoluene
Table 11 Chemical sensitizers

Contact sensitization
occurring through the nail
plate is probably rare. Usually
sensitizers alter the distal sub-
and periungual tissue
Flowers and plants Alstroemeria (onycholysis) (Rycroft and Calnan 1981; Marks 1988)
Hydrangea (paronychia) (Bruynzeel 1986)
Nasturtium (fingertip dermatitis) (Derrick and Darley 1997)
Tabernaemontana coronaria (fingertip dermatitis) (Bajaj et al. 1996)
Tulip fingers (painful onycholysis and fissured keratotic eczema) (Gette and Marks 1990)
Rhus dermatitis from poison ivy, oak, and sumac (onycholysis, yellowish discoloration
of the nail) (Fulghum 1972)
Chemicals Acrylic resinsa (Kanerva et al. 1997c, d) (Mendonca et al. 2015; Muttardi et al. 2016;
Ramos et al. 2014; Uter and Geier 2015); beauticians specializing in nail sculpturing
(Lazarov 2007) photobonded acrylic gel nails (occupational airborne dermatitis (Cravo
et al. 2008)
“Cain” (local anesthetics) and propanidid (Castalain and Piriou 1980)
Cement dermatitis from dichromate content (koilonychia, fissures)
Codeine (onycholysis, subungual hyperkeratosis, nail atrophy) (Romaguera and
Grimalt 1983)
Ethyl cyanoacrylate (Shelley and Shelley 1988)
Epoxy resin (Castelain et al. 1992)
Hydroxylamine (onycholysis, paronychia) (Baran 1991)
1-methylquinoxalinium-p-toluene sulfonate (periungual dermatitis)
Mydriatic agents containing tropicamide and phenylephrine hydrochloride (nurses)
Nail hardeners (Mestach and Goossens 2016)
Nonoxynol-6 (transverse nail dystrophy)
Quaternium-15 (subungual hyperkeratosis, onycholysis) (Marren et al. 1991)
p-Tertiary butyl phenol formaldehyde (onycholysis subungual hyperkeratosis, nail
atrophy, periungual dermatitis) (Rycroft et al. 1980)
Thiourea (Dooms-Goossens et al. 1988)
Turpentine (periungual dermatitis, subungual hyperkeratosis)
Protein contact dermatitis Baits (onycholysis, paronychia) (Montel and Gouyer 1957)
Food animal origin (food handlers) (Tosti et al. 1992)
Vegetable origin
a
Acrylic dermatitis usually starts from the fingertips. Fingertips paresthesia (dental nurses, orthopedic surgeons) can be seen
Kanerva et al. 1998). Most of the analyzed acrylate products contain undeclared highly sensitizing acrylics up to 46%
(Kanerva et al. 1997c). Acrylic tri-cure glass ionomer produces fingertip dermatitis (dental nurses) (Kanerva et al. 1997a).
Table 12 Chemical irritants Table 13 Fungal infections

Alkalis Candida fungal infection
Alkaline chlorine-containing compounds of the nail area is a
(Coskey 1974) common condition
Aminoethylethanolamine-containing soldering flux involving occupations that
(onycholysis, periungual dermatitis) (Goh 1985) require the hands to be wet
for prolonged periods
Detergents (onycholysis, subungual bleeding
ulcerations) (Göthe et al. 1972) Candida spp. (onycholysis Dishwashers, poultry, and
paronychia) fish handlers
Formaldehyde
Dermatophytic toenail
Gold potassium cyanide (purplish-brown discoloration,
infection
onycholysis) in electroplaters, electronic workers
(Budden and Wilkinson 1978) T. rubrum is the most Increased prevalence in
common dermatophyte, coal miners (Tappeiner
Hydrofluoric acid (excruciating pain, acute onycholysis)
sometimes responsible for and Maler 1966) and
(Shewmake and Anderson 1979; Baran 1980)
the one hand-two-foot others who work in hot,
Organic solvents and motor oils (onycholysis, subungual tinea syndrome humid environment
hyperkeratosis, nail softening)
T. mentagrophytes var. Washing facilities
Oxalic acid (bluish discoloration, brittle nails) interdigitale
Molds, especially Miners and green tea leaf
Neoscytalidium spp., pluckers (Barua et al.
may involve the 2007)
swimming pool granuloma, the association of toenails and the thumbnail
skin infection with aquariums and tropical Onychomycosis (not rare Dental nurses (Alanko et
among) al. 1997)
fish has been noted. A prick from a rose thorn
might also cause the infection. This is character-
ized by the presence of one papule, nodule,
or erythematous plaque with a verrucous
surface on the dorsum of the distal phalanx of
the finger. Table 14 Individuals at risk of fungal infections (Baran
Pasteurella tularensis is transmitted to man by 1997)
direct contact with infected wildlife (rabbits are Athletes
the principal reservoirs of tularemia in nature). Dust men
Over half the patients with any cutaneous ulcers Employees of indoor swimming pools
present with multiple lesions including shallow Excavation workers
erosions into the subungual tissues (Young et al. Footbal players (Buder et al. 2018)
1969). Green tea leaf pluckers (Neoscytalidium spp.)
Mine workers
Rubber industry workers
Sewer workers
3.6 Fungal Infections
Soldiers
Steel and furnace workers
The working environment in carpet industry was
Woodcutters
assessed by Wani et al. (2014) for fungal contam-
ination in Gwalior (India). The sampling was car-
ried out in five carpet units that were selected
randomly. It was found that various types of fun- 3.7 Viral Infections
gal species, viz., Aspergillus niger, A. parasitics,
Fusarium sp., Alternaria sp., Penicillium sp., Tri- Viral infections involving the distal digit include
choderma sp., Curvularia sp., Cladosporium sp., (Tables 13, 14, and 15):
and yeast, were present at the workplace, which
may cause various types of diseases among the 1. Foot and mouth disease (pustular paronychia)
weavers. (Armstrong et al. 1967).
Table 15 Occupational systemic conditions 5. Viral warts are more common in butchers
Clubbing (resulting Exposure to: (Jablonska et al. 1987; Aloi et al. 1988; Keefe
from pneumoconiotic et al. 1994), poultry handlers (Moragon et al.
lung diseases) 1987), and fish handlers (Rüdlinger et al. 1984).
Asbestos (Petry 1966)
Talc
Beryllium (Kern 1990)
Silica
Cobalt (Desoille et al. 1962)
4 Final Comments
Tungsten (Desoille et al.
1962) There are often pitfalls in diagnosis such as:
Pseudoclubbing Vinyl chloride monomer
(systemic sclerosis with 1. Where the presentation of cutaneous disease is
acroosteolysis)
restricted to an isolated sign involving the nail
Cutaneous Polyvinyl chloride (Davis et al.
hemangioendothelioma 1990)
2. Where dual pathology exists, such as fungal
Collagen diseases:
infection combined with any of the previously
Systemic sclerosis Vinyl chloride monomer mentioned conditions
Epoxy resin (vapors) 3. Where there is an isomorphic reaction, for
Trichlorethylene, example, in a psoriasis which may not be evi-
trichloroethane dent as yet and is even overlooked or might be
Silica (Rustin et al. 1989) latent
Sclerodactyly (nail-
fold capillary changes, The main goals when handling occupational
Raynaud’s
phenomenon, nail disorders are (1) long-term management and
acroosteolysis) (2) prevention. Management must take into
(Bachurzewska and account the patient’s continuing occupation; for
Boruka 1986; Flindt- example, protective gloves might be effective
Hansen and Isager
1987) when handling epoxy resins, as these chemicals
Lupus Coffee plantation workers have probably caused more instances of occupa-
erythematosus-like (Narahari et al. 1990) tional dermatitis than any other chemicals intro-
erythema and duced in recent years. However, the gloves might
periungual
impair the person’s manual dexterity. Further-
telangiectasia
more, rubber gloves are penetrated by acrylic
monomers, and this is relevant for orthopedic
surgeons, nurses, or dental personnel. The overall
2. Herpes simplex infection. This is the most
aims should include:
frequent viral infection. It occurs in dentists
(Rames et al. 1984), nurses (Kanaar 1967),
1. Efficacy of treatment
anesthesiologists (Rosato et al. 1970), and
2. Prevention of continuing cause
pathologists (Haedicke et al. 1989). In these
3. Cleanliness
occupations, it exhibits a particular tendency to
4. Hand comfort
frequent recurrence.
5. Facilitation of continued manual dexterity
3. Human orf can assume a target-like appearance
6. Above all, ease of application in the treatment
on the dorsum of the right index finger which is
and the preventive measures
the most commonly affected (Amichai et al.
1993).
Acknowledgments We would like to thank the publisher
4. Milker’s nodule is clinically similar to human for the permission to reproduce some of the tables which
orf and involves mostly agricultural workers appeared in Rycroft and Baran R (Wiley-Blackwell 5th
and veterinarians (Groves et al. 1991). edition).
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Hair Disorders Induced by External
Factors 26
Becky S. Li, Marcel C. Pasch, and Howard I. Maibach
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
3 Anatomy and Hair Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
3.1 The Hair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
3.2 Hair Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
3.3 Occupational Hair Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
3.4 Evaluation of Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
3.5 Diffuse Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3.6 Anagen Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
4 Telogen Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
4.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
4.2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
5 Mixed Types or Undetermined Types of Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
5.1 Hair Loss Induced by Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
5.2 Hair Loss by Plant Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
B. S. Li (*)
Howard University College of Medicine, Washington,
DC, USA
e-mail: Becky.Li@ucsf.edu; beckysiyunli@gmail.com;
becky.li@bison.howard.edu
M. C. Pasch
Department of Dermatology, Radboud University
Nijmegen Medical Centre, Nijmegen, GL,
The Netherlands
e-mail: M.Pasch@derma.umcn.nl
H. I. Maibach (*)

https://doi.org/10.1007/978-3-319-68617-2_26
346 B. S. Li et al.
5.3 Hair Loss in Semiconductor Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

5.4 Hair Loss Induced by Sanitary Cleaners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
5.5 Hair Loss in Toxic Oil Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
5.6 Localized Hair Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
5.7 Hair Disorders with Increased Hair Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Keywords disorders. Occupational and environmental fac-

Alopecia · Hair loss · Hair disorder · Anagen · tors belong to the more rare causes of hair disor-
Catagen · Telogen · Hirsutism · Hypertrichosis ders. However, not considering them and only
focusing on the more common causes of hair
disorders will result in persistence of situations
1 Core Messages which may lead to expanding the problem to
larger groups of people. On the other hand, some
• External factors may result in hair loss, causes of hair loss have such a high prevalence in
increased hair growth, or changes in the color the general population that involved coworker
and texture of the hair. might assume causality with their working envi-
• External factors responsible for hair loss are ronment and exposition to chemicals. However,
drugs, radiation, traction, fungi, pesticides, the incidence of alopecia areata was reported to be
plant toxins, heavy metals, and several other 1.7%, and male or female pattern hair loss is
chemicals. ubiquitous (Safavi et al. 1995). Confusion about
• Several groups of drugs may be responsible for occupational or external factors involved in devel-
unintentional induction of hair growth. opment of alopecia areata and pattern hair loss is
• Texture and color of hair may be changed by understandable but has never been convincingly
drugs, metals, and ultraviolet and other documented.
radiation. This chapter focuses on hair diseases and
• Full recovery is the rule after elimination of the external factors that may play a role in their
responsible factor. pathogenesis.
2 Introduction 3 Anatomy and Hair Cycle
Hair has many useful biologic functions, includ- Hair follicles cover almost the entire surface of the
ing protection from the elements and dispersion of body. Only the palms, soles, glans penis, and labia
sweat gland products. It also has psychosocial minora are devoid of them. The scalp possesses the
importance in our society, and patients with hair greatest density of hair follicles with a range of
loss (alopecia) or excessive hair growth (hyper- 300–500 hair follicles/cm2. Approximately five mil-
trichosis or hirsutism) often suffer tremendously. lion hair follicles are on the body, with 100,000 on
Not surprisingly, patients being confronted with the scalp.
hair disorders will seek for medical care in order The hair-producing matrix cells of the follic-
to find the cause of their hair disorder. Hair disor- ular bulb constitute a pool of undifferentiated
ders have a high incidence in the general popula- transit amplifying cells that have intense meta-
tion. Most of them can be explained by aging bolic activity. This metabolic activity is greater
(male and female pattern hair loss), factors than of any other tissue, except the bone mar-
concerning general health (e.g., thyroid dysfunc- row, making them vulnerable for cell cycle
tion, pregnancy, and malnutrition), use of medi- inhibiting factors like fever, endocrine abnor-
cation, and inflammatory and infectious scalp malities, parturition, major surgery, anemia,
26 Hair Disorders Induced by External Factors 347
and malnutrition. Also drugs, radiation, and Thus, under normal circumstances there is a bal-
external toxic factors, which are the focus of ance between hair growth and hair shedding.
this chapter, easily can inhibit cell cycle in the Since most people are born with about
follicular bulb, resulting in hair loss. Regulation 80,000–150,000 scalp hairs, and normally a hair
of hair growth and details on the biology of the cycle lasts about up to 8 years, shedding of
hair follicle are complex processes, which are 50–150 telogen hairs per day is normal. Loss of
beyond the scope of this chapter. Furthermore, anagen hair is always pathological. Hair loss and
one should realize that the hair follicle has more unwanted hair growth reflects aberrations of the
functions than producing a hair fiber. For exam- hair follicle cycling, except for rare congenital
ple, the hair follicle acts as a sensory organ and hair defects, caused by mutations in keratins or
immunologic sentinel of the skin. other structural proteins, and “scarring” alopecias.
Thus, in principle, hair loss and unwanted hair
growth are reversible phenomena.
3.1 The Hair
3.2.1 Anagen
The hair fiber is about 50–100 μm in diameter and Anagen is the stage of active hair growth. In this
consists of a cuticle, cortex, and medulla. The stage, which can last 2–8 years on the scalp or
cortex provides the majority of hair fiber mass, is beard areas, each hair follicle will produce
responsible for its strength, and contains melanin monthly about 10 mm of hair fiber. Other areas
pigment. It is made from cells which are tightly of the human body have hair follicles with
packed together. It contains keratins with a high shorter anagen stages. The anagen stage on the
level of sulfur-containing amino acids. Cross- brows or trunk does not exceed 6 months.
linking of these amino acids results in formation Because of the differences in duration of the
of disulfide bonds which give the hair most of its anagen stage, the maximum length of a hair
great tensile strength. The cuticle covers the cor- differs between the scalp and, for example, the
tex and consists of layers of scales, each about eyebrow and the pubic hairs. The maximum
0.5 μm thick, which overlap in a roofing tile length of an untrimmed hair is proportional to
manner. The cuticle protects the underlying cortex the duration of the anagen cycle. Cell division
and acts as a barrier against the external environ- rates are highest in anagen hair follicles. There-
ment. The medulla of the hair is only present in fore, areas with a high percentage of anagen
thick terminal hairs. It consists of air space follicles, such as scalp or beard, will be more
containing specialized cells, which may have a susceptible to factors affecting rapidly dividing
function in the thermal insulation of the body. cells. Areas with a high percentage of telogen
follicles, such as eyebrows, will be more resis-
tant to these factors. This difference explains
3.2 Hair Cycle why hair loss during chemotherapy or due to
exposure to toxic substances is often solely
Cyclic growth is a typical characteristic of the hair located on the scalp and beard and does not
follicle. Each hair follicle perpetually goes comprise other body hairs.
through three stages: growth (anagen), involution
(catagen), and rest (telogen). The release of dead 3.2.2 Catagen
hair is sometimes called exogen. The exogen Anagen is followed by an involutional stage
coincides with the end of the telogen stage and called catagen, which last a couple of weeks.
the entrance to the anagen phase of the next During this stage hair follicles go through a pro-
hair cycle. cess of involution that largely reflects a burst of
Normally, each human hair follicle cycles inde- programmed cell death (apoptosis) in the majority
pendently, so that while some hairs are growing, of follicular keratinocytes and cessation of follic-
others are resting and others are shedding. ular cell division.
348 B. S. Li et al.
3.2.3 Telogen 3.4.1 Clinical History

The catagen stage is followed by a resting or The thorough clinical history always will facili-
telogen stage. In this stage the hair remains tate making the correct diagnosis. The duration
loosely attached in the dormant follicle. The hair of hair shedding, the character (episodic or con-
shaft matures into a club hair, which is eventually tinuous), a subjective estimation of percentage of
shed from the follicle, usually during washing or hair loss, recent surgery, fever, illness, child-
combing. The time between entering the telogen birth, or physiological stress needs to be
stage and the shedding of the hair is 2–4 months addressed. Also the presence of chronic disease,
and is independent from the anatomical region. It malignancy, infection, autoimmune disease, and
is unknown whether shedding is an active, regu- liver or renal disease requires attention. The role
lated process or a passive event that occurs at the of mental stress is not clear but may also play a
onset of the next anagen stage, as a new hair grows role. Particular attention should be paid to the
in. Under normal circumstances all hairs that are time between a potential cause and the actual
shed are telogen hairs. beginning of the hair loss. Few simple questions
may rule out the presence of thyroid disease,
while presence of hirsutism, acne, seborrhea,
3.3 Occupational Hair Disorders irregular cycle, or infertility may be indications
for high androgen levels. Of particular impor-
Occupational hair disorders are abnormalities of tance is a meticulous history of drugs used in
structures of the hair follicle caused or aggravated the past months, including over-the-counter
by the working environment. Alopecia is not an drugs, vitamin A, and botanicals. Incidental,
uncommon phenomenon in toxicological animal acute, or chronic (occupational) exposure to
studies. The relevance for humans is frequently chemicals, animals, heavy metals, or radiation
not clear. Therefore, only substances with proven needs to be addressed. Most effluvium is loss of
or likely effects on hairs in humans will be telogen hairs caused by a premature disruption of
discussed. the anagen phase of hair cycle and entrance to the
The most common acquired hair disorder is telogen phase. After entering the telogen phase,
hair loss or thinning. The first, but often difficult, hair shedding will follow after completing this
task in diagnosing hair disorders is to distinguish phase. So hair shedding after exposure to a caus-
between true disorders and subjective complaints. ing factor mostly will follow 2–3 months later.
After having diagnosed a true disorder, the eluci- However, after exposure to many antimitotic
dation of the nature of the hair disease may be agents, too high doses of radiation, or to toxins,
even more challenging. However, before focusing an acute anagen effluvium may occur within
on occupational and other external factors, one days to few weeks.
should realize that hair disorders have a high
incidence in the general population, so common 3.4.2 Physical Examination
causes of hair disorders need to be ruled out. The physical examination of the scalp will show
the severity, a potential pattern of the hair loss, and
the presence of scalp disorders. As a rule of
3.4 Evaluation of Hair Loss thumb, one may take into account that hair loss
of less than 25–50% may not be visible for out-
Hair diagnostic tools in a dermatologic or occu- siders. The pattern will reveal whether the hair
pational medicine consultation comprise a thor- loss is diffuse or localized or has a distinctive
ough clinical history, physical examination clinical distribution like in male or female andro-
including the skin of the scalp, a hair pull test, genetic alopecia. Physical examination of the
and often microscopic examination of hair shafts scalp may show the presence of an inflammatory
and hair roots. A scalp biopsy is only indicated in or infectious skin disorder. Scalp psoriasis, der-
selected cases. matitis, fungal infections but also rare primary or
secondary cicatricial alopecias will present with roots will have the typical club-like characteristics
both hair loss and abnormal skin of the scalp. of telogen hair (Fig. 1a), in alopecia areata there
will be both telogen and tapered broken anagen
3.4.3 Hair Pull Test hairs (Fig. 1b), and in acute anagen effluvium,
The hair pull test is a simple test to determine the increased numbers of tapered anagen hairs or
ongoing activity and severity of any kind of hair anagen hair (Fig. 1c) can be seen.
loss. To perform the hair pull test, a bundle of After clinical evaluation a first estimation can
about 50 hairs is grasped between the thumb, be made of the extent, clinical diagnosis, and
index finger, and middle finger near the scalp. origin of the hair loss.
The hair is firmly tugged away from the scalp as
fingers slide along the hair shaft. This procedure is 3.5 Diffuse Hair Loss
repeated in the left and right parietal area, the
frontal area, and the occipital area. Hair that can Diffuse hair loss can be defined as a positive hair
be detached from the hair follicle in the hair pull pull test in both the vertex area and margins of the
test was only loosely attached to the hair follicle. scalp. It is further classified by the types of hairs
Extraction of no more than 10%, so five to six that are shed: are they anagen, dystrophic anagen,
hairs, is considered physiological. Extraction of or telogen?
more hairs constitutes a positive pull test, imply- Chemicals, drugs, or radiation may either
ing active hair shedding. Despite its simplicity, cause excessive hair shedding by precipitating
this test has some major drawbacks. The telogen development, directly poison the anagen
interobserver variability is very high, and the root, or work in a undetermined way. Precipita-
result greatly depends on hair care habits of the tion of telogen development results in telogen
patient. Recent washing; the use of sticky hair hair loss occurring 2–4 months after the insult,
cosmetics, like hair spray, gel, and wax; or exten- reflecting the time required for the full telogen
sive brushing will influence the outcome of this state to be accomplished. Direct poisoning of
test. Therefore, patients are asked not to wash the anagen hair may result in rapidly occu-
their hair and to avoid sticky hair cosmetics in rring hair loss, only days to few weeks after the
the 5 days before the examination. Nevertheless, insult.
the hair pull test is only a rough approach, which
appears to be useful only for acute and more
severe phases of hair loss. 3.6 Anagen Hair Loss
The nature of the extracted hairs can be ana-
lyzed by light microscopy to narrow the differen- Two types of anagen hair loss can be recognized:
tial diagnosis. In case of telogen hair loss, the hair dystrophic anagen effluvium and loose anagen
Fig. 1 (a) Telogen hair obtained by hair pull. (b) Tapered broken anagen hair from an alopecia areata patient. (c) Anagen
hair obtained by plucking
350 B. S. Li et al.
syndrome. The loose anagen syndrome is beyond 3.6.2 Treatment

the scope of this chapter, because it is predomi- Hair loss commences fast after exposure, and once
nantly described in children and no external or the insult is removed, regrowth is usually prompt
occupational factors have been recognized in because normal anagen growth has been only
this disorder. temporarily interrupted. So a rapid and generally
Dystrophic anagen hair loss is the result of complete clinical reversal within weeks to few
interruption of the anagen phase of hair cycle. months after withdrawal of the exposure is a hall-
It presents as abrupt anagen hair shedding mark of anagen hair loss, with only few excep-
with severe and diffuse scalp alopecia. Since the tions. Additional treatment is neither effective nor
loss affects the anagen hairs but not the telogen necessary.
hairs, eyebrow and body hair is relatively spared.
The time course for anagen hair loss is usually
3.6.3 Causes of Anagen Hair Loss
rapid after the insult to the hair follicles. All caus-
External and occupational factors able to cause
ative factors share one characteristic: they
anagen hair loss will be discussed in detail below.
abruptly stop normal cell division of rapidly
Chemotherapy-induced alopecia is the most frequent
dividing hair matrix cells in the hair bulb. Impor-
of them. It occurs with an estimated incidence of
tant causative factors are antineoplastic drugs,
65% in cancer patients. Forty-seven percent of
radiation, environmental or occupational expo-
female cancer patients consider it the most traumatic
sure to toxins, and diffuse alopecia areata. The
aspect of chemotherapy (Trueb 2009). It has been
common time frame is an onset within days to
reported several times that health workers involved
weeks after exposure to the causative factor. So
in preparation and administration of antineoplastic
hair loss commences fast after exposure, but a
drugs have a fivefold to sevenfold increased risk of
rapid reversal within weeks to few months after
developing hair loss (Krstev et al. 2003). Hair loss is
withdrawal of the exposure is another hallmark of
also part of the radiation sickness. Public and medical
dystrophic anagen hair loss.
interests have been stimulated following the poison-
ing incident of the Russian dissident Alexander
3.6.1 Diagnosis
Litvinenko with the radioactive compound polo-
Anagen hair loss is the consequence of a directly
nium-210 in 2006. Exposure to heavy metals is a
toxic effect on the hair matrix cells. This leads to
well-known cause for anagen hair loss and still might
hair loss in two ways. If the matrix itself suffers
play a role in hair loss in occupational medicine. The
a severe and prolonged insult, then much of the
same is true for other anagen hair loss-inducing
follicle is affected, and immediate anagen
chemicals, such as boric acid and selenium.
hair loss will occur in which there is an immedi-
ate release of dystrophic hairs. At the pull test,
the hairs are easily removed with a necrotic Anagen Hair Loss Induced by Chemotherapy
anagen sheath adhering to them (Fig. 1c). If the and Other Cytostatic Drugs
insult is less severe or of a short duration, then The three major toxicities of antineoplastic drugs
mitotic activity will decrease only temporally. are gastrointestinal disturbances, bone marrow
There will be hair damage without anagen suppression, and alopecia. They all are the result
release: the hair will continue growing but has of direct toxic effects on the rapidly dividing cells
developed a weak constricted area in the of the gastrointestinal tract, the bone marrow, and
shaft. As soon as this constricted area grows the cells of the hair matrix.
above the surface of the skin, a minor trauma Hair loss can be induced by all traditional
can cause a fracture of the hair, resulting in antineoplastic drugs: alkylating agents, alkaloids,
shedding. Under the microscope a tapered hair and antimetabolites, but also several monoclonal
is visible, which is a characteristic of anagen antibodies may have this distressing side effect. It
hair loss (Fig. 1b) and may be seen in alopecia is more common and severe with combination
areata as well. therapy than with the use of only a single drug,
but major differences exist between individual Table 1 Cytotoxic drugs and hair loss
antineoplastic drugs (Table 1). Hair starts to fall Cytotoxic agents that usually do cause Adriamycin
out usually few weeks after exposure to the anti- hair loss Cyclophosphamide
neoplastic drug. Complete baldness may have Daunorubicin
Docetaxel
developed 1 or 2 months later. Usually antineo-
Epirubicin
plastic drug-induced hair loss is reversible. Etoposide
Regrowth will occur 2–6 months after discontin- Ifosfamide
uation of the therapy, indicating that the empty Irinotecan
hair follicle has to run through the complete Sorafenib
telogen phase before a new and normal anagen Teniposide
hair will start growing. Full regrowth may be the Topotecan
Vindesine
rule, but permanent changes in texture or density
Vinorelbine
of hair may become apparent. Particularly regi- Cytotoxic agents that sometimes cause Amsacrine
mens containing busulfan are known to cause hair loss Bleomycin
permanent damage to the hair follicles, but per- Busulfan
manent baldness has also been observed after Cytarabine
other high-dose chemotherapy regimens, like Dacarbazine
Doxifluridine
with cyclophosphamide, thiotepa, and
Erlotinib
carboplatin (CTC) (Prussick 1996; de Jonge et
5-fluorouracil
al. 2002). Partial or total permanent alopecia Gefitinib
occurs in about half of the patients receiving Gemcitabine
busulfan. Possible explanations for follicular dis- Interferon-α2b
appearance can be either stem cell destruction or Ixabepilone
acute damage of the matrix keratinocytes that die Lomustine
Paclitaxel
in the hypodermis instead of entering the catagen
Sunitinib
phase (Tosti et al. 2005). Temozolomide
Thiotepa
Treatment Thioguanine
Great improvement has been achieved in devel- Trastuzumab
opment of strategies to manage chemotherapy- Vinblastine
Vincristine
induced gastrointestinal disturbances and sup-
Cytotoxic agents that rarely cause hair Capecitabine
pression of the bone marrow. Previously, no effec- loss Carboplatin
tive pharmacologic treatment was available for Carmustine
the third major toxicity of chemotherapy, alope- Cisplatin
cia. However, in recent years, options for chemo- Doxorubicin
therapy-induced alopecia have become available, Fludarabine
including topical vasoconstrictors and parathyroid Hydroxyurea
6-mercaptopurine
hormone agonists.
Methotrexate
Since the 1970s, scalp cooling has been Mitomycin C
used and studied. In most of these studies, a Mitoxantrone
significant decrease in hair loss was observed Procarbazine
with scalp cooling, most evident when Raltitrexed
anthracyclines or taxanes were used (Grevelman Streptozotocin
and Breed 2005). Concerns have been expressed Abele et al. (1983), Akerley (1996), Cascinu et al. (1997), Rajkumar
et al. (2000), Stafford-Fox and Guindon (2000), Hamilton et al.
about the risk of scalp metastases after cooling. (2002), Kumar et al. (2002), Leyland-Jones et al. (2003), Herrlinger
It is considered contraindicated for those with et al. (2003), Muggiano et al. (2004), Cohen et al. (2005), Conlin
and Vahdat (2006), Autier et al. (2008), Trueb (2009), Hartmann
hematological malignancies, and its use is con-
et al. (2009), Lee et al. (2009), Forde et al. (2011)
troversial in patients with nonhematological
352 B. S. Li et al.
malignancies who undergo curative chemother- responsible for additional exposure to radiation
apy (Trueb 2009). are tobacco (polonium-210), building materials
Given the side effects of scalp cooling, newer (radium and radon), fuels (gas, oil), television
options have been searched for. In 2015, Soref sets, X-rays at airports, and starters for fluores-
and Fahl showed that the application of topical cent tubes. The nuclear energy industry causes
vasoconstrictors, norepinephrine and epineph- only limited additional exposure to radiation, but
rine, in mice could effectively suppress alopecia this has never been measured reliably. Occupa-
after chemotherapy or radiation. Transient cuta- tional exposure to radioactivity may occur in
neous vasoconstriction protected hair follicles nuclear power stations, industrial quality control
from chemotherapy- and radiation-induced procedures, scientific procedures, hospital
DNA damage. Parathyroid hormone also seems workers, airline staff, military working with
promising in the treatment of chemotherapy- depleted uranium, and during food irradiation
induced alopecia. Skrok et al. (2015) revealed to destroy microorganisms, bacteria, viruses, or
that transgenic mice with an overexpression of insects. The best known example of intentional
PTHrP activity had impaired hair growth, radioactive poisoning concerns the Russian dis-
whereas those with a blockade of PTHrP activity sident Alexander Litvinenko with the radioac-
had increased hair growth. tive compound polonium-210.
Recently, Yang and Thai (2016) reported of a Radiation describes any process in which
39-year-old woman with permanent chemother- energy travels through a medium or through
apy-induced alopecia, which is the absence of space, ultimately to be absorbed by another
hair regrowth 6 months after the cessation of body. The energy can be emitted as waves (elec-
chemotherapy. She did not respond to standard tromagnetic radiation) or as particles, for exam-
treatments of scalp cooling or topical minoxidil. ple, α-radiation or β-radiation. α-Particles will
She did, however, have substantial hair regrowth cause severe damage if ingested. However, they
with 1 mg of oral minoxidil. Clinically, the have little energy and a low range; typically,
patient showed increased hair growth at α-particles can be stopped with a sheet of paper
6 weeks, and at 1 year, the patient had cosmeti- (or skin). Therefore, the cutaneous radiation syn-
cally meaningful lengthening. Biopsies of the drome, which is associated with high-dose irradi-
scalp 2 years post-minoxidil treatment compared ation of the skin, is not a feature of exposure to
to those taken before treatment showed a signif- α-emitters, such as polonium, plutonium, and
icant decrease in telogen follicles and a reversal uranium. However, decay products of α-particles
of follicle miniaturization. Thus, oral minoxidil may emit β- and γ-radiation. External conta-
may be a treatment option for chemotherapy- mination with α-emitters can be eliminated
induced alopecia, especially permanent chemo- through undressing, careful hand-washing, and
therapy-induced alopecia. showering. α-Emitters may be responsible for
acute or chronic radiation sickness after enter-
Anagen Hair Loss Induced by Radiation ing the body through eating or drinking contam-
Humans can be exposed to several sources of inated material, through breathing contaminated
radioactivity: natural background radiation, air, or through an open wound. β-Radiation is
exposure to medical sources of radiation, radia- less ionizing than α-radiation but more than
tion from consumer goods, nuclear energy γ-radiation and can be stopped with a few cen-
derived, occupational or accidental exposure, timeters of metal. γ-Radiation has high penetrat-
and poisoning. Background radioactivity is ing power. X-rays have higher energy than
everywhere in our environment. The main visible light or ultraviolet but with lower energy
source of human exposure to radiation is caused than γ-radiation.
by medical actions, like X-rays, radioactive Hair disorders are not directly induced by
drugs, and radiation therapy. Consumer goods nonionizing radiation (i.e., thermal, radio waves,
microwaves, terahertz radiation, infrared light, sebaceous glands may result in a dry skin, and
and visible light), but thermal destruction of the increasing numbers of telangiectasia may become
skin may result in scar formation with visible as a late sign of radiation of the skin.
corresponding focal hair loss. Another late injury to the skin includes develop-
ment of chronic skin fibrosis, skin contraction,
Skin Changes Following Exposition to and in rare cases even dermal necrosis owing to
Radiation vascular damage and resulting in chronic ulcers.
A wide variety of expressions of radiation- Development of squamous cell carcinoma might
induced skin effects have been described after be a serious late complication of exposure of the
exposure to external high-dose ionizing radiation skin to irradiation.
(Geleijns and Wondergem 2005). There are four
clinical stages in acute radiation sickness after Hair Loss Following Exposition to Radiation
systemic exposure to radioactivity. The first is Radiation has a dose-dependent effect on hair
the “prodromal” phase, in which there is nausea, follicles. The response may vary from temporary
vomiting, anorexia, and, if the exposure is high anagen hair loss after exposure to low doses of
enough, diarrhea. Following the prodromal ill- radiation, via telogen hair loss after intermediate
ness, there may be a “latent” phase. This phase doses of radiation, to permanent hair loss follow-
may last from a couple of days to few weeks. The ing high doses of radiation. In general, temporary
patient usually looks better. Subsequently, the epilation begins 8–10 days after a single dose of
“manifest illness” stage develops with bone mar- irradiation and continues for 2–3 weeks, with full
row, GI, cardiovascular, and skin symptoms, hair regrowth from surviving cells in the germinal
including hair loss. Of course, systemic signs of matrix by 8–12 weeks (Sinclair et al. 2003). The
radiation sickness will often be absent in the cuta- doses required to induce epilation vary between
neous radiation syndrome which is associated different areas of the body. Scalp hair is much
with high-dose external irradiation of the skin. more sensitive to radiation than axillary hair,
Early transient erythema occurs a few hours after beard hair, pubic hair, and eyelashes. The dose
irradiation and reaches a peak value within 1 day. A of radiation necessary to cause alopecia will also
second and more severe erythema, accompanied by depend on the quantum energy of the respective
a sensation of heat and itching, develops after a type of radiation. The threshold for damage to hair
latent period of 8–10 days. The maximum severity follicles is lower than that for erythema. A dose of
is reached in 14–16 days and it subsides after 3–5 Gy of low-LET radiation (X-rays of γ-rays)
4 weeks. Dry desquamation may take place during delivered in a single, brief exposure can cause
subsidence and the skin may become pigmented. temporary epilation. The threshold for permanent
Depending on the dose, radiodermatitis, induced by epilation is higher, i.e., about 7 Gy in a single
killing of basal layer cells, may progress from dry exposure or 50–60 Gy fractionated over several
desquamation to the exudative phase of moist des- weeks (Rubin and Casarett 1968; UNSCEAR
quamation. Damage to skin appendages may 1982; Geleijns and Wondergem 2005). In clinical
become apparent during the second or third week, radiotherapy dose fractioning is employed. Epila-
resulting in loss of sweat and sebaceous glands, as tion is then dependent on both the daily dose and
well as in hair loss. the time interval between doses. Radiation to the
Recovery of the skin commences after the des- skull for oncological indications characteristically
quamation reaches a peak value and starts from ranges from 20 to 50 Gy in divided doses. These
islands of epidermal stem cells in the hair follicle patients develop alopecia which ought to be
or interfollicular epidermis. The recovered skin temporary.
may be hypoplastic/atrophic, shows both hyper- Incomplete regrowth or regrowth of hair with a
pigmentation and hypopigmentation, and can be different texture or color may happen occasion-
devoid of any appendages. Disappearance of ally. The hair may become gray or white, effects
354 B. S. Li et al.
which are usually associated with the killing or is sulfhydryl groups. Heavy metals weaken these
inactivation of melanocytes. The depigmentation bonds by formation of covalent bonds with the
effect is permanent. In contrast, increased pig- sulfhydryl groups, resulting in abnormal develop-
mentation that involves the hair follicles occurs ment of the hair shaft. In consequence, the hair
only with photon and particle radiation (Geleijns shaft becomes increasingly sensitive to fragmen-
and Wondergem 2005). tation. The binding of heavy metals not only
weakens the hair shaft but also provides a lasting
Hair Loss After Occupational Exposure to record of the long-term exposure to these sub-
Radiation stances. Just like the nail plate, the hair shaft
X-rays used in intervention radiology or cardiol- may serve as a recoverable memory for exposure
ogy may expose patients to relatively high doses to heavy metals in the past months to years.
of radiation of up to 6 Gy. Also occupational Many metals have the capability of causing
exposure to X-rays may reach high levels since hair loss. A couple of them are particularly noto-
interventional radiology techniques are being rious for inducing hair loss because of a more
used by an increasing number of clinicians. Not frequent exposure to them. In the past, thallium,
all are adequately trained in radiation safety and mercury, and arsenic were the heavy metals most
radiobiology. Skin and hair abnormalities in staff commonly responsible for causing hair loss.
and physicians performing interventional proce- However, also copper, cadmium, and bismuth
dures have been observed after cumulative radia- have been reported to cause alopecia in human
tion dose of 10–12 Gy (Wiper et al. 2005). in isolated cases (Sinclair et al. 2003). No reports
Depleted uranium is a waste product of the exist on negative effects of lead on hair growth.
manufacture of nuclear fuel and has several
civilian and military applications. It has low Anagen Hair Loss Induced by Thallium
specific radioactivity with dominance of α-radi- Thallium is an odorless, colorless, and tasteless
ation above β- or γ-radiation. Therefore, no heavy metal formerly used in rodenticides and
acute risk is attributed to external exposure to still used in some manufacturing processes. It is
depleted uranium. Claims of causing health used in the manufacture of optical lenses, semi-
effects among troops and local populations conductors, scintillation counters, low tempera-
who were present at locations where depleted ture thermometers and switching devices, green
uranium ammunition had been used during con- colored fireworks, and imitation jewelry and as
flicts appear to be unfounded, and hair loss has chemical catalyst. Up to the 1940s, the metal has
never been claimed (Bleise et al. 2003). Also been used for depilation of children with tinea
ingestion of drinking water containing high nat- capitis, and hair loss has been described in those
ural concentrations of uranium or inhalation of with dermal exposure to thallium-containing pes-
depleted uranium particles does not represent an ticides. Thallium is still used as a pesticide in
acute risk, even though uranium miners have a Africa and was found to be a contaminant in
well-documented risk of lung cancer some Chinese herbal medications. Occupational
(Saccomanno et al. 1996). exposure and toxicity has been described in the
vicinity of a cement plant due to emission of
Anagen Hair Loss Induced by Heavy Metals thallium-containing dust. The major route of
Formation of the hair shaft may be disrupted by intake was found to be the consumption of vege-
many heavy metals. Almost all causative factors tables and fruit grown in the vicinity of the cement
able to induce anagen hair loss share one charac- plant. However, in the cases no positive correla-
teristic: they abruptly stop normal cell division of tion was found between the thallium levels in hair
rapidly dividing hair matrix cells in the hair bulb. and urine and the prevalence of hair loss
However, the mechanism by which heavy metals (Brockhaus et al. 1981). Another industrial case
are responsible for hair loss is different. Physio- of chronic occupational exposure to thallium-
logically, the major binding power within keratin containing dust in a glass manufacturing company
was published in 1998. In this patient alopecia follicular plugging and the development of white
was the first sign of thallium poisoning, followed transverse lines on the nail plate (Mees’ lines)
by other signs of intoxication (Hirata et al. 1998). (Tromme et al. 1998; Lu et al. 2007). In severe
Thallium is toxic by cumulative intake; it can cases, cranial nerve involvement may also be
be absorbed through the skin, respiratory, and present. The prognosis for acute thallium toxicity
gastrointestinal tract. Poisoning can cause exten- is serious, having a mortality rate of 6–15%.
sive hair loss, which usually develops 1–3 weeks Among survivors 33–50% will have neurological
after an acute exposure but may begin after or ocular sequelae. The lost hair always regrows
months in chronic thallotoxicosis. The hair loss and there are no dermatological sequelae
affects the scalp, the temporal parts of the eye- (Tromme et al. 1998).
brows, the eyelashes, the limbs, and sometimes
the axillary regions (Tromme et al. 1998). 3.6.4 Diagnosis
Regrowth of hair will be complete and starts Physicians who see a sudden onset of painful
1–2 months later. Since thallium has been banned peripheral neuropathy and hair loss in patients
from use as a household rodenticide more than should prompt consider thallium exposure.
30 years ago, reports of thallium poisoning sug- A high concentration in the serum and urine
gest that nowadays exposure usually results from may confirm clinical suspicion. Exposure to
criminal and suicidal behavior or from thallium weeks to months earlier can be detected
unintentional or occupational exposure. Most by analysis of hairs and nails, since this metal is
cases of thallium toxicity occur after oral inges- stored in these appendages after ingestion (Daniel
tion, but severe toxicity has been reported after et al. 2004).
inhalation of contaminated dust from pyrite Microscopic examination of the hair roots by
burners, in zinc and lead smelting, in the manu- polarized light shows a distinctive but not specific
facture of cadmium, and after dermal absorption pattern. The tapered, distorted anagen roots are
through protective rubber gloves (Moore et al. described as black and visible from the fourth
1993; Hirata et al. 1998; Atsmon et al. 2000). day after poisoning. If poisoning occurs in suc-
Initial features of thallium poisoning may cessive doses, several black zones are found,
occur within several hours or can be delayed by corresponding to the growth of the surviving
12–14 h after ingestion. The initial symptoms are hair. Their intensity directly corresponds to the
nonspecific: gastrointestinal disturbances (nausea, degree of severity of the intoxication. However,
vomiting, epigastric pain, diarrhea). Fluid loss can their specificity is insufficient to allow either the
be substantial. Within few days neurological man- early diagnosis or the chronology of thallium
ifestations are apparent, involving the peripheral absorption. Whether the black color is caused by
(sensorimotor neuropathy, characterized by light diffracting gaseous inclusions or hyperpig-
severe hyperesthesia, primarily of the soles and mentations is not clear (Tromme et al. 1998).
palms) and/or central (confusion, disorientation,
lethargy, thirst, convulsions, psychosis, chorei- 3.6.5 Treatment
form movements, and cerebral edema with central The treatment options for thallium poisoning are
respiratory failure) and/or autonomic (tachycar- rather limited and have not evolved due to its
dia, hypertension, salivation, hyperhidrosis, dry relatively rare occurrence. Activated charcoal
skin) nervous systems. Skin lesions are com- has been reported to be effective in vitro in
monly present as a chronic effect of thallium adsorbing thallium and may in vivo interrupt its
poisoning, appearing few weeks after exposure. enterohepatic and enteroenteric recirculation.
Not only hair loss is characteristic but also ery- However, the effectiveness is controversial, as
thematous rashes on the cheeks and perioral well as the usefulness of hemodialysis,
region, acneiform and pustular eruptions, scaling hemoperfusion, and forced diuresis. Currently,
as well as hyperkeratosis of the palms and soles, Prussian blue (or “Berlin blue”), a crystal blue
stomatitis, and glossitis. Late skin signs are lattice of potassium ferric ferrocyanide, is
356 B. S. Li et al.
regarded as treatment of choice for thallium ingested. Although no adverse health effects
poisoning. It acts by forming a nonabsorbable have been proven, the use of dental amalgam is
complex with thallium, thus interrupting its declining rapidly. Amalgam may represent an
enterohepatic recycling and increasing its occupational risk for dentists and can cause
excretion. release of mercury to the atmosphere during
cremation.
Anagen Hair Loss Induced by Mercury Thiomersal (sodium ethylmercurithiosa-
Mercury is a silvery-white heavy metal that exists licylate or thimerosal), which contains 49.6%
as a liquid at room temperature. It exists in a ethylmercury, has been used as a vaccine preser-
variety of inorganic and organic forms that exhibit vative since the 1930s. As ethylmercury does not
variable absorption, excretion, and toxicity. Expo- accumulate and is actively excreted via the gut,
sure to mercury can lead to balding, which is the health risk from this exposure is low. Cinna-
ironic considering many who were first discov- bar, which contains mercury sulfide, has been
ered to be victims of mercury poisoning were used in Chinese traditional medicines and is a
“hatters” of the nineteenth century. A hatter was widely unrecognized source for mercury
a person who used the toxin to cure fur from intoxication.
which they made hats. These workers inhaled
mercuric vapors, which not only led to hair loss Diagnosis
but the development of dementia, thus the term Contrary to thallium poisoning, hair loss is a much
“mad hatter.” More recent victims of mercury rarer phenomenon in mercury poisoning. The few
poisoning include those who ingest large amounts publications that exist do not allow a detailed clin-
of seafood, as methylmercury is abundant in ical description. Some publications mention patchy
shellfish and in many types of fishes including alopecia, while others do not specify the type of
king mackerel, swordfish, and shark (Brodkin alopecia. The time frame between exposure to the
et al. 2007). poison and onset of the alopecia is not clear but
Exposure to mercury in industrial processes likely depends on the dose of the exposure (Richter
may occur in mercury recycling factories; mining et al. 1982; Schrallhammer-Benkler et al. 1992;
for mercury, gold (where mercury is used to form Haas et al. 2003).
an amalgam before being burnt off), and other Neurological and behavioral disorders may be
metals, such as copper, zinc, and silver; as well observed after inhalation, ingestion, or dermal
as from refining operations. Chronic exposure to application of different mercury compounds. Ele-
metallic mercury vapor appeared to be responsible mental and methylmercury are toxic to the central
for hair loss in workers in a thermometer factory. and peripheral nervous system. The inhalation of
Other complains were headache, irritability, and mercury vapor can produce harmful effects on the
wrist and ankle pain (Richter et al. 1982). nervous, digestive, and immune systems, lungs,
Most of the mercury in the environment results and kidneys and may be fatal. The inorganic salts
from human activity, particularly from coal-fired of mercury are corrosive to the skin, eyes, and
power stations, residential heating systems, and gastrointestinal tract and may induce kidney tox-
incinerators of (medical) waste. Significant icity if ingested. Symptoms include tremors,
releases of mercury to the environment result insomnia, memory loss, neuromuscular effects,
from the use of thermometers and blood pressure headaches, and cognitive and motor dysfunction.
monitors. Health-care facilities may be responsi- Mild subclinical signs of central nervous system
ble for as much as 5% of all mercuries released in toxicity can be seen in workers exposed to an
wastewater. elemental mercury level in the air of 20 μg/m3 or
Dental amalgam is a potentially significant more for several years. Kidney and immune
source of exposure since it can contain up to effects have been reported. There is no conclusive
50% elemental mercury. It is released as vapor, evidence linking mercury exposure to cancer in
ions, or fine particles and may be inhaled or humans.
Children are especially vulnerable and may be such as coal-fired power generation plants,
exposed directly by eating contaminated fish. burning vegetation, and volcanism (WHO
Methylmercury bioaccumulated in fish and con- (World Health Organization) 2010).
sumed by pregnant women may lead to Soluble inorganic arsenic is acutely toxic, and
neurodevelopmental problems in the developing ingestion of large doses leads to acute gastrointes-
fetus. Transplacental exposure is the most danger- tinal symptoms, disturbances of cardiovascular and
ous, as the fetal brain is very sensitive. Neurolog- nervous system functions, and eventually death. In
ical symptoms include mental retardation, survivors, bone marrow depression, hemolysis,
seizures, vision and hearing loss, delayed devel- hepatomegaly, melanosis, polyneuropathy, and
opment, language disorders, and memory loss. In encephalopathy may be observed.
children, a syndrome characterized by red and Chronic arsenic exposure to humans mainly
painful extremities called acrodynia has been occurs from the ingestion of arsenic contaminated
reported to result from chronic mercury exposure. water and food and is responsible for various
Also some autism spectrum disorders might be types of skin lesions such as melanosis,
the result of mercury exposure (Kazantzis 2002; leucomelanosis, and keratosis. While the skin is
Brodkin et al. 2007). most susceptible for the chronic effects of arsenic,
Biological measurement of mercury, for exam- other organs may also become intoxicated by
ple, in hair and blood, allows exposure to be chronic exposure to arsenic. Other manifestations
quantified and is linked to possible health effects. include neurological effects, obstetric problems,
Mercury levels in hair can be used as an indicator high blood pressure, diabetes mellitus, diseases of
of environmental exposure and may reflect the respiratory system and of blood vessels
chronic exposure to this heavy metal. including cardiovascular, and cancers typically
involving the skin, lung, and bladder (Rahman
Anagen Hair Loss Induced by Arsenic et al. 2009).
Arsenic is a metalloid widely distributed in the Arsenic levels in both hair and nails are ele-
earth’s crust. Arsenic and its compounds are vated within 1 to a few weeks after poisoning and
used as pesticides, herbicides, insecticides, and return to background levels within a few months.
in various alloys. Elemental arsenic is not solu- Toxic effects of arsenic on hair are frequently
ble in water, but arsenic salts exhibit a wide repeated in literature, but evidence and reports
range of solubility. Inorganic arsenic of geolog- are rare, indicating that hair loss is not an impor-
ical origin is found in groundwater used as tant feature of arsenic poisoning (Wakhlu et al.
drinking water in several parts of the world. 2003; Amster et al. 2007).
Arsenic trioxide is produced as a by-product of
metal smelting operations. It has been estimated Anagen Hair Loss Induced by Boric Acid
that 70% of the world arsenic production is used The element boron is a normal constituent of the
in timber treatment as copper chrome arsenate, diet and is frequently used in commercial products
22% in agricultural chemicals, and the remain- such as boric acid or the sodium salts of tetra-
der in glass, pharmaceuticals, and nonferrous coordinated borates. These include the anhydrous,
alloys. Mining, smelting of nonferrous metals, pentahydrate, and decahydrate sodium tetra-coor-
and burning of fossil fuels are the major indus- dinated borates. Borax is the commonly used
trial processes that contribute to anthropogenic name for decahydrate sodium tetraborate.
arsenic contamination of air, water, and soil. Although the medical uses of boric acid have
Historically, the use of arsenic-containing pes- gradually dropped, it is still widely used in multi-
ticides has left large tracts of agricultural land ple industries including laundering, fireproofing
contaminated. The use of arsenic in the preser- wood and fabric, manufacturing leather, and
vation of timber has also led to contamination of producing pottery glazed and enamel. It is also
the environment. Arsenic is emitted into the sold commercially as a household pesticide (Sin-
atmosphere by high-temperature processes clair et al. 2003).
358 B. S. Li et al.
In several reports acute systemic poisoning of boric acid ingestion appears to be 18–20 g in
from ingestion of boric acid has been recognized adults and 5–6 g in children.
as a cause of hair loss among other skin, gastro-
intestinal, and renal symptoms after suicide Treatment
attempts with boric acid powder and medications One reason that boric acid poisoning, particularly
but also with chronic exposure to consumer prod- the acute form, is so serious is that there is no
ucts such as mouth washer (Stein et al. 1973; effective antidote for it. Spontaneous or induced
Schillinger et al. 1982; Beckett et al. 2001). Hair vomiting and diarrhea aid in emptying the intesti-
loss occurs 10–14 days after ingestion of the toxin nal tract of the substance. To speed up the removal
and may be complete, indicating anagen hair loss of the boric acid before irreversible damage has
as the nature of the alopecia. The skin symptoms been done, exchange blood transfusions have
are intense erythema, desquamation, and exfolia- been utilized with success. Both peritoneal dialy-
tion and are sometimes referred to as a “boiled sis and hemodialysis may be effective. Symptom-
lobster” appearance. Also psoriasiform lesions atic treatment is advised for the skin exfoliation as
and bullae may appear (Schillinger et al. 1982). well as maintenance of a good fluid balance.
In case of chronic exposure, hair loss may also Despite these measures, boric acid poisoning
occur but is generally milder in nature but some- carries a high mortality rate (Schillinger et al.
times is the most obvious presentation of chronic 1982; Sinclair et al. 2003).
boric acid intoxication (Tan 1970).
Ingestion is the most common cause of borate Anagen Hair Loss Induced by Selenium
intoxication. However, boric acid in solutions can Selenium is a nonmetal element that serves vital
also be absorbed through the intact skin of roles in normal physiologic function. Substantial
humans. Cases of systemic toxicity in children, toxicity can occur with excessive selenium con-
some with alopecia, from medical application of sumption. Hair loss may occur few weeks after
boric acid-containing compounds as wound treat- ingestion of high doses of selenium, which often
ments have been described in the 1960s is preceded by gastrointestinal complaints. Also
(Skipworth et al. 1967). muscle cramps, joint pain, fatigue, paresthesias,
Although industrial boron compounds have a and difficulty with concentration have been
high toxicity and have been used for decades as an reported, similar to those associated with arsenic
additive to metalworking fluids, antifreeze/cool- and other metal toxicities. Massive hair loss and
ants, and other industrial materials, it has only discoloration of fingernails, nail loss, and Mees’
infrequently been reported to cause toxic alopecia lines have been attributed to acute selenium poi-
in the workplace. Occupational alopecia from soning from ingestion of paradise nuts (Muller
long-term skin and possibly inhalant exposure to and Desel 2010) and chronic intoxication with
borax-containing washing powder has been nutritional supplements (Sutter et al. 2008) but
reported (Tan 1970). The development of patchy also from occupational exposure to a selenium
alopecia from acute exposure to boric acid- alloy used for the manufacture and maintenance
containing fluids has been suggested, but causal- of drums used in photocopy machines (Srivastava
ity was heavily disputed by others (Beckett et al. et al. 1995). An endemic chronic selenium intox-
2001; Tosti et al. 2002). Direct skin contact with ication was reported from China where vegetables
borax in the dry or powdered form, such as in were contaminated with water-soluble coal-
borax mining or processing, has not been associ- derived selenium in the soil (Yang et al. 1983).
ated with hair disorders. Clinically, the diffuse hair loss resembles alopecia
areata, but the Mees’ lines in the nails are typically
Diagnosis for an intoxication.
The diagnosis can be made by measuring blood Hair loss has been attributed to the disruption
boric acid levels: normal values are up to 0.3 mg of structural proteins in keratin. Similar to alope-
per 100 ml blood as boron. The acute lethal dose cia induced by heavy metals, selenium is thought
to interpolate into disulfide bridges, causing struc- colchicines induces telogen hair loss instead of
tural weakness that leads to hair loss. The hair loss anagen hair loss (Van Dooren-Greebe et al. 1994).
is completely reversible, and regrowth will start The list of drugs accused of being responsible
few months after discontinuation of the for hair loss is infinite and not the primary scope of
intoxication. this chapter. Frequently used drugs with relatively
high frequency of hair loss are ACE inhibitors,
Diagnosis amiodarone, amantadine, anticoagulants of all
Selenium levels can be determined in hair, blood, kinds, anticonvulsants, antiestrogens and aroma-
and urine (Yang et al. 1983). tase inhibitors, antiretroviral drugs, antithyroid
drugs, β-blockers, cholesterol-lowering drugs,
cimetidine, colchicine, some cytokines, etretinate
4 Telogen Hair Loss and vitamin A, heavy metals, hormones, isotreti-
noin, interferons, ketoconazole, leflunomide, lith-
Telogen hair loss is the result of a premature con- ium, penicillamine, propranolol, thiamphenicol,
version of a growing anagen hair into a resting and valproic acid (Tosti and Pazzaglia 2007; Tosti
telogen hair, which will be shed few months later. et al. 1994; Kimyai-Asadi et al. 1999; Scott et al.
Recognized factors able to induce telogen are thy- 2001; Trefzer et al. 2003; Luther and Glesby 2007;
roid dysfunction, pregnancy, hormonal contracep- Litt 2007). It has not been studied whether all these
tion, hormone replacement therapy, weight loss, drugs cause telogen type of hair loss - other mech-
and deficiency of essential fatty acids, iron, zinc, anisms resulting in effluvium may also be involved.
or biotin. Also physiological stress like fever, sys-
temic illness, and surgery and extreme psycholog-
ical stress are inducers of telogen hair loss. 4.1 Diagnosis
Many drugs have been reported to cause hair
loss. Antineoplastic drugs commonly are respon- Determining the etiology of diffuse alopecia is
sible for predictable acute anagen hair loss which always time consuming. Diagnostic tools for clin-
commences about 2 weeks after onset of the ther- ical evaluation of hair loss have been discussed
apy (see above). Other drugs may force the grow- above and apply unrestrained for telogen hair loss.
ing anagen hair to enter the telogen phase, The mechanism involved in developing telogen
resulting in telogen hair loss several months after hair loss is forcing growing anagen hair into rest-
the medication was started. The prevalence and ing telogen hair. The fate of these telogen hairs is
severity of alopecia depend on the drug as well as the normal fate of any telogen hair: shedding after
on individual predisposition. Some drugs cause 2–5 months. Therefore, a clinical history should
hair loss so uniformly that the relationship is con- start months before the shedding has started and is
vincing. Other drugs have been reported only the cornerstone leading toward a correct diagno-
occasionally to be able to induce telogen hair sis. At the pull test, an increased number of hairs
loss, and the causal relationship sometimes is can be detached from the hair follicles. In normal
doubtful. Transient shedding typically begins circumstances the number of extracted hairs will
2–5 months after the inciting event, and after not exceed five to six, and analysis by light
discontinuation of the responsible drug, the hair microscopy will reveal that all of these hairs are
cycle will be normalized only several months later telogen (Fig. 1a). In case of a positive pull test, the
because the hairs that already have entered the absence of anagen hair with a necrotic anagen
telogen phase will be shed before clinical normal- sheath adhering to them and the absence of
ization can occur (Paus and Cotsarelis 1999). tapered hair allows to differentiate telogen hair
Antimitotic agents given in high doses usually loss from anagen hair loss (Fig. 1c). However,
induce anagen hair loss; however, some follicles the hair pull test is only a rough approach, which
may later show a telogen effluvium. Sometimes appears to be useful only in acute and more severe
low dose of antimitotic agents methotrexate and phases of hair loss.
360 B. S. Li et al.
4.2 Treatment its toxic effects, its environmental persistence, and

its concentration in the food supply led to use
In general, the prognosis for regrowth is excellent restrictions and prohibition. DDT continues to be
if the provoking factor can be assigned and elim- used for malaria control in several African and
inated. After cessation of the provoking factor, Asian countries. Hair diseases are rarely promoted
regrowth may take several months because shed- by DDT; however possibly pesticide-related dif-
ding of telogen hairs is determined months before, fuse hair loss was described in a farmer spraying
at the moment the hair follicle leaves the growing DDT (Spiewak 2001).
anagen phase and enters the resting telogen phase. Hair loss due to exposure to dipyridyl herbi-
cides paraquat and diquat has not been reported in
humans. Local overexposure to paraquat may
5 Mixed Types or Undetermined cause reversible leukonychia of the nail plate
Types of Hair Loss and irritative skin reactions.
The fungicides with substituted benzene,
5.1 Hair Loss Induced by Pesticides chloroneb, and chlorothalonil are well known to
cause local irritant dermatitis. No reports exist on
Acute poisoning with pesticides is a global public any role thiocarbamates may play in induction of
health problem and accounts for as many as hair loss. Occupational exposure to organomercurial
300,000 deaths worldwide every year, mostly fungicides may play a role in development of hair
occurring in rural areas of the Asia Pacific region, loss, because methylmercury and phenylmercuric
where easy access to highly toxic pesticides turns acid contain mercury. This topic is discussed in
many impulsive acts of self-poisoning into suicide detail above.
(Eddleston and Phillips 2004). Not only suicide Metaldehyde, a cyclic tetramer of acetalde-
attempts but also unintentional exposures to pes- hyde, is a widely used molluscicide. Intoxication
ticides are responsible for intoxications (Spiewak with metaldehyde is exceptional, and toxicity
2001). Intoxications with pesticides have a broad from metaldehyde is largely mild, but the clinical
spectrum of clinical manifestations, including der- course of metaldehyde poisoning may be rapidly
matological symptoms and hair loss. Pesticides deteriorating and fatal on rare occasions. How-
are classified into insecticides, herbicides, fungi- ever, alopecia does not appear to be one of the
cides, molluscicides, rodenticides, and insect features of acute metaldehyde intoxication in
repellants. humans. Chronic metaldehyde intoxication
The insecticide albendazole is known to induce induces some alopecia in rats (Verschuuren et al.
reversible hair loss, but these reports derive from 1975).
its therapeutic use in humans and not from occu- Many chemically unrelated rodenticides are
pational exposure (Saimot 2001). Pyrethroids are used worldwide. Rodenticides containing the
the most frequently used indoor insecticides. heavy metal thallium are very well known to be
Exposure following indoor treatments with a dog able to induce massive alopecia. This topic is
flea powder was reported to lead to hair loss, most extensively discussed above. Aluminum phos-
likely alopecia areata, and gastrointestinal symp- phide and zinc phosphide are highly toxic roden-
toms in one patient (Schulze et al. 2002). Consid- ticides but without reported alopecia-inducing
ering the fact that this patient already had had a capacities. Warfarin and superwarfarin are roden-
period of complete baldness before exposure to ticide compounds with anticoagulative effects.
the insecticide, one might doubt about the role the Used as a drug, coumarins are reported to induce
pyrethroids did play in this case. No hair loss has telogen hair loss in a high proportion of users
been reported relating to human exposure to (Leong 2008). Occupational exposure to couma-
organophosphate or organochlorine insecticides. rins leading to hair loss has never been reported.
Dichlorodiphenyltrichloroethane (DDT) was used The rodenticide yellow phosphorus does not
worldwide until the 1970s, when concerns about appear to be able to induce hair loss. June 2007,
2484 persons were exposed to fume of yellow St John’s wort (Hypericum perforatum) is
phosphorus due to an accident of a Ukraine freight widely consumed since it has been proven to
train. Alopecia turned out to be no typical feature relieve symptoms associated with mild to moder-
of exposure to this fume (Badiugin 2009). Also ate depression. One case of hair loss has been
reports of suicide attempts with oral ingestion of attributed to the consumption of this popular
yellow phosphorus do not mention development herb, occurring several months after initiating
of hair loss (Tafur et al. 2004). St John’s wort. Microscopic analysis of hairs
The frequently used insect repellent diethyl revealed a mixed telogen and anagen morphology
toluamide (DEET) may have several dermal side that suggests rather a drug reaction than a
effects, like hives, rash, itching, redness, and swell- newly developed alopecia areata (Fig. 1) (Parker
ing. However, hair loss has never been attributed to et al. 2001).
the use of this compound (Osimitz et al. 2010). Hair loss has also been described after the
consumption of Leucaena leucocephala. This
is a species of small mimosoid tree that is
5.2 Hair Loss by Plant Toxins native to southern Mexico and northern Central
America (Belize and Guatemala). Common
Hair loss has been reported after poisoning with names include white leadtree, jumbay, and white
several plants. Hair loss after acute poisoning with popinac. Responsible for hair loss appears to be
autumn crocus, also known as meadow saffron or the alkaloid, β-3-hydroxy-4-pyridone amino acid
Colchicum autumnale, is the result of colchicine leucenol, also known as leucenine or mimosine,
intoxication (Brvar et al. 2004). Colchicine is a which can be found in growing tips, young leaves,
highly active alkaloid which is also used in the and seeds of this plant (Crounse et al. 1962; Luo
treatment of gouty arthritis, pseudogout, familial et al. 2000).
Mediterranean fever, and Behçet’s disease. Colchi- Cinnamon is the bark of the Cinnamomum
cine poisoning is a rare event which is characterized zeylanicum tree. True cinnamon is a native of Sri
by multiorgan involvement and a poor prognosis. Lanka and grows almost exclusively in this coun-
Hair loss is not the predominant feature but will try. It contains cinnamic aldehyde, which is an
occur in course of the history if the patient survives. irritant. Workers processing cinnamon are
The course typically shows three phases: initially exposed to much cinnamon dust. Uragoda inves-
gastrointestinal symptoms predominate, and in the tigated 40 cinnamon workers. Thirty-five of them
second phase, multiorgan failure may occur possi- had symptoms, 26 complained of loss of weight, 9
bly leading to death. In case the patient survives, the having asthma, 20 skin irritation, and 9 smarting
third phase of recovery follows in which the patient of the eyes while at work. Loss of hair was present
always presents with hair loss (Bismuth et al. in 15, so 37.5%, much more in women (57%) than
1977). This hair loss may occur weeks to months in men (21%) (Uragoda 1984). The hair loss was
after the intoxication, indicating telogen hair loss. mild and “did not alter their appearance.” A con-
However also cases with hair loss 1–2 weeks after trol group was not investigated, so the relative
the poisoning have been reported, indicating acute contribution of the cinnamon dust to the hair
disruption of hair shaft formation, so anagen hair loss, as well as the mechanism involved remains
loss (Atas et al. 2004; Bicer et al. 2007). to be illuminated.
Ingestion of the nut of coco de mono
(Couroupita nicaraguarensis) is an even rarer
cause of alopecia than autumn crocus; this wooly 5.3 Hair Loss in Semiconductor
plant is on the red list of threatened species. It Workers
belongs to the Lecythidaceae family and can only
be found in Colombia, Costa Rica, Ecuador, El In 1995, McCurdy et al. published a cross-sectional
Salvador, Nicaragua, Panama, and Puerto Rico survey among 3175 semiconductor industry
(Kerdel-Vegas 1964; Sinclair et al. 2003). workers. Alopecia was not defined properly but
362 B. S. Li et al.
was reported to be more common in the fabrication The toxic oil syndrome has been linked to the
room than in the nonfabrication room workers ingestion of oil mixtures containing rapeseed oil
(RR = 2.44). Alopecia showed a dose-response denatured with aniline. Aniline itself did not cause
relationship with isopropanolol and fluoride, the illness, but putative etiologic agents of toxic
although the authors concluded that the relationship oil syndrome are 3-(N-phenylamino)-1,2-pro-
between work exposures and alopecia was not panediol 1,2-dioleoyl ester, 3-(N-phenylamino)-
obvious (McCurdy et al. 1995). 1,2-propanediol 1-oleoyl ester, N-(5-vinyl-1,-
3-thiazolidin-2-ylidene)phenylamine, and
1-phenyl-5-vinyl-2-imidazolidinethione. How-
5.4 Hair Loss Induced by Sanitary ever, the precise identity of the etiologic agent
Cleaners has never been identified.
Exposition to drain and sanitary cleansing vapors

containing sodium hypochlorite and sodium 5.6 Localized Hair Loss
hydroxide was reported to provoke alopecia on
the scalp and beard region within 3–4 days after 5.6.1 Alopecia Areata
exposure which lasted for a period of 4 weeks. The Alopecia areata commonly presents as localized
alopecia was preceded by dermatitis of the scalp. patches of baldness. However, also diffuse alope-
The prerequisite for the exposure was the improper cia areata may occur. Clinically, the latter resem-
use of cleansing agents and other conditions which bles anagen or telogen hair loss, but the hair pull
lead to intense exposition of the scalp to sodium test contains both telogen and tapered dystrophic
hypochlorite vapor. A possible chemical reaction anagen hairs (Fig. 1). It is generally assumed that
between cleansing agent and dirt may have been alopecia areata is an immune mediated form of
responsible. Hair loss was caused by breakage of hair loss in which an autoimmune lymphocytic
the hair fiber within the hair follicle. Additional attack on the hair bulb takes place. The antigen
genital hair loss arose after sodium hydroxide use. which triggers the immune system remains
Body and scalp hair was completely restored after unidentified. Several factors have been shown to
1 year (Stuttgen et al. 1982). play a role in disease susceptibility and severity.
Genetic factors like an atopic diathesis, a positive
family history for alopecia areata, or Down syn-
5.5 Hair Loss in Toxic Oil Syndrome drome increase susceptibility to develop alopecia
areata and may indicate a protracted course. Also
In the spring and summer of 1981, an epidemic of environmental triggers may be important in dis-
a new illness occurred in central and northwestern ease expression but are partly speculative. Infec-
Spain, resulting in some 20,000 cases, 12,000 tions, vaccinations, desensitizations, emotional
hospital admissions, and more than 300 deaths in stress, and anxiety have all been implicated
the first year of the epidemic. The initial onset of (Madani and Shapiro 2000).
illness was usually acute, and patients presented
primarily with a respiratory syndrome. Half of Alopecia Areata as an Occupational Disease
patients recovered from this phase without appar- Whether occupational exposure to chemicals can
ent sequelae; the remaining patients developed induce alopecia areata or not is a matter of dispute.
an intermediate of chronic phase of illness Alopecia areata is common in 1.7% of the studied
involving severe myalgia, eosinophilia, peripheral population (Safavi et al. 1995). Therefore, it is not
nerve damage, sclerodermiform skin lesions, easy to prove an assumed cause and effect rela-
sicca syndrome, joint contractures, and alopecia tionship between a factor and the development of
(Kilbourne et al. 1991). The presence of alopecia alopecia areata. Occupation exposure to an acryl-
turned out to be predictive of outcome (Kaufman amide-like substance in a paper factory and to a
et al. 1995). selenium alloy has been suggested to play a role in
development of the disease (Srivastava et al. Trichophyton verrucosum is the usual cause of
1995; Roselino et al. 1996). Acrylamide is used ringworm in cattle throughout the temperate
as a water treatment agent and in the manufacture regions of the world and has been reported in
of adhesives, dyes, and fabrics. Beckett et al. parts of Europe including England, the USA,
reported an association between alopecia areata Canada, Iran, Australia, and New Zealand. There
and occupational topical exposure to borax- have been reports of isolations from horses, sheep,
containing solutions, but many experts in the dog, donkeys, an ass, a dromedary, and a goat
field disagreed with their conclusion (Beckett (Maslen 2000). Authors from Italy, Iran, and Aus-
et al. 2001; Tosti et al. 2002). tralia reported several cases of infection due to
Trichophyton verrucosum after working with
5.6.2 Tinea Capitis horses and cattle (Maslen 2000; Roman et al.
The introduction of griseofulvin in the late 1950s 2001; Aghamirian and Ghiasian 2011). In 2009
resulted in a largely disappearance of ringworm of Aghamirian and Ghiasian reported a prevalence
the head, tinea capitis, from the Western world. of dermatophytosis in over 20% in Iranian herds-
Over the past years, a large increase has been men, mostly with the zoophilic Trichophyton
noted in tinea capitis in Europe and North Amer- verrucosum as the prevalent causative agent,
ica. Alopecia resulting from infectious causes is confirming previous studies (Chadeganipour
most commonly focal and patchy. The predomi- et al. 1997; Aghamirian and Ghiasian 2011). So
nant fungi causing tinea capitis in a given area of Trichophyton verrucosum is a common cause of
the world depend on the dermatophyte species human ringworm and tinea capitis in rural areas,
that are circulating among the people or animals and infections are contracted directly or indirectly
in that area or are present in the soil. Most cases of from cattle. Not only dairy and cattle farmers and
tinea capitis occur in prepubertal children, but its their family can be involved but also
incidence among adults is increasing, in particular slaughtermen who work in an abattoir and labo-
among patients over 60 years of age. ratory assistants working with infected calves, and
Depending on geographical region, Tri- even Trichophyton verrucosum infection in a vet-
chophyton tonsurans (USA, UK, and Brazil) and erinary tutor has been reported. Apart from an
Microsporum canis (Central and Southern epidemic reported in 47 cattle keepers in Finland,
Europe) are the most relevant causes for tinea infections generally are sporadic (Lehenkari
capitis among man (Fuller 2009). Trichophyton and Silvennoinen-Kassinen 1995). Infection
tonsurans spreads directly from child to child at among animals can be largely controlled by vac-
home, school, or the hairdresser. However, Micro- cines. Occupational mycoses caused by other
sporum organisms and Trichophyton verrucosum Trichophyton species, Trichophyton mentagro-
are the most relevant fungi responsible for occu- phytes, and Trichophyton quinckeanum, with
pational tinea capitis, because they are transmitted mice as vector, were found in Eastern Europe
primarily from animal to human (zoophilic). (Balabanoff 1985).
Microsporum canis can be transferred by an
infected puppy or, more often, kitten. Tri- Clinical Features
chophyton verrucosum can be obtained from The morbidity of tinea capitis is significant. It may
infected cattle. Spontaneous resolution in humans cause local symptoms of inflammation, hair loss,
is the rule; however, transfer to other people may pain, pruritus, and kerion formation. Also consti-
occur, and damage to the scalp may be permanent, tutional symptoms, social embarrassment, and
so hairless areas may remain bald forever. secondary bacterial infections can be found.
The skin of the scalp may be red, swollen,
Tinea Capitis as an Occupational Disease tender, and warm as signs of local inflammation,
Tinea capitis and tinea barbae have been reported but clinical diagnosis can be difficult as signs of
to be transferred by cattle and horses, especially inflammation may be missing. Therefore, the
animals under 2 years of age raised in stables. diagnosis may be overlooked by inexperienced
364 B. S. Li et al.
clinicians. The presenting features can be divided immediate identification of the spores and hyphae
into six main patterns (Fuller et al. 2003). and thus confirms the diagnosis of tinea capitis.
Gray type: Circular patches of alopecia with Only culturing will allow definitive determination
marked scaling. of the species and its potential resistance for
Black dot: Swollen stubs of broken off hairs are antifungal treatments. However, this may take
visible within the patch of alopecia. The hair several weeks.
shafts break off because they become vulnerable
through invasion by the dermatophyte. Treatment
Kerion: Boggy, localized swelling occurs due Spontaneous remission of Microsporum canis and
to an aggressive inflammatory response to the kerions has been recognized. However, treatment
fungus. Concomitant cervical lymphadenopathy of all forms of tinea capitis is generally accepted
is common. because of the morbidity involved and risk of
Diffuse scale: Clinically resembles dandruff transmission (Seebacher et al. 2004; Gupta et al.
which covers the whole scalp. 2005; Fuller 2009). Topical antifungal prepara-
Moth eaten: Patchy hair loss. In contrast to tions are unable to penetrate the hair shaft suffi-
luetic alopecia, the scalp may be generally scaly. ciently to clear the infection. Therefore, systemic
Diffuse pustular pattern: This type is hardest to treatment for 6–12 weeks is unavoidable. Oral
diagnose with its widespread scattered pustules on griseofulvin in a daily dose of 10–25 mg/kg per
the scalp and its brisk inflammatory response but day is the classical treatment, but there is evidence
only sparse presence of fungus. Similar to kerion, of emerging resistance. Microsporum audouinii,
a simultaneous cervical lymphadenopathy is com- Microsporum canis, and Trichophyton violaceum
mon. It often is misdiagnosed as a bacterial appear to be more sensitive to griseofulvin than
infection. Trichophyton tonsurans. The latter may need the
higher advised daily dose.
Diagnosis In the 1980s new oral antifungal drugs were
Traditionally, the Wood’s lamp is used to diagnose introduced. The oral azoles ketoconazole
fungal infections of the skin and its appendages. (200–400 mg daily in adults), fluconazole
The Wood’s lamp shines ultraviolet light onto the (6–8 mg/kg daily), and itraconazole (100–200 mg
skin of the patient. In many fungal infections, daily in adults) were found to be effective for der-
fluorescence becomes visible. Microsporum matophyte infections. The oral allylamine
infections can be detected this way, since the terbinafine (250 mg daily in adults) is effective
fungal spores form a sheath on the outside of the against all dermatophytes, although moderately so
hair shaft and light green upon exposure to ultra- for Microsporum species. While fungistatic treat-
violet radiation. In contrast to these so-called ment with oral griseofulvin may take several
ectothrix infections of the hair, no fluorescence months, azoles and terbinafine are fungicidal and
can be detected in endothrix infections with Tri- commonly are used for 1–2 months. Termination of
chophyton tonsurans, where the spores reside treatment must always depend on mycological cure.
inside the hair shaft and there is no fluorescence None of the newer antifungal drugs is specifically
(Fuller 2009). EMEA or FDA approved for tinea capitis, and only
Since absence of fluorescence after shining fluconazole is FDA approved for use in children.
with the Wood’s light does not rule out a tinea The parallel use of antifungal creams or sham-
capitis, the diagnosis often relies upon mycologi- poos is often advised to reduce the risk of progres-
cal analysis of scales and broken off infected sion and transmission while waiting for the onset
hairs. Material for analysis can be collected by of action of the oral treatment. Most commonly
scraping off scales or brushing with a toothbrush ketoconazole shampoo or selenium sulfide is used
or cytobrush. Both microscopy with 10% potas- for daily adjunctive therapy for a period of
sium hydroxide (KOH) and culture can be used to 2 months. Preventive daily use of ketoconazole
detect the fungus. Microscopy will allow shampoo is a recommended topical therapy for
close contacts and an appropriate health measure. interferon alpha-2b, bimatoprost, cyclosporin, and
It is also important to discard or disinfect with tacrolimus (Jayamanne et al. 1996; Woo and Francis
bleach objects that may support fungal conidia, 2001; Hernandez-Nunez et al. 2002; Herane and
such as combs, hats, pillow, blankets, and Urbina 2004; Ward et al. 2006).
scissors.
5.7.2 Hypertrichosis and Hirsutism
Nurse’s Cap Alopecia Hirsutism and hypertrichosis are characterized by an
Prolonged traction due to religious or traditional excess of terminal hair. In hypertrichosis this excess
customs and cosmetic hairstyles imposes physical is localized or generalized, while in hirsutism there
stress on the hair follicle and results in a well- is excess of terminal hair in females and children
delineated form of traumatic alopecia known as with an adult male pattern of distribution. Hirsutism
traction alopecia. Traction alopecia associated is a distressing and relatively common problem,
with the nurse’s cap is a form of occupational affecting 5–10% of women in the reproductive age
hair loss which should be taken into consideration group. It is usually a sign of androgen excess, the
in the differential diagnosis of patchy alopecia. In commonest cause being the polycystic ovarian syn-
countries where wearing a nurse cap is the rule, an drome. Both hirsutism and hypertrichosis may be
incidence of 3.5% has been described (Hwang associated with drug administration. Drugs most
et al. 1999). commonly responsible for the development of hir-
Clinically it is characterized by circumscribes, sutism include testosterone, danazol, ACTH,
rectangular, symmetric, and bilateral hair loss on metyrapone, anabolic steroids, and glucocorticoids
the parieto-occipital scalp where the nurse cap is (Hosea et al. 1980; Tosti and Pazzaglia 2007).
secured. On close inspection, the lesions show a Hypertrichosis is a common adverse event of cyclo-
decrease in density of follicular orifices. Peri- sporine, prostaglandin analogs, minoxidil, and
follicular erythema, follicular hemorrhage, follic- diazoxide (Tosti and Pazzaglia 2007).
ular pustules, scales, and diffuse erythematous
swelling may also be observed. Avoidance of 5.7.3 Hair Changes Caused by
traction will only result in partial improvement, Ultraviolet Radiation
because the number of hair follicles is reduced due Exposure to ultraviolet radiation damages hair
to persistent traction. fiber. Dryness, reduced strength, rough surface
texture, loss of color, decreased luster, stiffness,
and brittleness of hair are caused by sun exposure.
5.7 Hair Disorders with Increased Photochemical degradation of hair results in
Hair Growth attack on both hair proteins and melanin. Destruc-
tion of hair protein is thought to be the result of
5.7.1 Trichomegaly UVB-induced oxidation of sulfur-containing mol-
Trichomegaly means excessively large eyelashes. ecules within the hair shaft (Santos Nogueira and
This may be part of a congenital syndrome or HIV Joekes 2004). Destruction of melanin within the
infection but also was reported to be induced by cortex of the hair has been studied extensively in
epidermal growth factor receptor (EGFR) inhibitors wool, where it is known as photoyellowing and is
erlotinib, cetuximab, and panitumumab. Hair abnor- more pronounced for light-colored hairs. It
malities were reported in almost 90% of patients appears to be caused by UVA through oxidation
using EGFR inhibitors. Trichomegaly was found of the amide carbon of polypeptide chains produc-
in 62% of patients, male pattern-like alopecia ing carbonyl groups (Muller et al. 2003; Nogueira
appeared in 44% of patients, diffuse alopecia in et al. 2004; Santos Nogueira and Joekes 2004).
19%, and over 80% complains of changes in the Trüeb postulated in 2003 that androgenetica
texture of their hair: more brittle, finer, curlier, alopecia might be a photoaggravated dermatosis
unruly, or straighter (Osio et al. 2009). Tri- (Trueb 2003). Definite evidence, however, is still
chomegaly may also be induced by latanoprost, lacking.
366 B. S. Li et al.
5.7.4 Changes in Hair Color Balabanoff VA (1985) Berufliche Dermatomykosen

Hair color changes result not only from alterations zoophilen Ursprungs in Bulgarien. Derm Beruf
Umwelt 33:170–174
of melanin production but also from changes in the Beckett WS, Oskvig R, Gaynor ME, Goldgeier MH (2001)
hair structure itself, altering its optical properties. A Association of reversible alopecia with occupational
variety of genetic, metabolic, nutritional, and topical exposure to common borax-containing solu-
acquired disorders result in hair color changes. tions. J Am Acad Dermatol 44:599–602
Bicer S, Soysal DD, Ctak A, Ucsel R, Karabocuoglu M,
Most drug-induced changes in hair color result in Uzel N (2007) Acute colchicine intoxication in a child:
lighter hair color, although PABA and some che- a case report. Pediatr Emerg Care 23:314–317
motherapy regimens have darkened hair (Cline Bismuth C, Gaultier M, Conso F (1977) Aplasie médullaire
1988). Exposure to copper from domestic water aprés intoxication aiguë à la colchicine. Nouv Press
Med 6:1625–1629
or cosmetics may result in green discoloration in Bleise A, Danesi PR, Burkart W (2003) Properties, use and
blond, gray, or white hair. In those who develop health effects of depleted uranium (DU): a general
this from swimming pools, the copper can be overview. J Environ Radioact 64:93–112
from copper-based algaecides, corrosion of pipes, Brockhaus A, Dolgner R, Ewers U, Kramer U, Soddemann
H, Wiegand H (1981) Intake and health effects of
and/or a low pH that allows leaching from copper thallium among a population living in the vicinity of a
pipes (Mascaro et al. 1995). An outbreak of green cement plant emitting thallium containing dust. Int
hair was reported secondary to fluoridation tap Arch Occup Environ Health 48:375–389
water that lowered the water pH from 8.0 to 5.8. Brodkin E, Copes R, Mattman A, Kennedy J, Kling R,
Yassi A (2007) Lead and mercury exposures: interpre-
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copper pipes can also cause leakage of copper soning with autumn crocus (Colchicum autumnale L.).
into the water (Nordlund et al. 1977). Metal expo- Wien Klin Wochenschr 116:205–208
Cascinu S, Del FE, Ligi M, Graziano F, Catalano G (1997)
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Oncol 20:477–478
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Pigment Disorders
27
Maryam Yazdani
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
2.1 The Epidermal Melanin Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
3 Melanogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
4 The KLM Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
5 Skin Types and Ethnic Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
6 Hyperpigmentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
6.1 Post-inflammatory Hyperpigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
7 Hypopigmentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
7.1 Post-inflammatory Hypopigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
8 Dyschromia Cutis/Discoloration of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
8.1 Bleaching Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
8.2 Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
8.3 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
8.4 Impact of the Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
8.5 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
8.6 Koebner Phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
8.7 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
8.8 Chemical-Induced (Occupational) Vitiligo and Leukoderma . . . . . . . . . . . . . . . . . . . . 380
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Keywords Hypopigmentation · Repigmentation therapy ·

Vitiligo · Monobenzone · Chemical Tyrosinase · Melanin · Melanocyte loss ·
leucoderma · Rhododendrol · Pigmentation · Whitening agents · Melanogenesis ·
Depigmentation · Hyperpigmentation · Autoimmunity · Oxidative stress · Phenol ·
Cathechols · Phytophotodermatitis · Pigment
disorders
M. Yazdani (*)
van Altena & de Jongh bedrijfsartsen bv, Amsterdam,
The Netherlands
e-mail: m.yazdani@live.nl

https://doi.org/10.1007/978-3-319-68617-2_27
372 M. Yazdani
1 Core Messages Table 1 Determinants contributing to skin color

Melanin associated Others
• Darker skin types are more prone to exogenous Melanin: Capillary blood flow and
pigmentary changes. Eumelanin (Black and its components variation:
• The most common exogenous hyper- dark brown) Oxyhemoglobin (Red),
Pheomelanin (Yellow, reduced hemoglobin
pigmentation is post-inflammatory. red, and light brown) Hemosiderin (Brown)
• Occupational pigmentary changes predomi- In: Carotene (Orange/
nantly consist of chemically induced hypo-/ Melanocytes Yellow)
depigmentations. Keratinocytes Lycopene (Red)
Dermal macrophages Bilin (Yellow)
• Chemical leukoderma is characterized by (melanophages) Chemicals or drugs
depigmentation on the area of contact with a Quantity of melanin Transparency of stratum
chemical versus chemical-induced vitiligo in Number, size, and corneum and epidermis
which the depigmentation spreads beyond the distribution of Light reflection,
melanosomes in the refraction, and absorption
areas of contact. keratinocytes to skin
• Most known and inducing chemicals are phe- Systemic, endocrine
nols which act as tyrosine analog disrupting diseases, DNA defects
melanocyte function–inducing autoimmunity. The balance between the carotene, hemoglobin, and most
• Chemical-induced vitiligo and chemical important melanin are the main determinants of the natural
skin color (Meys 2017)
leukoderma are rare in Western countries but
quite common in developing countries due to
lack of product and safety control. Nordlund et al. 2006; Nordlund 2007; Ansty
2010; Yamaguchi and Hearing 2014).
In 1963, Fitzpatrick and Breathnach proposed
the concept of the epidermal melanin unit, which
2 Introduction describes the interplay of epidermal melanocytes
and keratinocytes in constituting the color of
2.1 The Epidermal Melanin Unit the skin. One melanocyte produces melanin for
approximately 36 surrounding keratinocytes by
Skin color is determined by many factors (Table 1) delivering to their neighboring cells melano-
of which melanocyte derived epidermal melanin is somes, cell membrane enveloped organelles in
the most important. The melanocyte is a dendritic which melanin is produced and stored (Nordlund
cell present in the basal layer of the epidermis with and Ortonne 2006; Nordlund et al. 2006;
no desmosomes or tonofilaments. Melanocytes Nordlund 2007; Ansty 2010).
arise from the neural crest as melanoblasts and
migrate to the dermis, hair follicles, leptomeninges,
uveal tract, and retina. By the eighth week of intra- 3 Melanogenesis
uterine life, they start to migrate from the dermis to
the epidermis and this process will be completed Melanogenesis, the production of melanin within
prior to birth (Nordlund and Ortonne 2006; melanocytes, takes place in cell organelles called
Nordlund et al. 2006; Nordlund 2007; Ansty melanosomes. The melanosomes are transferred
2010; Yamaguchi and Hearing 2014). to the surrounding keratinocytes in order of 1
The hypopigmentation of the palms and melanocyte versus 36 keratinocytes, called an
soles is the result of early stagnation of melano- epidermal melanin unit. Basically, two types of
cytes migration during the embryogenesis, which melanin can be produced, the black-brown
results in a fivefold lower density of melanocytes eumelanin and red-yellow pheomelanin. The
in these areas. Some melanocytes can be left in photoprotective eumelanin predominant in darker
the dermis as can be seen in mongoloid spots skin types is synthesized from tyrosine, and
and nevus of Ota (Nordlund and Ortonne 2006; pheomelanin, barely protective against UV
27 Pigment Disorders 373
radiation, is predominant in very light skin which Table 2 Skin phototypes

is synthesized from two amino acids, tyrosine and Skin type and
cysteine. The enzyme tyrosinase plays a key role history Examples
in producing both types of melanin. I Always Very light/ Red hair and
The hormone α-MSH (melanocyte-stimulating burns, never Celtic freckles, green,
tans gray, or blue
hormone) is one of the key factors in the regulation eyes
of melanogenesis. It is produced in most cells of the II Always Light/light Light or dark
body including keratinocytes, Langerhans cells, and burns, tans skinned hair, Blue,
melanocytes. α-MSH not only stimulates melano- minimally European brown, or gray
genesis and transfer of melanosomes but also has eyes
III Burns Light Brown hair,
anti-inflammatory properties and stimulates DNA
moderately, intermediate/ blue, green
synthesis in keratinocytes. In this way, (hyper) pig- tans dark- skinned hazel eyes
mentation is linked to epidermal tissue repair gradually European
explaining the often found post-inflammatory hyper- IV Rarely Dark Black to brown
pigmentation (see below) (Nordlund and Boissy burns, tans intermediate/ hair, brown, or
well Mediterranean dark brown
2001; Bolognia 2003; Ansty 2010; Meys 2017). eyes
V Burns Dark/Brown Black hair and
minimally, type/Middle brown or dark
4 The KLM Unit tans well Eastern. Latin brown eyes
American,
Orientals
Nowadays, it is believed that also epidermal
VI Never Very dark/ Black hair and
Langerhans cells are important in the cellular burns, “Black” type/ dark brown
interplay regulating melanogenesis. Langerhans deeply African/ eyes, with
cells are immune macrophages playing a role brown Australian minor
in contact sensitivity and each one relating to 53 natives variations
surrounding keratinocytes.
Probably all epidermal cells cooperate in A classic way to classify skin types for clinical
the defense against noxious environmental stimuli purposes such as phototherapy is proposed by
and the concept of the Keratinocyte-Langerhans- Fitzpatrick and is based on the reaction of the
Melanocyte (KLM) unit has been proposed. skin to sun exposure (skin type I–VI) (Table 2)
These tree cells working together in the (Nordlund and Ortonne 2006).
epidermis can be considered as a troika to permit The average of 800–1000 melanocytes/mm2
optimal adaption to and protection against envi- of the epidermis are remarkably similar in
ronmental threats by building a mechanical different skin colors with some exceptions in the
barrier provided by keratinocytes, immune/ sun-exposed skin, such as face 1200–1800/ mm2
inflammatory by Langerhans cells, and biochem- and about 1800/mm2 in the genital area and distal
ical by melanocytes. (Nordlund and Boissy 2001; sites might suggest some circulating factor for
Nordlund 2007). stimulating melanogenesis in these areas.
The main responsible factor for the variation in
skin color is the quantity of melanin, the number,
5 Skin Types and Ethnic Skin size, and distribution of melanosomes transferred
to the surrounding keratinocytes which differ
The genetically basal state of skin pigmentation is from individual to individual.
called constitutive pigmentation. By UV-induced As opposed to white skin, colored skin (type
tanning and various hormones in particular mela- III–VI) has larger and more dendritic melano-
nocyte-stimulating hormone (MSH), facultative cytes, with larger melanosomes, which are being
pigmentation is being formed (Nordlund and transferred in larger amounts to the epidermal
Boissy 2001). keratinocytes.
374 M. Yazdani
Table 3 Normal pigmentary variations in ethnic skin

Description Area Remarks
Voigt’s or Futcher’s Lines of demarcation The posterior portion of the lower 75% of the African(- American)
lines between darker and limb, presternal area, the population
lighter skin areas posteromedial area of the spine,
bilateral aspect of the chest, upper
arm anteromedially
Hyperpigmentation Macular Palmar/plantar Differential diagnosis: palmar/
hyperpigmentations, plantar lesions of syphilis,
varying in shape or ephelides, nevi, melanoma
mottled
Fairly circumscribed Extensor side of the joints Caused by stretching of the skin
macules at the joints
Nail pigmentation Longitudinal linear Mostly thumb and index finger Mostly in black with a very dark
dark bands in the nail complexion. Absent at birth and
plates increases with age
Familial periorbital Childhood: lower eyelids Autosomal dominant hereditary
hyperpigmentation Adult: entire periorbital area disorder. Starting in childhood
and progressing with age
Linea nigra A line between the xyphoid Darkens during pregnancy
process and the symphysis
Oral pigmentation Usually: on the gingivae
Less common: hard palate,
buccal mucosa, tongue
Mongolian spot Gray-blue macular Sacrum, buttocks and back Most common congenital
lesions varying in hyperpigmentation, 80–100% of
size but usually the Asian and black newborns,
<5% of the body dermal melanocytosis due to
surface arresting of the fetal melanocytes
migration to the epidermis from
the neural crest
In skin type V or VI skin, some melanosomes in colored skin giving the vesicular dermatoses
are converted intact throughout the entire epider- of white skin a more popular appearance in
mis and are desquamated with the corneocytes the colored, the greater tendency for acne-like erup-
compared to other skin types in which the tions and subsequent hyperpigmentation, and
melanosomes are completely degraded before sometimes keloid formation in people with a
arriving in the stratum corneum from the basal black-African skin type and the greater risk for
layer. skin cancer in the white (Naafs 2006).
This highly productive melanogenesis is
more sensitive to noxious stimuli as can be
seen in post-inflammatory hyper- and hypo- 6 Hyperpigmentations
pigmentations (Nordlund and Boissy 2001).
Apart from these very common but temporary 6.1 Post-inflammatory
melanogenetic dysregulations, colored skin can Hyperpigmentation
show several physiological pigment patterns
(Table 3) that should be recognized as such (Van Post-inflammatory hyperpigmentation (PIH) is one
der Veen et al. 2006). Other differences between of the most common pigmentary disorders specifi-
white and colored skin include the clinical expres- cally in dark skin (type III–VI) and can be psycho-
sion of erythema which is hardly or not visible logically devastating to some patients. Inflammatory
in black skin, the larger cohesion of keratinocytes skin conditions like infection (occupational),
chemical irritation, or repetitive trauma, including can take years to fade away to normal and is very
scratching, can cause increased pigmentation. The therapy resistant. Long-term sun protection in PIH
two processes involved are an epidermal inflamma- is the paramount treatment next to treating the
tory response and incontinentia pigmenti (Fig. 1). underlying condition. Although epidermal hyper-
The epidermal inflammatory response consists pigmentation can be influenced by a combination
of an increased synthesis of melanin, resulting in of topical agents like retinoids, corticosteroids,
epidermal melanosis. The final common pathway and hydroquinone with caution for the side
of chemicals like prostaglandins, leukotrienes, effects. Chemical peelings and laser therapy
and α-MSH released during inflammatory pro- could be used in some cases.
cesses has an effect on cyclic AMP, which stimu- Sun exposure, chemicals, and certain drugs can
lates pigment synthesis. aggravate or cause hyperpigmentation. Plant and
Incontinentia pigmenti occurs after disruption fruit substances like psoralens and furocoumarins
of the epidermal basal cell layer causing dermal are known as photosensitizers inducing phytopho-
melanosis. Apoptosis of the pigment cells due to todermatitis with subsequent sun exposure.
the inflammatory reaction will cause melano- Citrus fruits such as lime and grapefruit, bergamot,
somes to leak to the dermis, which will be accu- celery, cow parsley, and giant hogweed
mulated in macrophages called melanophages. are examples of well-known culprits.
In lighter skin types, epidermal hyper- The typical presentation of phytophotodermatitis
pigmentation can be differentiated from pure occurs within a couple of minutes to hours with
dermal hyperpigmentation by Woods lamp illumi- erythematous swelling at the sites of contact, vesi-
nation. Under this, light epidermal pigment cles and large blisters, and itching and burning
becomes more accentuated, while deep dermal sensations. Due to this inflammation process,
pigment is hardly visible. brown pigmentation arises which disappears spon-
Epidermal melanosis usually disappears in taneously within a couple of weeks. Hyper-
6–12 months, whereas dermal hyperpigmentation pigmentation can also appear after high doses of
Fig. 1 Post-inflammatory hyperpigmentation after a blistering skin disease

376 M. Yazdani
UV exposure without clinical findings of phytopho-

todermatitis between 1 and 2 weeks after exposure
to the photosensitizer and development of
pigmentation. Histopathological results in these
cases revealed an orthohyperkeratosis, slightly
increased number of melanocytes, and basal hyper-
pigmentation, suggesting for a nonimmune reactive
hyperpigmentation (Van der Veen et al. 2006; Meys
2017; Plensdorf et al. 2017; Choi et al. 2018).
7 Hypopigmentations
7.1 Post-inflammatory
Hypopigmentation
In dark skin, even minor triggers of an inflamma-

tory response can lead to hypopigmentation.
Triggers can be common inflammatory skin
disorders like psoriasis, any kind of dermatitis (seb-
orrheic, atopic, contact- etc.), or repetitive trauma
or irritation. An excessive release of nitric oxide
from Langerhans cells can be melanocytotoxic,
resulting in hypo- or depigmentation. The presen-
tation occurs usually as a mottled pattern and often
coexisting hyperpigmentation due to appropriate Fig. 2 Post-inflammatory hypopigmentation after
psoriasis
release of nitric oxide (Fig. 2).
The prognosis is favorable although the process
of repigmentation takes time. Treating the primary
condition and sun protection are the main general 8.1 Bleaching Products
treatments. In general, post-inflammatory hyper-
pigmentation is seen much more frequently and Modern humans probably all stem from black-
poses a larger therapeutical challenge than its hypo- skinned ancestors with curly hair. In moderate
pigmented counterpart (Nordlund 2007; Meys climates, adaptation of skin color took place and
2017; Plensdorf et al. 2017). this new white-skinned variant appeared to be
very successful in the ages to come. A classic
example of white-skinned domination can be
8 Dyschromia Cutis/Discoloration found in India, where the ruling white elite stem
of the Skin from white-skinned ancestors who invaded the
Indian subcontinent more than 5,000 years ago.
Color changes in the skin as mentioned above can Nowadays, lots of people all over the world try
be caused by external or internal determinants. to lighten their skin in order to be more successful
Dermal hyperpigmentation needs to be differenti- in society (Westerhof 2007). To this end, many
ated from other dyschromia caused by other products have been developed by the cosmetic
determinants then melanin like iron, silver industry. These over the counter creams contain
(agyria), gold (chrysiasis), mercury, arsenic, car- compounds like arbutin, licorice extract, mul-
bon, bismuth, chlorpromazine, chloroquine, and berry, kojic acid, magnesium l-ascorbyl-2-phos-
psoralen (further reading). phate, alpha-tocopherol, n-acetyl- d-glucosamine,
Fig. 3 Effects of bleaching with monobenzone in a patient with universal vitiligo
or carvacrol. Most of these compounds work 8.2 Vitiligo

through inhibition of tyrosinase. For medical pur-
poses such as the treatment of melasma, hydro- Vitiligo probably is the best-known pigment
quinone, retinoic acid, and azelaic acid are disorder as it has a worldwide prevalence of
currently being used in several prescriptions approximately 1% and can be very conspicuous,
often combining different compounds, for exam- especially in dark skin. It is an acquired usually
ple, hydroquinone, tretinoin, and a corticosteroid. asymptomatic disorder characterized by the
Though effective in downregulating melanogene- development of white patches due to a progressive
sis, these prescriptions often induce irritation loss of epidermal melanocytes (Fig. 4), although
which in dark skin always comes with the hazard in some cases, mild preceding pruritus has been
of post-inflammatory hyperpigmentation as a reported. Vitiligo often runs in families (25–30%
paradoxical side-effect. The more effective pre- prevalence). Both sexes are equally affected with
scription-only compounds are illegally available no difference in rates of occurrence in skin types.
on a large scale and can be very harmful because Vitiligo is associated with autoimmune endo-
uncontrolled prolonged use can give rise to crinopathies of which thyroid disease (20–30%
unwanted pigmentary changes like ochronosis prevalence) is the most important. Pernicious ane-
and leukoderma en confetti (hydroquinone), mia, diabetes mellitus, alopecia areata are also
chemical-induced vitiligo (monobenzone), skin some examples of related diseases. The onset is
atrophy, and Cushing syndrome (corticosteroids). commonly related to trauma (e.g., Koebner phe-
Strong bleaching agents with melanocytotoxic nomenon (see below), recent stress, or illness.
properties like monobenzone 20% and In half of the cases, the first symptoms already
4-methoxyphenol can be used in treating patients start before the age of 20, and the disease runs a
with universal vitiligo (see below) to remove chronic course with exacerbations and relapses,
disfiguring areas with remnant pigmentation eventually leading to more and larger white areas
(Fig. 3). that can be found in different patterns. Nowadays,
378 M. Yazdani
Fig. 5 Segmental vitiligo. Pseudo-dermal distribution and

involving hair compartment
Fig. 4 Generalized vitiligo. Symmetrical white patches
due to a progressive loss of epidermal melanocytes in
generalized vitiligo
considered when depigmentation covers more
than 10% of body surface and can be divided
into four categories (Table 4b). Very rare is uni-
vitiligo is subdivided into three types, and versal vitiligo, in which >80% of the body sur-
the term is used for all forms of non-segmental/ face is affected and the familial disposition
generalized vitiligo. Other two subsets of is greater, as is the association with other
vitiligo are segmental (focal) and unclassified/ autoimmune diseases (Linthorst Homan et al.
undetermined vitiligo (rare variants). Unclassified 2008; Taiëb and Picardo 2009; Plensdorf et al.
vitiligo is a cutaneous or mucosal type which 2017; Meys 2017; Boniface et al. 2018; further
consists of a small isolated patch not fitting in a reading: https://www.huidziekten.nl).
segmental distribution or evolving into non- We will focus here on generalized vitiligo,
segmental vitiligo for at least 2 years. accounting for 85–90% of adult cases, which
Important is to differentiate between non- has a lot in common and can overlap with (occu-
segmental vitiligo (NSV)/generalized vitiligo pational)/chemical-induced vitiligo.
(Fig. 4) and segmental vitiligo (SV) (Fig. 5),
the latter being a disease on its own with a
different presentation, a different therapy, and 8.3 Diagnosis
probably different pathogenesis (Table 4a).
Both types of vitiligo can start with focal vitiligo, The observation of depigmentations distributed in
characterized by a small affected area a characteristic pattern together with a carefully
(<15 cm2). In some cases, both types coexist, taken (family) history leads to an easy diagnosis
in which segmental lesions are less responsive to in most of the cases. In patients with a very light
the treatment. Nonsegmental vitiligo is skin type, depigmentations sometimes are
Table 4a Segmental versus non-segmental vitiligo. Table 4c Major differential diagnosis (hypo- or depig-
(Adapted from Taiëb and Picardo 2009) mentation) for nonsegmental vitiligo. (Adapted from Taiëb
and Picardo 2009)
Nonsegmental/generalized
Segmental vitiligo vitiligo Inherited or genetically Occupational/chemical
Often begins in Can begin in childhood, but induced: leukoderma:
childhood later onset is more common Piebaldism, tuberous e.g., phenolic-catecholic
Has rapid onset and Is progressive, with flare-ups sclerosis, nevus derivates
stabilizes depigmentosus, Ito’s
hypomelanosis,
Involves hair Involves hair compartment Waardenburg’s syndrome,
compartment soon after in later stages Ziprkowski–Margolis
onset syndrome
Usually no association Is often associated with Auto-immune associated: Drug-induced:
with autoimmune personal or family history of Vogt-Koyanagi-Harada e.g., chloroquine,
disease autoimmunity syndrome, pseudovitiligo fluphenazine
Unilateral, pseudo- Bilateral, often symmetrical or hypopigmentation in
dermatomal systemic sclerosis, Lichen
Most common on the Commonly at sites sensitive Sclerosus
face to pressure, friction, or Paramalignant: Post-traumatic:
trauma Mycosis fungoides/ e.g., after burns or toxic
Excellent response to Variable results with surgical cutaneous T cell lymphoma epidermal necrolysis
surgery therapy (may present in dark-
Distribution of segmental vitiligo is pseudo-dermal and is skinned patients),
also being mentioned as unilateral or zosteriform vitiligo melanoma/melanoma-
associated leukoderma
Post-inflammatory: Malnutrition:
e.g., psoriasis, atopic Copper and selenium
Table 4b Categories of non-segmental/generalized dermatitis, syphilis
vitiligo (leukoderma syphiliticum)
Focal vitiligo One or few lesions Parainfectious: Progressive macular
Acrofacial Distal extremities and face Tinea versicolor, leprosy hypomelanosis, halo
vitiligo nevus, idiopathic guttate
Vitiligo Multiple symmetrical lesions over the hypomelanosis, nevus
vulgaris whole body anemicus, poliosis
circumscripta,
Universal >80% depigmentation of body surface
pseudoleukoderma,
vitiligo
melasma (contrast
difference)
difficult to judge by the naked eye and Woods

lamp examination can be helpful in these cases. some regions, whereas in some societies vitiligo is a
A majority of differential diagnoses for non- legally acceptable reason for divorce, and marital
segmental vitiligo are listed in Table 4c, prospects for vitiligo patients are very poor.
and some of them need to be ruled out by specific Nevertheless, vitiligo can profoundly influence
procedures including a skin biopsy (Taiëb and the quality of life and self-esteem of patients
Picardo 2009; further reading). in any society, causing isolation, depression,
stigmatization, low self-esteem, and self-
consciousness.
8.4 Impact of the Disease A striking example of the burden of vitiligo was
given by a (white) patient suffering from both type
Vitiligo should be considered a serious and traumatic 1 diabetes and vitiligo. Though well aware of the
disease. There certainly are cultural differences physical threats imposed by his diabetes, he judged
regarding the social acceptance of the disease. An the vitiligo to be more devastating for his quality of
association with leprosy has always played a role in life (Austin 2004; Grimes and Miller 2018).
380 M. Yazdani
In general, however, vitiligo has more impact 8.7 Treatment

on dark-skinned people than on whites in terms
of quality of life (Linthorst Homan et al. 2009). The first-line treatment of vitiligo is to avoid trig-
gering factors and sun protection next to psycho-
logical support. In the localized depigmentation
8.5 Pathogenesis <2–3% of body surface, topical corticosteroids
and calcineurin inhibitors may be effective.
The combination of different pathogenic mecha- The second line is twice a week narrowband
nisms appears to play a role in vitiligo and their UVB therapy (not on two successive days)
exact interplay is still under debate. The hallmark which is the first line treatment for the
of vitiligo pathogenesis is the loss of the epider- NSV >3% of body surface. The response of seg-
mal melanocytes resulting from a complex inter- mental vitiligo to UVB therapy is limited.
play of genetics, oxidative stress, melanocytes Combination of UVB and topical therapy is
intrinsic abnormalities, altered inflammatory and considered when phototherapy is not responsive
immune response as the leading hypothesis after 3 months. Vitiligo treatment can take months
theory. (Westerhof and d’Ischia 2007; Taiëb and to years and regimentation of more than 50–75%
Picardo 2009; Plensdorf et al. 2017; Grimes and is considered as successful. Camouflage or
Miller 2018; Boniface et al. 2018). depigmentation therapy by topical or laser is
The biochemical factors, interfering with another option for widespread disease.
melanogenesis in genetically susceptible Surgical methods including minigrafting in
individuals, lead to the formation of auto-anti- combination with UVB therapy is considered in
gens triggering an autoimmune reaction stable lesions for at least 1 or 2 years, covering
destroying melanocytes. The biochemical factors less than 3% of body surface area. The success in
mentioned above may be external as in chemical- SV is more common since the grafted cells are
induced vitiligo or intrinsic, due to a defective gathered from the disease-free area. Koebner
free-radical defense affecting melanin content phenomenon has to be considered especially in
and synthesis (Dell’Anna and Picardo 2006). In the areas such as dorsum of hands (Taiëb and
the end, the immune response takes the lead and Picardo 2009; Meys 2017).
propagates the depigmentation process indepen-
dent from the original trigger (Westerhof and
d’Ischia 2007; Taiëb and Picardo 2009; Plensdorf 8.8 Chemical-Induced
et al. 2017). (Occupational) Vitiligo and
Leukoderma
8.6 Koebner Phenomenon Occupational vitiligo can essentially comprise

vitiligo patches elicited by mechanical trauma
An important etiopathogenetic factor in vitiligo is in a work situation or vitiligo induced by contact
the Koebner phenomenon, which can be defined with chemicals during work.
as a cutaneous disease-specific response to a non- Moreover, also contact with chemicals on other
specific, usually traumatic stimulus such as occasions can play a role. Here, we will speak
pressure or friction (Taiëb and Picardo 2009). about chemical-induced vitiligo or chemical
Local loss of melanocytes could be found 24 h leukoderma in general.
after the mechanical stimulus suggesting an Chemical leukoderma is characterized by
intrinsic vulnerability of the melanocytes. depigmentation on the area of contact with a
This Koebner phenomenon can easily explain chemical. In patients with a genetic predisposition
the distribution of vitiligo in many patients and for vitiligo, preexisting non-segmental vitiligo, or
can play a role in nonchemical occupational the involvement of several causative agents,
vitiligo. the depigmentation spreads beyond the areas of
contact and here we can speak of chemical- Table 5a Chemicals associated with chemical
induced vitiligo. leukoderma/vitiligo
Wood lamp examination and a careful history Phenolic and catecholic Others
taking are of importance for the diagnosis. derivates
The depigmentation might occur years after Alkylphenol PPD (Para-
Phenylenediamine)
being in contact with the chemical. Nearly
Butylphenol Captan (ethanethiol/ ethyl
12.9% of the cases have a family history mercaptan)
of vitiligo versus 0.7% for chemical leukoderma. Amylphenol DPCP (diphencypron/2,3-
Most cases are of the involving chemicals diphenylcyclopropenon 1)
solvents by skin contact, but chemical ingestion, Butylhydoxytoluene Mercurials
injection, or inhalation can also be one of Dihydoxyphenylbutane Arsenic
the factors. There have been some reports of Rhododendrol (4-(4- Benzyl alcohol
hydroxyphenyl)-2-
organ involvement like hepatosplenomegaly
butanol)
and hypothyroidism suggesting systemic Hydroquinone (benzene- Cinnamic aldehyde
involvement. “Chemical leukoderma syndrome” 1,4-diol/ quinol)
is still an unproven hypothesis of Ghosh for MBEH (Monobenzone/ Chloroquine
delayed depigmentation involving organs, Monobenzyl ether of
lymphatic, and hematogenous spreading of hydoquinone)
chemical leukoderma. Spontaneous peri- Monomethyl ether of Fluphenazine
hydroquinone
follicular repigmentation within few weeks to
Catechol (pyrocatechol/ Corticosteroids
months is possible in some cases after avoidance 1,2-dihydroxybenzene)
of the causative agent. The therapy is the Methylcatechol Guano nitrofuracin
same as vitiligo from topical to UVB or a 4-TBC (4- tert- Triethylene-
combination. Butylcatechol) thiophosphoramide
A list of compounds associated with occupa- 4-TBP/ PTBP (4- tert- Physostigmine
Butylphenol)
tional chemical leukoderma/vitiligo is given
4-TAP (4- tert- Azaleic acid
in Tables 5a and 5b and professions prone to
Amylphenol)
have contact with these chemicals are listed in 4-Isopropylcatechol Kojic acid
Table 6. 4-Hydroxy-anisol Squaric acid dibutylester
Many of these compounds are phenolic/ Sulfhydryls
catecholic derivates, and most research has Bèta-mercapto-
been done on 4- tert-Butylphenol (4-TBP, ethylamine
PTBP). These compounds have chemical hydrochloride
similarity with tyrosine and dopa, the endoge- 3-Mercaptopropylamine
hydrochloride
nous substrates of the melanocyte-specific
Sulfanolic acid
enzyme tyrosinase. Apart from down-
N-2-mercapto-
regulating melanogenesis by competition, these ethyldimethylamine
compounds clearly are able to be mela- hydrochloride
nocytotoxic. Recent data indicate that immune
destruction of melanocytes preceded by
haptenization of tyrosinase by binding to
oxidation products of the involved compounds melanocytes of genetically predisposed individ-
probably plays the main role. The depig- uals (Boissy and Manga 2004; Westerhof and
mentation hypothesis for the small group of phe- d’Ischia 2007; Bonamonte et al. 2016;
nolic chemicals like PPD is still unknown. Harris 2017).
Whether these chemicals are close enough to A prototype of such a reaction can be seen
phenols or are metabolized into phenols before during treatment of patients with universal viti-
generating a toxic environment for the ligo. Many of these patients ask for bleaching
382 M. Yazdani
Table 5b Consumer products associated with chemical Table 6 Professional fields at risk for chemical-induced
leukoderma/vitiligo vitiligo
Nylon, Production workers in contact with: antioxidants,
plastic Rubber bacteriostatic agents, organic chemicals, glues, dyes,
Alta Synthetic leather rubber, plastic stabilizer
Bindi Medication Beauticians, hairdressers
Adhesive Deodorants Health workers
tapes Workers in contact with paints, glues, photographic
Latex gloves Cinnamic aldehyde in toothpaste chemicals, printing ink, motor oil additives
Germicides Cosmetic face sponges Farmers
Insecticides Bleaching crèmes
Soap Dyes:
antioxidants p-Phenylenediamine, Rhodamine B,
crocein Scarlet MOO 4-TBP (4-tert-Butylphenol), monobenzone, and
Condoms Acrylates azo dyes. Table 5b gives a list of consumer prod-
ucts associated with chemical-induced vitiligo or
chemical leukoderma (Ghosh and Mukhopadhyay
of their often disfiguring remaining pigmented 2009; Bonamonte et al. 2016).
skin areas and to this end, monobenzone is
employed.
These patients develop dermatitis strictly References
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Ansty AV (2010) Disorders of skin colour. In: Burns T et
depigmentation, also in areas that have not
al (eds) Rook’s textbook of dermatology, 8th edn.
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cytes and macrophages at the dermal–epidermal Acad Dermatol 51:57–58
Boissy RE, Manga P (2004) On the etiology of
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Choi JY et al (2018) Asymptomatic hyperpigmentation
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without preceding inflammation as a clinical feature
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2003–2007, only in four patients were 4-tert- Ann Dermatol 30(1):75–78
Butylphenol (n = 2), captan (n = 1), and Dell’Anna ML, Picardo M (2006) A review and a
new hypothesis for non-immunological pathogenetic
diphencyprone (n = 1) as elicitating factors
mechanisms in vitiligo. Pigment Cell Res 19:406–411
(Vrijman et al. 2013). Ghosh S, Mukhopadhyay S (2009) Chemical leucoderma:
On the other hand, in developing countries like a clinico-aetiological study of 864 cases in the
India, chemical leukoderma is seen far more fre- perspective of a developing country. Br J Dermatol
160:40–47
quently due to lack of quality control and here Grimes PE, Miller MM (2018) Vitiligo: patient stories,
predominantly induced by common domestic self-esteem, and the psychological burden of disease.
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35(2):151–161
remote areas in 26.3%, while one-third had a
Linthorst Homan MW et al (2008) Characteristics of
history of preexisting vitiligo. The chemicals patients with universal vitiligo and health-related
involved included PPD (para-phenylenediamine), quality of life. Arch Dermatol 144:1062–1064
Linthorst Homan MW et al (2009) The burden of vitiligo. Taiëb A, Picardo M (2009) Vitiligo. N Engl J Med
Patient characteristics associated with quality of life. 360:160–169
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Meys R (2017) Skin pigmentation. Medicine 45(7):438–443 black skin. In: Faber WR et al (eds) Imported skin
Naafs B (2006) Coloured versus white skin. In: Faber WR diseases. Elsevier, Maarssen
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Nordlund JJ (2007) The melanocyte and the epidermal chemicals, in Dutch patients with vitiligo. Br J
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Dermatological clinics. Pigmentary disorders. W.B. Westerhof W (2007) Evolutionary, biologic, and social
Saunders, Philadelphia aspects of skin color. In: Lotti T (ed) Dermatological
Nordlund JJ, Boissy RE (2001) The biology of clinics. Pigmentary disorders. W.B. Saunders,
melanocytes. In: Freinkel RK, Woodley DT (eds) Philadelphia
The biology of the skin, 1st edn. The parthenon Westerhof W, d’Ischia M (2007) Vitiligo puzzle: the pieces
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Nordlund JJ, Ortonne JP (2006) The normal color of Yamaguchi Y, Hearing VJ (2014) Melanocytes and their
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system, 2nd edn. Blackwell, Malden a017046. https://doi.org/10.1101/cshperspect.a017046
Nordlund JJ et al (2006) A more precise lexion for pig-
mentation, pigmentary disorders, and “chromatic”
abnormalities. In: Nordlund JJ et al (eds) The pigmen-
tary system, 2nd edn. Blackwell, Malden Further Reading
Plensdorf S et al (2017) pigment disorders: diagnosis
and management. Am Fam Physician 96(12):797–804 https://www.huidziekten.nl
Noneczematous Occupational Contact
Reactions 28
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3 Erythema-Multiforme-Like Reaction (UPPEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3.1 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3.2 Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
3.3 Woods and Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
3.4 Metals and Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
3.5 Laboratory Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
3.6 Industrial and Agricultural Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
4 Pigmented Purpuric Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
5 Lichen-Planus-Like and Lichenoid Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
6 Nodular and Papular Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
7 Granulomatous Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
8 Pustular Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
9 Erythema and Exfoliation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
9.1 Trichloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
9.2 Methyl Bromide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
10 Scleroderma-Like Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
11 Lymphomatoid Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Contact reaction · Contact allergy · Non-
eczematous eruptions • Allergic contact dermatitis may present as non-
eczematous lesions.
• Patch tests often produce an eczematous
A. T. J. Goon · C. L. Goh (*)
reaction.
National Skin Centre, Singapore, Singapore
e-mail: anthonygoon@nsc.com.sg; clgoh@nsc.com.sg; • EM-like eruption can occur with woods,
drgohcl@gmail.com plants, metals, and chemicals.
https://doi.org/10.1007/978-3-319-68617-2_28
386 A. T. J. Goon and C. L. Goh
• Purpuric eruption can occur with IPPD- multiforme-like” eruptions. These allergic con-
containing rubber products. tact reactions can be confirmed by positive
• Lichen-planus-like eruption can occur with patch-test reactions. The morphology of these
color developers. reactions includes target-like erythemacular
• Papular and nodular eruption can occur with and urticarial lesions. Such eruptions have
gold salts. been described as UPPE to distinguish them
• Granulomatous reaction can occur with gold from the classical erythema multiforme
and beryllium salt. (Goh 1989).
• Pustular eruption can occur with metallic salt.
• Erythema and exfoliation can occur with TCE.
• Pseudoscleroderma can occur with chlorinated 3.1 Clinical Features
hydrocarbon and solvents.
The characteristic presentation is usually an
eczematous lesion on the primary contact site.
2 Introduction Within a few days, urticarial papular and plaque
lesions appear on the primary contact site,
Contact reactions may present as noneczematous spreading to adjacent skin and occasionally dis-
lesions. A variety of noneczematous occupational tant sites. The urticarial eruptions persist longer
contact reactions have been described. The exact than the primary eczematous lesions and tend to
pathomechanism of these reactions is unknown. persist after the disappearance of the initial
The following noneczematous contact reactions dermatitis.
have been described: In all cases, a positive patch test to the
contact allergen can be elicited. The patch-
1. Erythema-multiforme-like eruption [urticarial test reaction is always eczematous and often
papules and plaque eruptions (UPPE)] severe.
2. Purpuric eruption
3. Lichen-planus-like eruption
4. Papular and nodular eruption 3.2 Histology
5. Granulomatous reaction
6. Pustular eruption The epidermis is normal or shows mild spongiosis
7. Erythema and exfoliation with upper dermal edema and perivascular
8. Pseudoscleroderma lymphohistiocytic infiltrate. Vacuolar degeneration
9. Lymphomatoid contact dermatitis of the basal cells is occasionally present. The clas-
sical features of erythema multiforme are absent.
Other noneczematous contact reactions The morphology, clinical course, and histology of
have also been described. However, these the eruptions are not characteristic of classical ery-
have been mainly in nonoccupational thema multiforme.
settings, i.e., bullous reactions, pigmented con- The pathomechanism of these papular and urti-
tact dermatitis, and vascular occlusive contact carial eruptions is unknown. An immune complex
dermatitis. reaction may be the basis of the clinical manifes-
tation here. Goh postulated that the allergen is
absorbed percutaneously and evoked an allergic
3 Erythema-Multiforme-Like contact dermatitis at the primary site while con-
Reaction (UPPEs) currently forming immune complexes with a cir-
culating antibody (Goh 1989). The immune
Several contact allergens, e.g., metal, topical complexes were probably deposited in the micro-
medicaments, wood, and industrial chemicals, vasculature and triggered by an inflammatory pro-
have been reported to cause “erythema- cess that led to the UPPE. Occupational allergens
28 Noneczematous Occupational Contact Reactions 387
reported to cause UPPE include woods and/or described by Calnan (1956). Cook also reported
plants and chemicals. UPPE in a 13-year-old girl due to allergic contact
dermatitis from nickel and cobalt from the metal
studs in her jeans (Cook 1982). Friedman and
3.3 Woods and Plants Perry (1985) described a garment worker who
developed UPPE from nickel dermatitis on her
Hoist et al. (1976) described three carpenters who hands from her scissors. Patch test revealed
developed erythema-multiforme-like eruption allergy to nickel and paraphenylenediamine. Dur-
from contact allergy to three different tropical ing patch testing, there was exacerbation of the
woods – Rio rosewood (Dalbergia nigra), pao worker’s hand dermatitis and UPPE. Similar erup-
ferro (Mackerium scleroxylon), and Eucalyptus tion appeared when the worker was patch tested to
saligna. The antigen in pao ferro was R-3, 4- nickel alone.
dimethoxy-dalbergione. A wooden bracelet
(Fisher 1986a) and pendant (Fisher and Bikowski
1981) made from Dalbergia nigra were also 3.5 Laboratory Chemicals
reported to cause erythema-multiforme-like erup-
tion. The specific chemical antigen was identified De Feo reported chemistry students who devel-
as quinone R-4-methoxy-dalbergione (Hausen oped UPPE while synthesizing 9-bromofluorene
1981). Nonoccupational causes have also been in the laboratory (De Feo 1966). Roed-Petersen
reported. Irvine et al. (1988) reported such reac- reported of a 22-year-old chemistry student who
tion to pao ferro (Mackerium scleroxylon) in a developed UPPE on the exposed parts from a
hobbyist handling the wood. Plants reported to phenyl sulfone derivative which he was synthe-
cause erythema-multiforme-like eruption include sizing. Patch test gave a strong positive reaction to
poison ivy (Toxicodendron) (Schwartz and Down- the compound (Roed-Petersen 1975). Tjiu et al.
ham 1981; Mallory et al. 1982), primula (Primula (2004) reported on a 22-year-old female chemis-
obconica) (Hjorth 1966), and mugwort (Artemisia try student who developed widespread erythema-
vulgaris) (Kurz and Rapaport 1979). Mallory et multiforme-like lesions after local contact with
al. (1982) reported urticarial eruptions with black 1,2-ethanedithiol. The patient had a positive
deposits on the skin of four patients with patch test to 1,2-ethanedithiol.
Toxicodendron radicans dermatitis. Urticaria,
erythema-multiforme-like eruptions, in a patient
from Rhus dermatitis, was reported by Schwartz 3.6 Industrial and Agricultural
and Downham (1981). They recommended that Chemicals
patients with such reactions should be screened
for systemic involvement as previous reports have Nethercott et al. (1982) reported of four men
shown that nephritis can be an associated feature working with printed circuit boards who devel-
(Meneghini and Angelini 1981; Fisher 1986b). oped erythema multiforme. Liver involvement
More recently, there have been reports of ery- was documented in three cases. Formaldehyde
thema-multiforme-like contact dermatitis from was suspected to be the cause of the eruption
Primula obconica (Gallo et al. 2005) and primin since two of the workers gave a positive reaction
(Bonamonte et al. 2008). to formaldehyde. However, these workers were
also exposed to other substances, including tri-
chloroethylene. Trichloroethylene was suspected
3.4 Metals and Chemicals to cause erythema multiforme in five workers in
an electronic factory. The liver was involved in
Metals and several industrial chemicals have been three workers, and one died of liver failure. Patch
reported to cause UPPE in sensitized patients. test to trichloroethylene on one worker was nega-
Nonoccupational UPPE from nickel was first tive. The reaction was suspected to be due to a
hypersensitivity reaction from percutaneous and/ exact mechanism of the reaction is unknown. It
or transrespiratory tract absorption of trichloroeth- appears to represent an immune complex disease.
ylene (Phoon et al. 1984). Percutaneous absorption of contact allergens
Goh (1988) reported erythema-multiforme-like appears to form immune complexes with a circu-
eruption in a worker with contact allergy to trini- lating antibody that becomes deposited in the
trotoluene who was employed at an ammunition microvasculature, producing the vasculitic
factory. The systemic absorption of trinitrotoluene lesions. However, such immune complexes can-
appeared low as its urinary metabolite, dinitro- not be identified (Calnan and Peachey 1971). Pur-
aminotoluene, was not detected. Patch test to tri- puric eruption associated with allergic contact
nitrotoluene gave a strong eczematous reaction. dermatitis to rubber chemical N-phenyl-N-isopro-
An occupational erythema-multiforme-like con- pyl PPD (IPPD) in clothing was described by
tact reaction to iodoacetonitrile has been documented Batschvarov and Minkov in 1968 (Batschvaros
in a chemistry student in Italy (Foti et al. 2011). and Minkow 1968). Allergic contact dermatitis
A 26-year-old printing worker whose forearms to IPPD, which is used in the manufacture of
had accidentally come into contact with acrylate- some types of rubber in rubber boots, was also
based printing ink that spilled from a container reported to cause purpuric eruption (Calnan and
developed erythema-multiforme-like contact der- Peachey (1971). Fisher (1974) reported similar
matitis (Córdoba et al. 2015). He developed posi- eruptions in three patients caused by a rubber
tive patch-test reactions to 2-hydroxyethyl diving suit, elasticized shorts, and a rubberized
methacrylate 1% petrolatum (pet), 2-hydroxyethyl support bandage. Romaguera and Grimalt (1977)
acrylate 0.1% pet, 2-hydroxypropyl methacrylate also reported similar eruption from IPPD in a
2% pet, ethyl acrylate 0.1% pet, and tetra- rubberized brassiere due to nonoccupational
hydrofurfuryl methacrylate 2% pet. cause. Shmunes (1978) reported a woman with
Contact dermatitis to natural rubber latex was purpuric allergic contact dermatitis to para-
also reported to present with features of erythema- phenylenediamine from black hats she was han-
multiforme-like eruptions (Bourrain et al. 1996). dling as a saleswoman.
Contact with laurel oil was reported to cause ery-
thema-multiforme-like eruption (Athanasiadis et
al. 2007). 5 Lichen-Planus-Like and
Airborne erythema-multiforme-like eruption Lichenoid Reaction
was also reported in individuals exposed to pyre-
thrum (Garcia-Bravo et al. 1995). Occupational allergic contact dermatitis to
Dong et al. (2014) described an erythema- some color developers may manifest as
multiforme-like eruption following acute aller- lichen-planus-like eruptions. Such eruptions
gic contact dermatitis after occupational expo- often present as itchy, dusky, or violaceous
sure to the emulsified herbicide acetochlor in a papules or plaques on areas of the skin
35-year-old Chinese man. A report of erythema- exposed to the allergen. The eruptions
multiforme-like eruption due to an irritant con- behave like any allergic contact derm-
tact dermatitis from a glyphosate pesticide atitis and tend to clear when the allergen is
has also been reported in Spain (Heras-Mendaza removed.
et al. 2008). The histological features of patients with
lichen-planus-like eruptions from color devel-
oper pose an interesting feature. Buckley
4 Pigmented Purpuric Reaction (1958), Canizares (1959), and Hyman and
Berger (1959) reported the histology as compat-
Occupational contact allergy occasionally pre- ible with lichen planus in a number of instances,
sents as purpuric eruption. The eruption may or but some authors reported nonspecific chronic
may not be preceded by erythema or itch. The dermatitis changes. Fry reported that only two
of five patients’ biopsies showed histology sug- individuals appeared to provoke lymphoplasia.
gestive of lichen planus (Fry 1965). Histology of Histology of such eruptions or its patch-test reac-
the lesions may show nonspecific superficial tion may show dense lymphomonocytic infiltrate
perivascular dermatitis or lichenoid infiltrate in in the dermis (Iwatsuki et al. 1982).
the upper dermis.
There is controversy about the etiology of
the lichen-planus-like eruption from color 7 Granulomatous Reaction
developers. Color developers are known to
cause lichen-planus-like eruptions. Kodak Contact reactions to metals and metallic salts can
CD2 (4-N, N-diethyl-2 methylphenyle- manifest as granulomatous lesions. Skin injury
nediamine), Kodak CD3 (4-N-ethyl-N-2-methan- from zirconium, silica, magnesium, and beryllium
esulfonylamino-ethyl 2 methyl-phenylenediamine may cause granulomas (Rubin 1956). Some reac-
sesquisulfate monohydrate), Agfa TSS (4-amino- tions are due to delayed-type allergic reaction, and
N-diethylanilinesulfate), Ilford MI 210 (N-ethyl-N some are nonallergic reactions. Clinically, the
[5-hydroxy-amyl] paraphenylenediamine hydro- granulomatous eruptions appear as inflamed pap-
gen sulfate), and Kodak CD4 (2-amino-5-N-ethyl- ules. Eczema is usually present, but pruritus is
N-[beta-hydroxyethyl] amino toluene sulfate) usually minimal. The histology shows epithelioid
are reported allergens (Goh et al. 1984). cells and may be indistinguishable from sarcoid.
Lichen-planus-like eruptions have been Contact with sheep wool has been reported to
reported from contact with methacrylic acid cause granulomatous eruptions. An unusual case
esters. The patient presented with lichen- of cutaneous foreign body granulomas was pro-
planus-like lesions on sites repeatedly exposed voked by sheep wool. The patient presented,
to methacrylic acid esters used in the car within 1 year, two episodes of a papular eruption
industry. Histologically, the lesions showed on her neck and limbs. She was working as a
all the features of classical lichen planus. Patch farmer’s wife, and each episode occurred after
testing revealed positive reactions to methacrylic preparing the ewes for coupling. She had to keep
acid esters in concentrations (Kawamura a tight hold on the ewes, while the farmer intro-
et al. 1996). duced warm and moist compresses in the genitals
of the animals. Each diseased skin area was
closely related to the tight contact with the sheep’s
6 Nodular and Papular Reactions wool, and on histological slides, each granuloma
was centered by a tiny ply of wool (Lambert et al.
Contact allergy to gold has been reported to cause 1995).
papular and nodular eruptions (Shelly and Epstein
1963). These occurred peculiarly on the earlobes
after ear piercing with gold earrings. Similar erup- 8 Pustular Reaction
tions have been observed on the hands and fore-
arms of gold electroplaters who develop contact Pustular reaction to contactant was first observed
allergy to gold salts. The eruptions characteristi- in patch-test reaction. The pustules are sterile and
cally persist for months after the patients have are transient. Fisher et al. (1959) reported that
avoided contact with metallic gold (Petros and metallic salts, e.g., nickel, copper, arsenic, and
Macmillan 1973). In some patients, the patch mercurial salts, may produce pustular reaction.
test also evokes an unusual reaction, the reaction Stone and Johnson explained that such reactions
being infiltrative, and tends to persist for months may represent an enhanced reaction of prior
(Monti et al. 1983). In most of these patients, the inflammation, rather than an irritant or allergic
patch test produced strong positive and persistent reaction, because such a reaction can be elicited
delayed-type hypersensitivity reaction to gold in non-nickel-sensitive patients on skin sites pre-
compounds. The reaction to gold in these viously injected with heat-killed corynebacterial
acne organisms (Stone and Johnson 1967). Hjorth that the reaction was mediated by delayed-type
reported that atopics are more predisposed to such hypersensitivity. In their patient, the skin eruption
reactions (Hjorth 1977). The significance of such continued to appear after cessation of exposure to
reaction remains controversial. Wahlberg and trichloroethylene. This was explained by the
Maibach believed that such pustular reactions action of trichloroethylene and its metabolites
are usually irritant in nature but may also be a accumulated in the fatty tissue and released from
manifestation of allergic reactions (Wahlberg and there. Trichloroethylene appears to have an affin-
Maibach 1981). ity for adipose tissue.
Conde-Salazar reported a subcorneal pustular Goh and Ng (1988) reported of a patient with
eruption in a patient with trichloroethylene expo- recurrent localized erythematous xerotic plaques,
sure (Conde-Salazar et al. 1983). The patient which became parched and fissured on the arms
reacted systemically upon cutaneous challenge and trunk of a patient with trichloroethylene.
test made by exposing only the right leg to an Biopsy showed superficial perivascular
environment saturated with trichloroethylene (to lymphohistiocytic infiltrate. The epidermis
avoid inhalation) with reappearance of erythema shows parakeratosis. The route of entry of trichlo-
on the exposed area within a few hours and fleet- roethylene was from the respiratory tract, and it
ing exanthema on the trunk and in the flank. was believed to be a form of systemic trichloro-
ethylene toxicity in a sensitized individual.
9 Erythema and Exfoliation

9.2 Methyl Bromide
Exposure to some industrial organic chemicals,
e.g., trichloroethylene, appears to cause localized Exposure to methyl bromide was reported to
or generalized erythema with or without papular cause sharply demarcated erythema with vesicu-
and/or vesicular eruption to be followed by skin lation in six workers during fumigation work by
exfoliation. The skin eruptions usually take sev- Hezemans-Boer et al. (1988). Plasma bromide
eral weeks to clear. In most of cases, the skin levels after exposure strongly suggested percuta-
reaction was believed to be a toxic or allergic neous absorption of methyl bromide. The lesions
reaction from percutaneous or mucosal absorption were especially more prominent on the skin that
of the chemicals. was relatively moist or subject to mechanical
pressure, such as axillae, groin, and abdomen.
Microscopically, early skin lesions revealed
9.1 Trichloroethylene necrosis of keratinocytes, severe edema of the
upper dermis, subepidermal blistering, and diffuse
Generalized erythema followed by exfoliation infiltration of neutrophils. The skin lesions were
after exposure to trichloroethylene was reported believed to be due to the direct toxic effect of
by Schwartz et al. (1957). It was believed to be methyl bromide as an alkylating agent.
due to systemic sensitization to trichloroethylene.
The route of entry may be inhalation of the vapor
or percutaneous penetration or a combination of 10 Scleroderma-Like Reaction
both. Similar eruption was also documented by
Bauer and Rabens (1977). Solvents have been reported as predisposing or
Nakayama et al. (1988) also reported a gener- eliciting factors in some patients with sclero-
alized erythema and exfoliation with mucous derma-like reaction. The reaction is suspected to
membrane involvement in a patient exposed to result from repeated cutaneous contact with the
trichloroethylene. The patient gave positive solvent. The pathogenic mechanism is unknown.
patch-test reaction to trichloroethylene and tri- Walder (1983) reported six scleroderma patients
chloroethanol (its metabolite). It was believed who had close contact with aromatic hydrocarbon
solvents, such as benzene, toluene, and white spirit. References

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Occupational Connective Tissue
Disorders 29
Uwe-Frithjof Haustein and Bettina Lietzberg
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
2 Systemic Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
2.2 Silica (Quartz) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
2.3 Epidemiological and Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
2.4 Silica and Other Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
2.5 Silicon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
2.6 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
2.7 Vibration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
2.8 Human Lymphocyte Antigen Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
2.9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
3 Scleroderma-like Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.1 Vinyl Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
3.2 PVC Dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
3.3 Bis(4-Amino-3-methylcyclohexyl)Methane (Polymerization of
Epoxy Resins) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
3.4 Chlorinated Hydrocarbons, Aliphatic Hydrocarbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
3.5 Aromatic Hydrocarbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
3.6 Solvents in General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
3.7 Pesticides/Herbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
3.8 Mercury Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
4 Mixed Connective Tissue Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
5 Sjögren’s Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
6 Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
U.-F. Haustein (*) · B. Lietzberg

Department of Dermatology, Venerology and Allergology,
University of Leipzig, Leipzig, Germany
e-mail: ufh@medizin.uni-leipzig.de;
lietzberg-haut@t-online.de

https://doi.org/10.1007/978-3-319-68617-2_29
394 U.-F. Haustein and B. Lietzberg
7 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
8 Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Keywords Connective tissue disorders involving occupa-

Connective tissue disorders · Systemic tional factors are, first of all, systemic sclerosis
sclerosis · Systemic lupus erythematosus · (SSc), probably also lupus erythematosus (LE)
Dermatomyositis · Overlap syndromes · and very rarely dermatomyositis, mixed connec-
Rheumatoid arthritis · Scleroderma-like tive tissue disease (MCTD), rheumatoid arthritis
diseases · Silica · Quartz · Organic solvents · (RA), and Sjögren’s syndrome (Zschunke et al.
Long-term occupational exposure 1990; Koeger et al. 1991).
1 Core Messages 2 Systemic Sclerosis
• Systemic sclerosis (SSc) can be induced by 2.1 Introduction

long-term silica exposure.
• In terms of clinical and laboratory features, SSc, characterized by fibrosis of the skin and
this silica-induced scleroderma is indistin- internal organs, is a disease of unknown etiology
guishable from idiopathic scleroderma. with a pathogenesis that is still vague. The prev-
• Silica is able to trigger the immune alence in a Caucasian population is estimated at
system, vasculature, as well as fibro- 0.3–1.9/100,000 (Haustein and Albrecht 1993), in
blasts on the basis of an increased genetic geographic variation 31 to 658 per million
susceptibility. (Barnes and Mayes 2001). Women are affected
• Silica can also contribute to the pathogenesis three to six times more frequently (Medsger and
of other autoimmune diseases such as Masi 1971; Sluis-Cremer et al. 1985). In recent
(systemic) lupus erythematosus, dermatomyo- years, some environmental substances have
sitis, rheumatoid arthritis, overlap syndromes, been reported as inducing factors in SSc and
and Sjögren’s syndrome. in so-called scleroderma-like diseases (SLDs)
• If silica exposure has been long enough and its (Table 1). De Martinis et al. (2016) gave a current
concentration high enough under occupational overview of environmental risk factors in SSc.
conditions, SSc should be acknowledged as an
occupational disease and financially 2.2 Silica (Quartz)
compensated.
• Silicon (breast augmentation) does not induce Next to oxygen, silicon is the most common sub-
the so-called adjuvant disease. stance in the environment. Silicon has never been
• Organic solvents such as (chlorinated) found in its elementary state. In nature, it exclu-
aliphatic and aromatic hydrocarbons can sively occurs in compounds derived from silicon
trigger scleroderma-like diseases (SLDs) dioxide (silica = SiO2). Silica is a regular constit-
characterized by scleroderma and, in addi- uent part in about 92% of all sorts of rock.
tion, toxic effects to liver, kidney, nervous The three important crystalline structures of
system, sometimes absence of autoanti- silica are quartz, tridymite, and cristobalite.
bodies, and to some extent reversibility of These compounds are also called “free silica” to
the disease. distinguish them from the silicates, minerals
29 Occupational Connective Tissue Disorders 395
Table 1 Factors inducing systemic sclerosis (SSc) or miner) and nine female patients with SSc and
scleroderma-like diseases (SLDs), respectively suggested a greater incidence among miners than
SSc SLDs among nonminers. In the following years (from
Mineral Chemical compounds 1960 until 1969), 29 additional cases of SSc were
Silica Plastics registered in miners who had been working in the
Solvents Vinyl chloride South African gold mines. That corresponds to an
Chlorinated Epoxy resins (bis(4-amino-3- incidence of 7.7 cases per 100,000 miners per year
hydrocarbons methylcyclohexyl)methane)
in contrast with an incidence of 0.33 in 100,000 in
Aromatic Solvents
hydrocarbons a control group consisting of railway and harbor
Chlorinated hydrocarbons
workers. From 1955 to 1984, a total of 79 definite
Aromatic hydrocarbons
Aliphatic hydrocarbons
or probable cases of SSc in miners were regis-
Pesticides tered. These investigations were related exclu-
Drugs (e.g., bleomycin, sively to Caucasian individuals (Sluis-Cremer
pentazocine) et al. 1985). Cowie (1987) analyzed the occur-
Others rence of SSc in a native South African male pop-
Aniline and fatty acid anilides ulation. Among miners, he found an incidence of
(oleylanilides) 8.2/100,000 versus merely 0.3/100,000 among
Paraffin, silicon inhabitants serving as a control group. In the
Republic of South Africa, SSc has been acknowl-
containing silica bound to one or more metallic edged since 1974 as an occupational disease in
cations (American Thoracic Society 1997). miners that has to be compensated by law (Sluis-
From the chemical point of view, quartz is an Cremer et al. 1985).
extremely inert material. It cannot be destroyed by In the United States, Rodnan and colleagues
water or solvents. Only hydrofluoric acid is capa- (1967) analyzed the occupations of 60 male
ble of dissolving quartz. It may easily be detected patients with SSc. They reported that 26 of them
by crystallographic methods, e.g., X-ray diffrac- had been coal miners and ten of them had been
tometry and polarization microscopy, but it is foundry workers exposed to quartz sand. In eight
difficult to trace by chemical analysis. of the patients, SSc was associated with silicosis
of the lungs. This association between SSc and
silicosis has been confirmed by other groups
2.3 Epidemiological and Clinical (Beck et al. 1976; Ziegler et al. 1982).
Aspects One report on the increased prevalence of SSc
in workers exposed to silica dust, mainly in the
In 1914, the Scottish physician Bramwell reported mining of ores in the former German Democratic
a coincidence between “sclerodermia” and occu- Republic, was published in 1976 by Zschunke,
pations involving exposure to silica dust. Five of whose findings initiated a study that appears to
the nine patients who reported diffuse SSc worked be the most extensive evaluation until now
as stonemasons. Bramwell supposed that holding (Zschunke 1976). A first analysis, which included
the chisel and working under cold-weather out- all SSc patients of the whole country, was
door conditions might be work-associated causa- performed by Ziegler and colleagues in 1981
tive factors (Bramwell 1914). and revealed that 77% of all male patients with
Erasmus (1957) observed 17 cases of SSc SSc had been exposed to silica dust in the work-
among 8000 underground miners in South Africa, place. In addition, half of the patients showed
six of them with silicosis. In order to get an simultaneous silicosis of the lungs (Ziegler et al.
impression about the morbidity of SSc, he exam- 1981, 1982, 1986; Haustein and Ziegler 1985).
ined 25,000 male and 27,000 female infirmary Continuing this evaluation, records are currently
patients. He found one male patient (also a available on 137 male patients with SSc. Silica
dust exposure was established in 111 of these Table 2 Occupations of systemic sclerosis patients of the
patients, and silicosis was found in 57 of them Leipzig group with verified silica dust exposure (n = 111)
(Haustein and Herrmann 1994). The comparable Occupation Number of patients
occupational silica exposure in the general popu- Miner 77
lation of an industrial area is estimated as being Foundry worker 10
10% or less. Utilizing epidemiological tools, the Quarryman 6
following risk was calculated. The likelihood Sandblaster 5
(odds ratio) that SSc will develop in men with Dental mechanic 4
Sandstone sculptor 3
silicosis who are older than 40 years of age is 12
Glass grinder 3
times higher than in workers who are the same
Cast polisher 3
age but not exposed to silica dust. Ten female
patients with SSc were also exposed to silica dust
in the workplace. One of them had also devel- Today, only a few patients are still alive or have
oped silicosis. In contrast to the male patients, been recently diagnosed.
the epidemiologic research concerning females It is possible that sclerosis of the lungs, fibrosis
lacks evidence, probably due to their small due to nonspecific dust impact, and genuine sili-
numbers. cosis might be confused in several cases; how-
All the patients fulfilled the criteria of the ever, fibrosis of the lungs accompanied by SSc
American College of Rheumatology (ACR). obviously occurs in subjects exposed to silica dust
The average time of exposure was 13.6 years. rather than in those who have not been exposed in
The delay in symptomatic disease (from begin- such a way. The rate of silicosis in the male
ning of exposure to onset of SSc) was 24.3 years patients with SSc presented in this group is higher
on average. In some cases, the silica exposure than the number reported by Erasmus (1957) and
lasted until the onset of SSc. The majority of Rodnan et al. (1967). This difference might be
pulmonary silicosis started before SSc in 41 of explained by regional variations in defining sili-
57 (72%); the reverse was true in a minor frac- cosis in the past, by differences in the composition
tion (19%). In 9%, both diseases were detected at of the rocks, and at least in several cases by the
the same time. From the remaining 54 SSc radioactivity of the uranium. Progress in the dif-
patients without silicosis, 25 (46%) developed ferential diagnosis has been achieved by high-
lung fibrosis within 2 years. Raynaud’s phenom- resolution computer tomography. In 1959, 6 SSc
enon was observed as a preceding or concurrent patients with silicosis were reported in Italy
symptom in 107 of the 111 silica-dust-exposed (Francia et al. (1959).
SSc patients (96%). Skin involvement occurred Sluis-Cremer et al. (1985) suggested that a
before pulmonary symptoms in 36 of 111 (32%), brief exposure to dust with high silica content
at the same time in 5 of 111 (5%), after silicosis causes SSc without simultaneous silicosis. This
in 41 of 111 (37%), and in 29 of 111 (26%) would imply that the mode of exposure deter-
patients no respiratory disorders were observed. mines whether SSc with or without silicosis
The occupations of the silica-exposed SSc might develop. Haustein and colleagues (1986)
patients are listed in Table 2. Fifty-seven of the do not share the opinion that SSc in these patients
77 miners were exclusively exposed through ura- is not idiopathic SSc, but rather should be labeled
nium mining, 8 through coal mining, and 12 as SLD (Siegel 1977). The symptomatic criteria
through both. Forty-two of the 111 patients have for diagnosing SSc (compiled by the ACR; Masi
never worked in uranium mines. Twelve of these 1980) have been fulfilled by almost all patients
42 suffered from silicosis. The odds ratio of the 42 investigated (Table 3). According to this view,
patients who never worked in uranium mines to Rodnan et al. (1967), Rustin et al. (1990), and
develop SSc was still 3.9. Since uranium mines Gabay and Kahn (1992) emphasized the lack of
were shut down between 1980 and 1989, only the differences between so-called idiopathic SSc and
sequelae of this exposure could be followed up. SSc in patients with silicosis.
Table 3 Clinical features and laboratory findings of sys- Table 4 Workplaces associated with silica dust exposure
temic sclerosis patients associated with silicosis (n = 37), (According to Zschunke et al. 1990)
limited: diffuse form = 22:15
Mining industry Underground workers
Number Extracting and processing Quarrymen, crushers,
Symptoms/ of Limited Diffuse of stones (sandstone, sculptors, stonemasons,
laboratory findings patients form form granite, slate, fluorspar, workers producing slate
Raynaud’s 36 21 15 mica) pencils, workers handling
phenomenon slate powder, e.g., as a
Fingertip ulcers 28 15 13 carrier for
Arthralgia 28 13 12 hexachlorocyclohexane
insecticides, workers
Lung involvement 37 22 15
producing roof paper
Esophagus 29 16 13
Producing and processing Grinders, mixers, stove
involvement
of chamotte blast furnace- fitters
Heart involvement 11 3 8 lining bricklayers
Muscle 9 2 7 Foundry industry Molders, coremakers,
involvement casters, cast dressers
Kidney 5 0 5 Tire industry and Workers handling talc that
involvement industries producing other is sometimes heavily
Antinuclear 35 20 15 products made from
antibodies (ANAs) natural or synthetic
Antitopoisomerase 13 1 12 rubber, e.g., cables
antibodies (ATAs) contaminated by silica
Anticentromere 9 8 1 Industries producing Workers handling raw
antibodies (ACAs) pottery including material, in particular sand
Platelet factor 4 27 14 13 glassware and kaolin; the latter also
regularly contains
β-Thromboglobulin 27 15 12
considerable quantities of
Endothelin 17 7 10 silica
Dental technical Dental technicians
laboratories (polishing
Typical workplaces in which exposure to sil- and embedding materials)
ica dust must be taken into account are listed in
Table 4. However, numerous hidden sources of
silica exposure exist, e.g., cleansers used in on polishing watches with an abrasive agent com-
housekeeping (Mehlhorn et al. 1990; Koeger et posed mainly of aluminum, chromium dioxide,
al. 1992) and polishes used in various jobs. Even and silica, obviously the first patient in association
fondant powders contained quartz in the past and with chemical agents.
were found to be a cause of silicosis (Beck and It is also known that dental technicians are
Irmscher 1974). Silicosis was also observed in exposed to various particulate matters including
female laundry workers washing dust-contami- silica, alloys, and acrylic plastics, which may
nated clothes (Evans and Posner 1971). One induce pneumoconiosis and probably other occu-
anecdote refers to a husband and his wife who pational lung diseases (Choudat 1994). Three epi-
both developed SSc, the husband after silica demiological studies have reported a prevalence
exposure and his wife probably by inhaling of pneumoconiosis 1/0 or greater of about 15% in
dust from his clothes (Christy and Rodnan technicians with 20 or more years of exposure.
1984). Koeger et al. (1992) reported of two However, silica is probably not the sole causative
patients who developed edematous scleroderma agent. Since pneumoconiosis is a frequent risk
and subluxing arthropathy, respectively, after among dental technicians, compensation should
applying aerosolic silicon glaze on cables over be paid to those suffering from this work-related
a 20-year period. disease (Choudat 1994).
Yamamoto et al. (1994) described a patient Yanez-Diaz et al. (1992) presented two male
with nodular scleroderma who had been working patients with SSc and pulmonary silicosis after
occupational exposure to silica and one of them to odds ratios were nonsignificantly increased among
trichloroethylene as a degreasing agent. Michigan woman potentially exposed to “silica
Gabay and Kahn (1992) have analyzed 202 dust, sand or other silica products” (Burns et al.
SSc patients diagnosed at the Rheumatology 1996) and among crystalline silica exposed men
Department, University Bichat (Paris), since from Italy (Bovenzi et al. 1995).
1976. Among them were 39 male patients In a meta-analysis of Medline, Toxline, BIOS,
(women/men = 4.2/1). Twenty-five men were and Embase (1949 and 2009), McCormic et al.
included in a subsequent study, 14 of them with (2010) calculated the combined estimator of rela-
a high occupational risk and a duration of expo- tive risk (CERR) of occupational silica exposure
sure between 4 and 33 years (mean SD for scleroderma as 3.20 (95% confidence interval
14.5 11.4 years). Eleven of them had been 1.89–5.43), for males 3.02 (95% CI 1.24–7.35),
exposed to silica dust (as miners, foundry and for females 1.03 (95% CI 0.74–1.44). In the
workers, or bricklayers), one to solvents (as a case-control studies, it was 2.24 (95% CI
painter), and two to both. The mean age at onset 1.65–3.31) and in the cohort studies 15.49 (95%
of disease was 50.4 10.19 years (range CI 4.54–52.87).
31–72 years) with Raynaud’s phenomenon before Individuals with silicosis have a 28-fold risk of
onset of disease in 24 cases (mean duration developing SSc (Makol et al. 2011). Lately, Marie
6 months). The delay between the beginning of et al. (2014) confirmed a significant risk between
exposure and onset of disease was SSc and exposure to crystalline silica (OR 5.32;
24.4 12.2 years (range 4–45 years). There p = 0.0001) only in males (OR 9.63; p = 0.0001).
were no significant differences between the two The risk appears to be markedly associated with
groups (induced SSc versus “primitive” SSc) cumulative exposure.
regarding age at onset of disease, mortality, sys- Freire et al. (2015) reviewed 32 published
temic manifestations except myositis (which series (MEDLINE, EMBASE) from 1985 to
occurred only in the “primitive” group), therapy, 2013 with clinical data in 254 silica-exposed SSc
antinuclear antibodies (ANAs), and anti-Scl-70 patients (96% males) with the predominance of
antibodies [anti-topoisomerase antibodies diffuse forms (61%) and interstitial lung disease
(ATAs)]. Among the 163 female patients, there (81%). Their own group (n = 9) showed predom-
was no silica-induced case. inance in diffuse, anti-Scl70 positive, interstitial
In an Australian population-based case-control lung disease positive forms, with lower survival as
study, Englert et al. (2000) found 60 out of 160 compared to nonexposed man (Rocha et al. 2016).
SSc patients with silica exposure (odds ratio 3.93) Similar findings described Marie et al. (2015),
including a long latency and clinical characteris- namely, a correlation of silica exposed SSc
tics indistinguishable from idiopathic disease. (n = 18) with more severe diffuse forms, intersti-
Maitre et al. (2004) reported on 93 SSc patients tial lung disease, digital ulcers, myocardial dys-
(10 men, 83 women). Construction workers were function, and association with cancer, the latter
at higher risk (odds ratio = 4.01). This was not one with 1.5 to5 fold risk.
strictly related to silica exposure rather than due to Case reports and epidemiological studies
various other offenders simultaneously. reporting on patients suffering from SSc and sili-
Smith et al. (2008) reported on a tenfold higher cosis are summarized in Table 5.
prevalence of construction-related professions in
males with SSc than in the general working pop-
ulation preferentially in electricians in 91 patients, 2.4 Silica and Other Autoimmune
20 of them males in Belgium. Diseases
Surprisingly, the occupational analysis of 56
men with SSc in the United Kingdom showed no Evaluating 764 patients with connective tissue
evidence of silica exposure implicated in the onset disease (CTD) hospitalized in the clinic of the
of the disease (Silman and Jones 1992). In addition, University Pitiè/Salpétière/Paris, Koeger et al.
Table 5 Published cases of systemic sclerosis (SSc) in association with silica exposure and silicosis, respectively
Year Author Cases Diagnosis Occupation Exposure
1914 Bramwell 5 Diffuse Stonemasons Silica dust
scleroderma
1957 Erasmus 17 SSc, six with Underground miners Silica dust
silicosis
1959 Francia et al. 6 SSc and
silicosis
1967 Rodnan et al. 36 SSc, eight 26 coal miners, 10 Silica dust (coal
with silicosis foundry workers miners), quartz
sand (foundry
workers)
1955–1984 Sluis-Cremer et al. 79 SSc Gold miners Silica dust
(including the cases of
Erasmus 1957)
1987 Cowie 10 SSc, six with Gold miners Silica dust
silicosis
1981–1997 Haustein and 111 SSc, 57 with Uranium mining (57), Silica dust
Herrmann (1994) silicosis coal mining (8), both (uranium)
(some of these patients (12)
were also reported by
Ziegler et al. 1986;
Baur 1994; Mehlhorn
1994)
1984 Christy and Rodnan 2 SSc The husband Silica dust
developed SSc after
silica exposure and his
wife probably by
inhaling dust from his
clothes
1990 Mehlhorn et al. 1 SSc Cleaning woman Scouring powder
containing
crystalline silica
1992 Koeger et al. 1 Edematous Sprayed silicon glaze Silicon glaze
scleroderma on cables
1992 Yánez-Díaz et al. 1 SSc, silicosis Lead mine Silica dust
1992 Yánez-Díaz et al. 1 SSc, silicosis Lead mine Fiberglass,
(trichloroethylene)
1992 Gabay and Kahn 11 SSc Miner, foundry Silica dust
worker, bricklayer
1992 Gabay and Kahn 2 SSc Miner, foundry Silica and solvents
worker, bricklayer
1994 Yamamoto et al. 1 Multiple Polishing watches Abrasive agent
papules in an (aluminum,
area of chromium
nonsclerotic dioxide, silica)
skin in SSc
1995 Koeger et al. 8 SSc, three Underground worker, Silica dust
with silicosis sand molder, dental
prosthetist, foundry
engineer, marble
sculptor, miner,
sandblaster, mason,
sandstonecutter
(continued)
Table 5 (continued)
Year Author Cases Diagnosis Occupation Exposure
1996 Wichmann et al. 12 SSc Scouring powder Silica content:
(including the patients 70–90%
reported by Sanchez- powdered quartz
Roman et al. 1993)
Total = 287
2000 Englert et al. 60 of 160 SSc Population-based Odds ratio 3.93
study
2002 Diot et al. 10 SSc Case-control study Odds ratio 3.74
2003 Calvert et al. 2 of 2895 SSc US national Mortality odds
death occupational mortal ratio 2.00
certificates surveillance
2004 Maitre et al. 4 of 93 (10 SSc Case-control study
men, 83
women)
2004 Bovenzi et al. 3 of 55 SSc Worker in the pottery Ceramic materials
industry case control Odds ratio 1.7 and
5.2 (1995) resp.
2008 Smith et al. 10 of 20 SSc Construction-related Prevalence tenfold
occupations higher
2010 McCormic et al SSc Meta-analysis, 16 Rel risk 3.02 male,
series 1.03 female
2015 Marie et al 18 of 142 SSc, diffuse, Case control OR 5.92
ILD, digital OR 9.63 male
ulcers,
myocardial
dysfunction,
cancer
2015 Freire et al. 7 m, 2f of SSc, diffuse, Sandblaster bricklayer Meta-analysis
2016 Rocha et al 254 ILD, stone work (marble) 32 series
antiScl70, cutter shotfirer Own SSc pat. 9
lower milling, granite kaolin
survival
Total = 327
(1995) found 24 (3%) patients with silica-associ- rich in silica for 12 years developed a CTD
ated CTD. Eight of them had SSc, in four cases in consisting of destructive inflammatory
association with Sjögren’s syndrome, and in three oligoarthritis, Gougerot-Sjögren’s syndrome,
cases in association with silicosis. RA has been Raynaud’s syndrome, ANA, and hypo-
found in five patients (four in association with complementemia. Another woman, who had
Sjögren’s syndrome), systemic LE in four patients sprayed silicon glaze on cables for 15 years, suf-
(three with silicosis), discoid LE in one patient, fered from edematous SSc. A man who had
and dermatomyositis in association with applied the same silicon glaze on cables over a
Sjögren’s syndrome in three patients. The last 20-year period developed a subluxing arthropa-
three patients had erosive polyarthritis and thy. The authors pointed out that these means of
Sjögren’s syndrome, Grave disease, and inflam- exposure have not been reported previously and
matory polyarthralgia. Three additional cases of merit recognition in the name of future
autoimmune diseases after unusual exposure to prevention.
silica or silicons have been reported by the same Steenland and Brown (1995) updated a study
authors (Koeger et al. 1992). A woman who had of 3328 gold miners who worked underground for
extensively used an abrasive cleansing powder at least 1 year between 1940 and 1965 in South
Dakota. Multiple-cause analysis revealed signifi- risk of developing SSc and systemic LE than miners
cant excesses of arthritis, musculoskeletal dis- with slight or no exposure, because they showed
eases, and various cutaneous disorders a higher frequency of SSc-specific autoantibodies
(including SSc and systemic LE). [anticentromere antibodies (ACAs), ATAs,
Evidence that occupational exposure to silica is antinucleolar antibodies] related to the intensity of
also associated with autoimmunity was reinforced the silica exposure and to preceding symptoms of
by the observation that workers from a factory that SSc (Raynaud’s phenomenon, diffuse interstitial
produced scouring powder with an increased sil- lung fibrosis).
ica content (70–90% powdered quartz) exhibited By summarizing various studies and case
a high prevalence of clinical and biological auto- reports, Gregorini (working in Brescia)
immune manifestations (Table 6). Among a group showed that extrapulmonary silicotic lesions
of 50 workers, Sanchez-Roman et al. (1993) dem- and/or autoimmune processes may play a
onstrated symptoms of systemic illness in 32 role in kidney diseases after silica exposure,
(64%) and ANA in 36 (72%) of them. more specifically MPO-ANCA-positive
Wichmann et al. (1996) showed that individ- microscopic polyangiitis and its renal-limited
uals chronically exposed to silica, independent of form of “idiopathic,” rapidly progressive
whether they are suffering from CTD, have anti- glomerulonephritis (Conrad et al. 1997).
bodies to myeloperoxidase (MPO) as detected by In conclusion, silica may induce systemic
enzyme-linked immunosorbent assay (ELISA) in diseases with various clinical and sero-
a range higher than the normal population and in logical manifestations: systemic sclerosis with
the same range as systemic diseases not induced ACA, ATA, or antinucleolar antibodies,
by silica (i.e., systemic LE, SSc). systemic LE and systemic LE-like diseases
In 9 of 11 patients with silica exposure and with anti-dsDNA and/or anti-RO/SS-A and
renal involvement with systemic vasculitis, Che- anticardiolipin antibodies, and necrotizing
valier et al. (working in Angers) found various systemic vasculitis with renal involvement
antibodies indicative of autoimmunity, such as and MPO-ANCA (Conrad et al. 1997).
MPO-antineutrophil cytoplasmic antibodies
(ANCAs) and ANA at low titers, with anti-RO/
Sjögren’s syndrome A in two patients, but 2.5 Silicon
without anti-double-stranded DNA (dsDNA)
(Conrad et al. 1997). For many years, controversial discussions contin-
Conrad et al. (1997) demonstrated that uranium ued concerning whether silicon breast implants
miners with heavy exposure to silica run a higher performed for augmentation mammaplasty are
Table 6 Autoimmune diseases in association with silica exposure (According to Sanchez-Roman et al. 1993; Wichmann
et al. 1996)
Sanchez-Roman et al. (1993), 50 workers; Wichmann et al. (1996), 52 workers, same
number (%) factory; number (%)
Systemic sclerosis (SSc) 5 (10) 12 (23)
Systemic lupus 3 (6) 16 (31)
erythematosus (SLE)
Polymyositis (PM) 1 (2)
Overlap syndrome 5 (10) 7 (14) (included in SLE, SSc, PM, and
(SLE/SSc) undefined collagen disease)
Secondary Sjögren’s 6 (12) (included in the three first clinical
syndrome diagnosis)
Undefined collagen 19 (38) (including three cases of primary 15 (29)
disease Sjögren’s syndrome)
Asymptomatic subjects 19 (38) 15 (29)
able to cause autoimmune disease and SSc. The significantly increased risk in the adjusted analy-
term “human adjuvant disease” was introduced by sis restricted to silicon-gel-filled implants. This
Miyoshi et al. in 1964, who reported two patients meta-analysis was conducted both with and with-
with CTD after direct injections of paraffin and out adjustment for confounding factors
silicon to augment breast size. Later, implantable (Janowsky et al. 2000). Kjoller et al. (2001)
cushions of silicon gel or saline were applied. came to similar conclusion for 2761 Danish
After a delay of approximately 20 years, 50 of women with cosmetic silicon breast implants
85 subjects treated in this way suffered from a (8807 control subjects). Karlson et al. (2001) did
definite CTD, including 25 patients with SSc, 13 not found signs of activation of the immune sys-
with RA, 8 with systemic LE, and 4 with MCTD tem such as elevated levels of C3, C4, or antinu-
(Hochberg 1993). In addition, corresponding clear antibodies.
autoantibodies, including antisilicon antibodies, Finally, it is doubtful whether silica can be
were detected. Apart from leakage in the sur- released from silicon. Using electron-probe
rounding tissue followed by foreign body granu- microanalysis, however, it has been shown
loma, connective tissue formation, and fibrosis, that silicon or even silica may escape from
the current scientific literature no longer supports breast implants (even without frank rupture)
the idea of systemic autoimmune diseases, due to and may migrate beyond the capsule to
a lack of convincing evidence that implants are a regional lymph nodes and distant sites where
major risk to the integrity of the immune system. inflammatory and fibrotic processes can
This is confirmed by a retrospective cohort take place, triggered by vacuolated, silica-incor-
study evaluating 395,543 women via a question- porating macrophages (Varga et al. 1989; Silver
naire. The self-reported data indicated that the et al. 1993).
relative risk of any CTD among the women with
implants was 1.24 (Hennekens et al. 1996). Sim-
ilar results were reported from three university- 2.6 Pathogenesis
based tertiary-care scleroderma research centers
with 837 women and 2507 race-matched local Silica-associated SSc is clinically, serologically,
control individuals. The adjusted odds ratio was and immunologically indistinguishable from idi-
1.07 versus 1.11 (no significant difference) opathic SSc (Haustein and Ziegler 1985; Rustin et
(Hochberg et al. 1996). al. 1990; Gabay and Kahn 1992).
In addition, Burns et al. (1996) reported on a Quartz is absorbed both via inhalation and
population-based case-control study among 274 percutaneously. Silicosis of the lung is caused by
female patients with SSc and 1184 controls in particles with a diameter of less than 5 μm. The
Michigan. They found no increased risk of SSc orifice of the sebaceous glands in healthy individ-
among women with silicon breast implants, uals is approximately 24 times wider than the
equivocal evidence of risk from other silicon particle size relevant for silicosis. At the extrem-
exposures, and no evidence of risk from silica ities, there are up to 50 follicles per square centi-
exposure. In an US retrospective cohort study meter (Plewig and Kligman 1978). Miners
between 1960 and 1996, Brinton et al. (2003) experience microinjuries of their hands and fore-
showed that the results of self-reports of connec- arms quite frequently. Therefore, it is not surpris-
tive tissue disorders are influenced by reporting ing that about 150 particles of quartz between 1
and surveillance biases. and 20 μm could be traced in a single biopsy
The meta-analyses of nine cohort studies, nine specimen (Ziegler et al. 1988).
case-control studies, and two cross-sectional stud- In several patients, Ziegler and colleagues
ies did not give evidence that breast implants were (1988) determined the silica content in skin spec-
associated with a significant increase in the sum- imens obtained from fingers, dorsum of the hand,
mary adjusted relative risk of individual connec- and lower arms by polarization and phase-contrast
tive tissue disease. Nor was there any evidence of microscopy and in two cases by electron
spectroscopy for chemical analysis. As shown in remains in the tissue over an extended period.
Table 7, silica crystals can be found in a high Nevertheless, it has toxic effects on macrophages
percentage of silica-exposed subjects. In the in a dose-dependent manner. After phagocytosis
majority of occupations, the mechanical forces and destruction of these cells, silica is set free
(e.g., in air or compressed air, drilling, or hewing) in the tissue, and the process of ingestion
are substantial and may promote the penetration through phagocytosis might start again. In this
of silica crystals by microwounding. However, way, a vicious cycle of a dysfunctional inflamma-
these data do not distinguish patients from silica- tory response is established (Haustein and Herr-
exposed miners without skin and lung diseases. mann 1994).
This mechanism of penetration might serve as However, Adamson et al. (1989) have shown
an explanation for the observation that symptoms that silica and irradiation are each able to enhance
start at the distal portions of extremities in the the number of interstitial cells in the lung. In
majority of cases. addition, the content of cells, protein, and
Silica particles are ingested by macrophages hydroxyproline is increased in bronchoalveolar
(Fig. 1), e.g., in the lung or skin, and can be lavage fluids. Taken together, irradiation plus sil-
transported to extrapulmonary sites (Holt 1981). ica exposure might lead to a synergistic enhance-
Subsequently, activated macrophages release ment of their effects.
enhanced amounts of interleukin (IL)-1α and β Obviously, the endothelial cell damage
(Oghiso and Kubota 1986). Similarly, silica-stim- occurs early, before systemic symptoms appear.
ulated monocytes can release fibroblast-prolifera- This is suggested by the observation that Ray-
tion-inducing factors (Schmidt et al. 1984), naud’s phenomenon often precedes SSc and by
leading to stimulation of collagen production by elevated levels of von Willebrand factor and
fibroblasts, too. The spontaneous secretion of IL-1 circulating immune complexes not only in sil-
from silicotic rat alveolar macrophages can be ica-induced SSc, but also in healthy silica-
inhibited by anti-Ia antibodies (Struhar and exposed miners.
Harbeck 1989). Furthermore, silica added to anti- Concerning the involvement of blood vessels,
gen- or mitogen-stimulated lymphocyte cultures Dowd and Ziegler (1987) demonstrated decreased
increases the number of immunoglobulin-secret- formation of prostacyclin, a vasodilating lipid
ing cells (Moseley et al. 1988). IL-1α and β also mediator originating from endothelial cells. The
affect T-helper lymphocytes promoting produc- lack of prostacyclin formation was shown in
tion, and release of IL-2. IL-2 may stimulate B patients with Raynaud’s phenomenon as well in
lymphocytes synthesizing immunoglobulins and patients with SSc who had been exposed to silica.
(auto) antibodies. Activated T lymphocytes also Furthermore, there are certain patterns of ultra-
produce other lymphokines (e.g., macrophage- structural changes of the endothelial layer which
activating factors) which are capable of stimulat- seem to be characteristic of SSc (Haustein and
ing macrophages and fibroblasts. Klug 1975; Haustein et al. 1986). Accordingly,
These mechanisms are continuously triggered subintimal fibrosis of small arteries has been
by silica, which is not chemically reactive and described by Fleischmajer et al. (1983).
Silica seems to be a potent activator of
endothelial cells in vitro, too. Incubation of
Table 7 Silica in exposed skin areas human dermal microvascular endothelial cells
Positive/ (HDMECs) with silica at nontoxic concentrations
Subjects total increased the steady-state levels of the messenger
Silica-induced SSc 24/26 RNA (mRNA) for intercellular adhesion molecule
Silicosis 4/5 1 (ICAM-1), and also increased the corresponding
Silica-exposed miners (without SSc/ 3/5 levels of this cell-surface protein as shown by fluo-
silicosis)
rescence-activated cell-sorter (FACS) analysis; the
Nonexposed controls 1/6
incubation also increased the level of soluble
Fig. 1 Silica can activate various cell types involved in Dermal fibroblasts are affected by silica in vitro, and fibro-
the pathophysiology of systemic sclerosis (SSc) Macro- blasts are the cells producing large amounts of extracellular
phages activated by silica in vitro liberate the same cyto- matrix in vivo. In vitro, the synthesizing capacity of fibro-
kines and growth factors known to be active in the blasts depends greatly on culture conditions. All these
pathophysiology of idiopathic SSc. Microvascular endo- effects are based on the in vitro experiments with silica
thelium is involved in silica-induced as well as idiopathic shown in italic. These effects are similar to pathophysio-
SSc with similar activation patterns in vitro and in vivo. logical events known from idiopathic SSc
protein in the culture fluid, as shown by means of increased collagen synthesis in silica-associated
ELISA, in a dose- and time-dependent manner. SSc.
Additionally, increased levels of IL-6 in the culture The incubation of fibroblasts in culture with
supernatants have been found. In addition, a signif- silica demonstrated the induction of interstitial
icant increase in collagenase I mRNA in HDMEC collagenase I mRNA and protein in the monolayer
has been demonstrated (Anderegg et al. 1997). and a decreased ability to contract collagen fibers
The intratracheal instillation of silica crystals in a three-dimensional gel. Unexpectedly,
(α quartz) into the lungs of C57BI/6 mice resulted Anderegg and colleagues (1996) could not find
in a significant increase in levels of ICAM-1 in an increase in the expression of collagen I or III
lung tissue and bronchoalveolar lavage fluids mRNA.
(Nario and Hubbard 1996). Taken together, the enhanced expression of
In patients with SSc, Frank et al. (1993) found ICAM-1 by endothelial cells might cause
a slight decrease of IL-1 basal secretion from enhanced adhesion of activated (and activating)
monocytes in comparison with healthy volunteers mononuclear cells to the microvascular wall.
and no changes in IL-6 and tumor necrosis factor Together with increased collagenase activities
α (TNF α) production. In monocyte-enriched cul- originated from endothelial cells and the neigh-
tures from healthy donors, a dose-dependent mod- boring dermal fibroblasts, the extravasation of
ulation of the cytokine pattern (IL1 α, IL-1 β, IL-6, monocytes into the surrounding tissue could be
TNFα) could be demonstrated after silica phago- realized. The resulting perivascular infiltrate may
cytosis. Using titanium dioxide for phagocytosis, take part again in the activation of fibroblasts to
no comparable effects were observed. The impact produce more collagen and matrix proteins in skin
of silica on cytokine secretion of monocytes or lung tissue. The mechanism of SSc due to silica
might explain inflammatory tissue reactions and is summarized in Fig. 1.
Recent studies discuss the induction of CD 69 2.7 Vibration

expression in peripheral blood mononuclear cells
on silica exposure (Wu et al. 2004), alterations of Vibrations caused by pneumatic tools are known
Fas and Fas-related molecules, in particular alter- to induce Raynaud’s phenomenon, which
natively spliced variant messages of Fas gene, and regresses after cessation of the exposure. To
attenuated function of the CD4+ CD25+ T cell what extent vibration hammers, which are often
function due to silica (Otsuki et al. 2000, 2007). used in mining and treating stones, take part in
In addition, Brown et al. (2004a, b) reviewed in promotion of SSc is still vague (Blair et al. 1974).
detail the effect of silica on Fas/Fas-ligand, caspase However, it is extremely unlikely that some of the
activation, TNFα, protein kinase C, as well as on T patients, such as sandblasters, glass grinders, cast
and B lymphocytes, thereby explaining the pro- polishers, and stove fitters, have ever worked with
gression from an autoimmune response into sys- pneumatic tools. Increased incidences of
temic autoimmune disease and helping to Raynaud’s phenomenon, sclerodactyly, and
understand the etiology of environmental autoim- edema of the hands were observed in chainsaw
mune disease process (Yoshida and Gershwin workers and in individuals operating jackham-
1993). Finally, Xiong et al. (2008) found in a mers (Nagata et al. 1993). In two case-control
state-space model for the regulatory network that studies in the provinces Trento (n = 21) and
TGFβ pathway under perturbation of silica shows Verona (n = 55), Bovenci et al. (2001) did not
significant differences in dynamic properties show a significant association between sclero-
between normal and scleroderma fibroblasts. derma and hand-transmitted vibration probably
In an experimental study with 20 brown Nor- owing to the rarity of the disease and the small
way rats, Al-Mogairen (2010) has shown that number of cases. Bovenzi et al. (2001) ruled out a
subcutaneous sodium silicate administration significant association between SSc and hand-
(3 mg) induced serum ANA and anti-RNP, transmitted vibration.
but neither Scl 70 nor ACA antibodies after 7
and 14 weeks, respectively, i.e., to some extent
scleroderma-related autoantibodies, but no 2.8 Human Lymphocyte Antigen
sclerodermatous lesions. The histology of the Association
injected areas has not been investigated.
Altogether, silica exposure activates T-cells The association of immunological disorders to
resulting in increased levels of soluble IL-2 recep- certain human lymphocyte antigen (HLA) alleles
tor and hampers Treg development/expansion and emphasizes the role of genetic factors determining
causes functional deficits and possibly loss of susceptibility to environmental factors (Table 8).
tolerance (Rocha-Parise et al. 2014). In associa- Rihs et al. (1994) analyzed the association of
tion, the increased inflammasome reactivity may circulating autoantibodies and HLA alleles in 71
trigger cytokines like IL-10 and TGF-ß. Lee et al. uranium miners and 1 cleaning woman. They
(2012) reported on the chronic activation of Tresp could show a positive correlation of anti-Scl-70
and Treg cells by silica exposure, dominant to DR3 (1 0300) and DQ2 (1 0201) as well as of
expression of FoxP3, and cytotoxic T-Lympho- ACA to DR1 (1 0101-1 0103), DR8 (1 0801-1

cyte antigen 4 (CTLA-4) in the CD4+ 25+ frac- 0804), and DQ4 (1 0400). Significant differ-
tions. Finally, inflammasome activation is argued ences between affected and unaffected miners
to occur following uptake of silica by scavenger have not been observed.
receptors, lysosomal rupture, and release of In addition, Rihs et al. (1996) studied the
cathepsin B accompanied by production of reac- genetic association of HLA-DPB1 alleles in 54
tive oxygen species (ROS) and potassium efflux patients with idiopathic SSc, 26 uranium miners
(Pollard 2016). This results in apoptosis of mac- with SSc, and 70 unrelated, healthy control sub-
rophages and the release of proinflammatory jects. SSc patients with and without former
mediators again. employment in mines were assigned to two
Table 8 Association between human lymphocyte antigen silica-associated SSc patients, and DRB1 0800
(HLA) alleles and several subgroups of systemic sclerosis and DQB1 0402 were elevated in ACA-positive,
(SSc) patients (According to Rihs et al. 1994, 1996; Baur
et al. 1996; Conrad et al. 1997) silica-associated SSc patients compared with
unrelated controls and the idiopathic SSc group
SSc
Circulating patient studied (Conrad et al. 1997).
autoantibody subgroup HLA alleles One TNFα2 allele (associated with an
Anti-Scl-70/ Uranium DR 3 (DRB increased TNF production capacity) was only
antitopoisomerase miner 1*0300), DQ2 increased in silica-associated SSc, indepen-
antibodies (DQB 1*0201) dently of any DRB alleles. The prevalence of
Silica- DRB 1*0301, DQB TNFα2 in ATA responders was significantly
associated 1*0201
SSc different between idiopathic SSc (decreased
Idiopathic DPB 1 (1*1301, compared with controls) and silica-associated
SSc *0601, *1701) SSc patients (increased). A similar result
Anticentromere Uranium DR 1 (1*0100, was found with TNFα-308A. The results of this
miners *0101-*0103), DR study reinforce the idea that not only structural
8 (1*0800, *0801-
*0804), DQ
conditions of antigen binding encoded by
(1*0400) major histocompatibility class-II genes, but
Silica- DRB 1*0800, DQB also an association to a certain TNF region,
associated 1*0402 may be important for the generation of an
SSc immune response through regulation of TNF
production, which is modified in silica-associ-
ated SSc patients due to continuous ingestion
subgroups according to their scleroderma-specific of silica by macrophages (Conrad et al. 1997).
autoantibody pattern – anti-Scl-70 positive and In Japan, Ueki et al. (2001) found a different
ACA positive – and a third subgroup comprising distribution of HLA class II alleles in anti-
the rest. Statistical analysis revealed a signifi- topoisomerase I antibody responders between
cantly increased frequency of DPB1 1301, silicosis and systemic sclerosis patients, with a
DPB1 0601, and DPB1 1701 ( p = 0.0001, common distinct amino acid sequence in the
corrected p = 0.011) in idiopathic anti-Scl-70- HLA-DQB1 domain.
positive SSc cases when compared with
unexposed controls. Since these three alleles con-
tain the genetic information encoding a glutamic 2.9 Conclusion
acid residue in position 69 of DPB1, a strong
association of this residue with anti-Scl-70 As silica cannot be removed from the body once it
expression was observed in idiopathic SSc is incorporated, its deleterious precipitating effect
patients when compared with anti-Scl-70-nega- is unavoidable. This indicates that the clinical
tive idiopathic SSc patients ( p = 0.0009) or course of silica-induced disorders is quite similar
unrelated controls ( p = 0.0007). ACA expression to classical autoimmune diseases or SSc, charac-
was not associated with the presence of any DPB1 terized by progressions and remissions. The sub-
allele tested. The data show that anti-Scl-70 sequent therapy should take these findings into
expression in idiopathic SSc patients is linked account and has to be adjusted according to the
with DPB1 1301, whereas anti-Scl-70-positive criteria for the extent, organ involvement, and
miners do not exhibit such a DPB1 association. clinical activity of the disease. The best way to
Furthermore, the data indicate that glutamate at prevent this type of SSc is to minimize the expo-
position 69 of DPB1 might be involved in the sure to silica.
susceptibility to idiopathic anti-Scl-70 expression. However, continuous efforts are still required
Additionally, DRB1 0301 and DQB1 0201 to encourage acknowledgment of SSc as an occu-
were significantly increased in ATA-positive, pational disease after long-term silica exposure.
Individual decisions by clinical experts should 1967; Dinman et al. 1971; Markowitz et al. 1972).
provide the basis enabling social and financial The disease is characterized by Raynaud’s phe-
support to reduce the harm caused by silica- nomenon, papular-fibrotic skin lesions on the
induced SSc. wrist and dorsa of the hands, and osteolysis in
the middle of the distal phalanges (bullet holes),
mainly of the first three fingers, which became
3 Scleroderma-like Diseases shortened and shapeless. OAOL occurred only
in those workers who had been exposed to the
In contrast to silica and several solvents, a whole VC monomer and was most common in reactor
variety of substances is reported to induce SLD, cleaners (Lelbach and Marsteller 1981).
which can be distinguished from SSc using the Histopathological examination of sclero-
following criteria: derma-like lesions showed distended collagen
fibers, shrinkage of elastic fibers, interstitial
Type of skin manifestation, in particular edema, sometimes perivascular lymphocytic infil-
acrosclerosis, circumscribed and generalized trates, swollen endothelial cells of the enlarged
morphea, fibrotic nodules, or joint capillaries, and marked acanthosis in the epider-
contractures. mal layer (Czernielewski et al. 1979).
Visceral involvement due to toxic damage of liver, In 1974, Lange et al. reported of a systemic
kidney, nervous system, and muscles, or form of VC disease (Lange et al. 1974). Changes
angiosarcoma of the liver. included skin sclerosis, pulmonary fibrosis,
Laboratory findings, discrete thrombocytopenia, fibrosis of the liver and spleen, and disturbances
and absence of autoantibodies. in the capillary vascular system, joints, and
Cessation or reversal of the disease process after musculature. Further manifestations are pares-
early discontinuation of exposure. thesia, thrombocytopenia, leukopenia, and
Female preponderance for idiopathic SSc is often splenomegaly (Bachner et al. 1974). Capillary
not observed in occupationally induced SLD. microscopy reveals that abnormalities of the
nail fold in VC workers are similar but less
pronounced than those found in SSc (Maricq
3.1 Vinyl Chloride et al. 1976). Distal pitting scars, esophageal
dysmotility, renal disease, and cardiac disease
Individuals cleaning or inspecting autoclaves for are generally absent.
polymerization of vinyl chloride (VC) to polyvi- Leukopenia, as well as angiosarcoma of the
nyl chloride (PVC) are in danger of developing liver, drew attention to the carcinogenic and
SLD with high incidence (Lelbach and Marsteller mutagenic properties of VC. Whether other
1981; Ostlere et al. 1992). Cleaning is usually kinds of malignancies are caused by VC was
performed by scraping and water splashing. In questioned by Fox and Collier (1977) based on
this way, workers are exposed to the remnants of an extensive epidemiological study. The rela-
the monomer. tionship between VC disease and SSc is shown
The first large study was conducted in Ruma- in Table 9.
nia in 1963, where 168 PVC workers had been Finally, common symptoms of VC-related dis-
observed over 4 years (Suciu et al. 1963). The eases such as fatigue, cold, burning pain, emo-
symptoms included pruritus of the arms and tional instability, loss of libido, and impotence
face, and scleroderma-like lesions which mostly should be mentioned (Penin et al. 1975; Veltman
disappeared after removal from the workplace. 1980). After discontinued exposure, skin lesions,
Later on, the disease was described in detail and capillary abnormalities, and acro-osteolytic
labeled as occupational acro-osteolysis (OAOL) lesions will revert to an almost normal status
in England, France, and the United States (Cordier (Veltman 1980). VC is a volatile gas. It is
et al. 1966; Harris and Adams 1967; Wilson et al. not quite clear to what extent inhalation of VC
Table 9 Relationship between vinyl chloride (VC) dis- their fingers than patients with SSc, but they have
ease and systemic sclerosis (SSc) (according to Veltman more than healthy controls (Maricq 1981).
1980; Haustein and Ziegler 1985)
In rats fed for 2 years with 30 mg VC per
Features of VC disease resembling SSc Percentage kilogram of body weight, thickening of the skin
Raynaud’s phenomenon 33–74 with collagen deposition as well as an increase in
Fibrotic skin, sclerodactyly 10 glycosylated lysine and hydroxylysine has been
Resorption of bone at the distal phalanges 11
described, indicating an increased collagen syn-
Pulmonary fibrosis 13
thesis (Knight and Gibbons 1987).
Esophageal variation 23
Reducing maximum concentrations in the
Skin capillary abnormalities 23
workplace from 500 ppm to negligible levels
Arthralgia 82
Myalgia 16
(<5 ppm) by automation and contact-free tech-
Features of VC disease different from SSc Percentage nology will subsequently decrease the number of
Paresthesia 80 reported cases.
Thrombocytopenia 76
Splenomegaly 48
Reticulocytosis 35 3.2 PVC Dust
Central nervous system symptoms 17
Leukopenia 8 In 1993 a case of MCTD in a male patient occu-
Angiosarcoma of the liver 6 pationally exposed to PVC and other toxic agents
No calcinosis was presented. Clinical symptoms consisted of
typical signs of systemic LE, rheumatoid arthritis,
and lupoid hepatitis. MCTD diagnosis was con-
might induce skin lesions; however, remnants of firmed serologically by the presence of u 1-ribo-
the gaseous monomer VC have been demon- nucleoprotein-autoantibodies. Prednisone, 60 mg
strated in the polymer PVC. VC is stored and daily, produced remission (Panaszek et al. 1993).
metabolized by the organism. One of its metabo- Studnicka et al. (1995) presented a 58-year-old
lites, thiodiglycolic acid, can easily be detected in patient exposed to thermoplastic dusts, mainly
urine samples, even when levels of VC in the PVC, for 10 years. He developed pneumoconiosis
atmosphere are considerably lower (Mueller and secondary SSc.
et al. 1978). So-called activated metabolites of
VC (Fig. 2) may participate in the pathogenesis.
Other mechanisms might affect the individual’s 3.3 Bis(4-Amino-3-
cellular immune response, especially in workers methylcyclohexyl)Methane
exposed to the small molecules of VC (Kohanka (Polymerization of Epoxy
1982). Circulating immune complexes were Resins)
found to be increased (Milford 1976). However,
autoantibodies – particularly ANA, ATA, and Two male patients (of 233 workers) with a newly
ACA – could not be traced (Black et al. 1983). diagnosed SLD induced by epoxy resins were
HLAs of the pattern HLA DR5, HLA DR3, HLA reported from Japan in 1980 (Yamakage et al.
A1, HLA B8, and HLA B3 prevail in patients with 1980). Ishikawa et al. (1995) described the clin-
VC disease. The genetic background, together ical and laboratory findings of these patients
with the impairment of cellular immune functions, after a 17-year follow-up from 1976 to 1993.
might lead to an increased susceptibility to the Both patients have been employed by a chemical
disorder (Black et al. 1983). One of the main factory since May 1975 and were continuously
targets of VC-inducible effects seems to be micro- exposed to a polymerization process of epoxy
vascular tissues. Fibrosis of the vessel wall results resins. First symptoms appeared after 1 month
in fibrosis of other organ systems. Patients with (patient 1) and 1.5 months (patient 2). After this
VC disease have fewer capillary abnormalities of brief exposure, the patients developed erythema
Fig. 2 Metabolism of
chlorinated ethylenes
(According to Bolt et al.
1982)
and edema, which evolved to generalized dermal polymerization during surfboard manufacturing
sclerosis and alopecia, weakness, and muscle (Inachi et al. 1996). The symptoms included a
atrophy, but no Raynaud’s phenomenon or shortening of the frenulum linguae, diffuse hyper-
ANA. Treatment was started with a small dose pigmentation and facial telangiectasia, positive
of prednisolone and discontinued in 1980. ANA, and pulmonary dysfunction, but no
The hair loss recovered in 1977, the sclerotic acrosclerosis or sclerodactylia. Modest dermal
skin changes disappeared by 1980, and collagen proliferation in the forearm skin con-
the sclerodactyly recovered in 1993. Bis(4- firmed SSc without scleroderma. Diot et al.
amino-3-methylcyclohexyl)methane (BAMM), (2002) found an association between SSc and
a new type of plasticizer belonging to the epoxy resins (OR 4.24), on the contrary Silman
cyclohexamines (Fig. 3), was suspected as the and Jones (1992) and Marie et al. (2014) failed to
causative agent from the list of chemical sub- reveal this association.
stances used.
BAMM may interfere with the amine metabo-
lism which has been suggested to be disturbed in 3.4 Chlorinated Hydrocarbons,
SSc patients (Stachow et al. 1979). In addition, Aliphatic Hydrocarbons
oligomers of epoxy resins, being strong sensi-
tizers, might induce dysfunctional immune The chlorinated hydrocarbons trichloroethylene
responses (Thorgeirsson et al. 1978). Using SSc- and perchloroethylene (Fig. 2) are widely used as
inducing glycosaminoglycans in lymphocyte solvents and cleaners. They may be considered
transformation tests, splenocytes of mice experi- closely related to VC because of the clinical simi-
mentally treated with BAMM showed a positive larity of the disorders caused by these compounds
response (Ishikawa et al. 1982). Intraperitoneal to VC disease. Trichloroethylene is more volatile
injections of one compound produced skin scle- (boiling point 87.2 C) and much more toxic than
rosis in a murine model (Yamakage et al. 1980). perchloroethylene (boiling point 121.1 C). It pen-
A 33-year-old man developed SSc without etrates the skin and, in its vaporous state, is also
scleroderma while working and being exposed absorbed by the alveolar capillaries. Prolonged
from age 20 to 30 years to epoxy resin contact with the skin will induce irritative
Trichloroethylene elicits acute pulmonary

cytotoxicity in mice, which involves Clara cells
of bronchioles. Forkert and Forkert (1994) exam-
ined the effects of a single dose of trichloroethy-
lene in lungs of mice and showed that structural
and functional abnormalities progress for at least
3 months. Pulmonary fibrosis was first detected at
Fig. 3 Bis(4-amino-3-methylcyclohexyl)methane 15 days and was ongoing which diffuses in the
alveolar zone, resulting in thickening of alveolar
dermatitis (Schirren 1971; Bauer and Rabens septa and destruction of lung structure. The fibro-
1977). Besides the well-described toxic effects in sis was most pronounced at 90 days. Levels of
the nervous system, liver, kidney, and bone mar- total lung hydroxyproline content were not signif-
row, several reports on SLD resembling VC disease icantly different in control and treated mice at
have been published (Reinl 1957; Saihan et al. days 30 and 60, but were significantly increased
1978). Sparrow (1977) observed a SLD similar to at day 90, while the proline content remained
VC disease, probably caused by perchloroethylene. unchanged. The increase in collagen deposition
Flindt-Hansen and Isager (1987) reported three at 90 days coincided with a significant increase in
cases of SSc after occupational, prolonged lung elastic recoil (Forkert and Forkert 1994).
(4–12 years), and intensive exposure to tri- In addition, Griffin et al. (2002) demonstrated
chlorethylene and trichorethane during metal- the acceleration of a nonspecific autoimmune
cleaning procedures. According to the ACR-criteria, response (Th1, CD44) in MRL +/+ mice includ-
all three cases could be classified as definite SSc. ing trichloroethylene-specific immune response
The analysis of 61 patients with SSc (Czirjak after long-term trichloroethylene exposure.
et al. 1989) revealed a female-to-male ratio of As shown in Fig. 2, chlorinated hydrocarbons
60:1. Prior occupational exposure to chemicals such as VC, perchloroethylene, and trichloroeth-
(mainly organic solvents) was found in 17 (28%) ylene are metabolized in similar pathways
of the patients, with a mean age of 49 8 years. (Lockey et al. 1987). However, the significance
The exposure preceded the onset of disease by of the P 450 system for metabolization and in the
9 7 years. The mode of exposure was mainly detoxification of putative SSc-inducing environ-
through inhalation, with a duration of mental toxins has not been studied so far.
6.3 6.5 years. Features from patients with expo-
sure to organic solvents were clinically indistin-
guishable from the other cases studied (Czirjak 3.5 Aromatic Hydrocarbons
and Kumanovics 2002).
As mentioned by Yamakage and Ishikawa In 1983, Walder reported of six patients with
(1982), various aliphatic hydrocarbons, such as limited scleroderma who were exposed to aro-
naphtha and n-hexane, are able to induce general- matic hydrocarbon solvents, such as benzene,
ized morphea-like sclerosis, either by exposure to toluene, xylene, white spirit, and diesel oil
vapor or by direct skin contact with the liquid (Walder 1983). Unlike chlorinated hydrocar-
substance. Further features of the induced disor- bons, these aromatic hydrocarbons do not cause
der are sclerodactyly, Raynaud’s phenomenon, systemic disorders. The scleroderma-like lesions
esophageal dysfunction, and fibrosis of the lung. were limited to hands and feet, body parts
The disease could be reproduced by chronic intra- directly exposed.
peritoneal injection of these organic compounds However, a sclerodermatous syndrome
in animal experiments. with unusual features and visceral involvement
Further cases of SSc and SLD in association has been reported following prolonged occu-
with chlorinated and aliphatic hydrocarbons are pational exposure (32 years) to a wide variety
listed in Table 10. of organic solvents (including benzene in
Table 10 Cases of systemic sclerosis (SSc) and scleroderma-like diseases (SLDs) in association with exposure to
solvents
Clinical
Author Number symptoms Exposure
Sparrow (1977) 1 SLD Perchloroethylene
Walder (1983) 6 SLD Benzene, toluene, xylene, white spirits, diesel oil
Czirjak et al. 8 of 21 females SSc Trichloroethylene (1), organic solvents (6),
(1987) polyethylene (1)
Lockey et al. 1 SSc Trichloroethylene
(1987)
Flindt-Hansen 3 SSc Trichloroethylene, trichloroethane, metal-cleaning
and Isager (1987) 4-12y
Owens and 2 SLD Meta-phenylenediamine, silicon tetrachloride
Medsger (1988) (hydrochloric acid and free silica), meta-
phenylenediamine, vinyl chloride, and silicon
tetrachloride
Czirjak et al. 17 of 61 SSc Benzene and petroleum-derived crude solvents (3),
(1989) organic solvents (isopropyl alcohol, terpene
derivatives) (4), ethyl acetate and other solvents (3),
organic solvents (not well defined) (4), silica dust,
paints, and solvents (1), ethylene derivatives (1),
trichloroethylene (1)
Szeimies et al. 1 SSc Perchloroethylene
(1992)
Brasington and 1 SSc Trichloroethane, xylene, naphthalene,
Thorpe-Swenson trimethylbenzene
(1991)
Yanez-Diaz et al. 1 SSc, silicosis Trichloroethylene, fiberglass
(1992)
Tibon-Fisher et al. 1 SSc Trichloromethane
(1992)
Gabay and Kahn 3 SSc Solvents (1), solvents and silica dust (2)
(1992)
Czirjak et al. 1 SSc Trichloroethylene
(1993)
Tanaka et al. 1 SLD LOC (domestic detergent, constituents:
(1993) Polyoxyethylene alkyl ether, fatty acid alkanol amide)
Bottomley et al. 1 SLD Organic solvents (including benzene in various forms,
(1993) toluenes, toluidines, xylenes, xylidenes, aniline
compounds, and ethanolamine and its derivatives)
Waller et al. 2 Fasciitis, Trichloroethylene, drinking contaminated water in one
(1994) eosinophilia case
Czirjak et al. 1 Localized Trichloroethylene, tetrachloroethylene, acetone,
(1994) scleroderma benzene, isopropyl alcohol, dimethyl phthalate,
methoxyethanol, polyethylene glycol, polyvinyl
alcohol, polyvinyl acetate, xylene, phenol
Garcia-Zamalloa 1 SSc Toluene, heptane, dimethylbutylphenyldiamine, and
et al. (1994) octyphenol formaldehyde, exposure to nonchlorinated
hydrocarbon and sulfated substances was also assessed
Hinnen et al. 1 Disseminated Perchloroethylene
(1995) morphea
Bovenzi et al. 4 Scleroderma Organic solvents (aromatic hydrocarbons)
(1995)
(continued)
Table 10 (continued)
Clinical
Author Number symptoms Exposure
Haustein and 2 SLD Wide variety of organic solvents (for
Albrecht (1996) 30 years), various oils and organic solvents
(for 12 years)
Nietert et al. 37 of 178 case Scleroderma, Trichlorethylene (OR 3.3), trichloroethane, carbon
(1998) control anti Scl 70 tetrachloride, benzene (OR 2.9)
pos,
Povey et al. 7 Scleroderma Organic solvents
(2001)
Aryal et al. 2001 Meta-analysis, 7 SSc Organic solvents
case-control 1 Rel. Risk 2.91 for all, 3.14 for the 7 case-control studies
cohort study
Czirjak and 16 Scleroderma Solvents
Kumanovics
(2002)
Diot et al. (2002) 57? Systemic Solvents: Trichloroethylene, chlorinated solvents
sclerosis toluene, aromatic solvents, ketones, white spirit
Garabrant et al. Among 660 pat. Scleroderma Solvents (OR 2.0)
(2002) Case control
Diot et al. (2002) Of 80 case control SSc Solvents (OR 2.66)
Bovenzi et al. 11 of 55 case Systemic Solvents (OR 2.3)
(2004) control sclerosis
Maitre et al. 28 Systemic Solvents, OR = 3.23
(2004) sclerosis
32 Systemic Cleaning products, OR = 1.66
sclerosis
Kettaneh et al. Meta-analysis of 11 Systemic Solvents, OR 1.8 for all, 3.0 for men
(2007) studies! 1291 cases sclerosis
Detailed figures and
odds ratios!
Barragan- Meta-analysis SSc Solvents OR 1.54
Martinez et al.
(2012)
Marie et al. Case control, 100 SSc Solvents OR 5,91 for pat. With
(2014) pat. very final cumulative score, 3.28 for
all solvents
various forms, toluenes, toluidines, xylenes, aromatic hydrocarbon), heptane (an aliphatic
xylidenes, aniline compounds, and ethano- hydrocarbon), dimethylbuthylphenyldiamine (an
lamine and its derivatives) (Bottomley et al. aromatic amine), and octhyphenol formaldehyde
1993). Associated functional changes include (a formaldehyde derivative), cutaneously and by
cold sensitivity, restrictive pulmonary disease, inhalation. Exposure to nonchlorinated hydrocar-
peripheral neuropathy, esophageal dysfunction, bon and sulfated substances was also assessed.
labile hypertension, and a monoclonal Two male patients developed SLD after occupa-
paraproteinemia. tional exposure to various chemicals (meta-
Garcia-Zamalloa et al. (1994) described a phenylenediamine, VC, and silicon tetrachloride,
56-year-old patient who developed SSc with skin, respectively) in the same building. One patient had
lung, and pericardial affections after he had worked been exposed to VC, a known cause of SLD.
in a rubber transformation section of a tire factory Because of the prolonged delay between the VC
for 23 years. He had been exposed to toluene (an exposure and the onset of scleroderma, the authors
excluded this agent as the causative one. In addi- 3.6 Solvents in General
tion, both patients were intermittently exposed to
silicon tetrachloride, which yields hydrochloric Recent reports did not specify the different sol-
acid and free silica upon chemical breakdown. It vents; their studies are related to solvents in
might be speculated that the disease described general. In the majority of reports, case-control
therein was precipitated by an unusual indirect studies have been conducted and relative risks
exposure to silica, which seems unlikely. The (odds ratio) have been calculated. Nietert et al.
most attractive candidate for a potential causative (1998) reported on a high cumulative intensity
agent in this SLD is meta-phenylenediamine score (odds ratio 2.9) and a high maximum inten-
(Owens and Medsger 1988). sity score (OR 2.9) for any solvent exposure in
In their clinical practice, Haustein and 37 men with preference to anti-Scl-70 autoanti-
Albrecht (1996) examined a 58-year-old painter body positive patients. Garabrant et al. (2002)
who had been exposed to a wide variety of investigated 660 female SSc patients from Mich-
organic solvents for 30 years. He developed a igan and Ohio in a case-control study and con-
SLD of the skin, esophagus, and lung, with poly- cluded that exposures to paint thinners and
neuropathy and chronic hepatosis and elevated removers were associated with scleroderma in
titers of ANA and Scl-70-antibodies. The second woman but showed no evidence of increasing
patient was a 49-year-old woman who had sewn risk with increasing duration. Other petroleum
leather in an oil bath containing various oils and distillates such as gasoline and mineral spirits
organic solvents for 12 years. She suffered from were not significantly associated with sclero-
an acrosclerosis of the hands, lung fibrosis and derma in multivariable analyses.
kidney involvement, chronic hepatitis, and Diot et al. (2002) conducted a case-control
peripheral neuropathy including positive ANA study of 80 SSc patients in Tours (France) from
and ACA titers. 1998 to 2000. They calculated an exposure score
Bovenzi et al. (1995) examined 21 patients (16 for each subject based on probability, intensity,
women, 5 men) with SSc or localized variants of daily frequency, and duration of exposure for each
scleroderma. A significant association was found period of employment. They found among other
between exposure to organic solvents (aromatic known associations also one for welding fumes.
hydrocarbons) and SSc (three men, one woman). Maitre et al. (2004) found significantly increased
Among the male subjects, an increased odds ratio risk for workers with cleaning products (odds
for SSc was observed for exposure to organic ratio = 1.66) and with solvents (odds
solvents, silica dust, and hand-transmitted vibra- ratio = 3.23).
tion. Exposure to solvents and other chemicals In a new meta-analysis conducted by Kettaneh
was associated, albeit not significantly, with SSc et al. (2007), the risk of SSc associated with organic
among the women. solvent exposure was variable among 11 studies
Finally, SLD has also been reported in a 53- (1291 pat, 3435 controls), and there was an over-
year-old man after exposure to LOC, a domestic representation in smaller studies suggesting “pub-
detergent widely used in Japan. Its constituents lication bias” with an average odds ratio of 2.4 and
are polyoxyethylene alkyl ether and fatty acid 1.8 after adjusting of bias, respectively. The relative
alkanol amide (Tanaka et al. 1993). risk was higher in man (OR 3.0) than in woman
In an occupational analysis of 56 men with (OR 1.8), whereas women were predominantly
SSc in the United Kingdom showing no affected by SSc in general.
evidence of silica exposure implicated in the In terms of gene-environment interaction,
onset of the disease, only exposure to organic Povey et al. (2001) found that cytochrome P2
solvents was reported to any extent. No significant polymorphisms may be involved in the increas-
increase in exposure to organic solvents was ing susceptibility to SSc among subjects who
found in a case-control analysis (Silman and have been exposed to organic solvents. All
Jones 1992). seven patients carry the 2C19EM genotype and
the 2E1 3 allele was found in two of seven of macroscopically uninvolved skin from
patients. the gluteal region of 56 patients with acute
Cooper et al. (2009) reported on autoimmune- phospho-organic pesticide intoxication
related effects of trichloroethylene exposure in between days 2 and 15 after intoxication
mice (MRL +/+ lupus mice) such as increased (Tashev and Tsonev 1990). Two hundred and
antinuclear antibodies, interferon y, decreased seventy-two biopsies from 17 healthy
IL-4, and autoimmune hepatitis, and in humans individuals and published data served as
they described symptoms such as increased controls. Nonspecific changes affecting mainly
interferon y, IL-2, decreased IL-4, as well as the elastic and collagen components were
hepatitis. found, in some cases paralleled with the
Table 10 summarizes data on patients with SSc severity of intoxication. The reticular net,
or SLD in association with exposure to organic vessels, matrix, and cell elements were far less
solvents. affected, indicating their relative stability to the
pesticides’ toxicity. More recent epidemiological
studies rule out a possible association between
3.7 Pesticides/Herbicides pesticides and SSc (Marie et al. 2014). The same
authors demonstrated a strong correlation
Dunnill and Black (1994) reported a case of gen- between SSc and welding fumes (OR 2.60,
eralized cutaneous sclerosis associated with p = 0.021).
prominent myositis and esophageal involvement
in a patient exposed to herbicides containing
bromocil, diuron, and aminotriazole. There was 3.8 Mercury Chloride
no evidence of lung involvement, and antibody
titers were in the normal range. Treatment with Mean urinary Hg levels were significantly ele-
oral prednisolone resulted in modest improve- vated in the antifibrillarin antibody-positive SSc
ment of the cutaneous changes, particularly of patients (Arnett et al. 2000). Mercury chloride
the face, trunk, and proximal limbs. The consid- induces a strong immune activation and
erable exposure to chemicals, time course, dysregulation, but does not accelerate the devel-
and unusual pattern of organ involvement was opment of dermal fibrosis in tight skin 1 mice
suggestive for the diagnosis of occupational (Hanson and Abedi-Valugerdi 2002). Therefore,
scleroderma. the potential occult exposure to Hg has to be
Another case of sclerodermiform lesions after considered in antifibrillarin-positive SSc
use of various herbicides has been described by patients in future until further epidemiological
Poskitt et al. (1994). A 53-year-old man devel- and basic research studies can prove or refute
oped chloracne, palmoplantar keratoderma, and this observation.
scleroderma after many years of exposure to a
variety of chloracnegens. Chloracne is a rare but
important acneiform eruption associated with 4 Mixed Connective Tissue
exposure to halogenated aromatic compounds Disease
used primarily in agriculture. However, to the
authors’ knowledge, the association of Vincent et al. (1996) reported a 25-year-old
palmoplantar keratoderma and scleroderma woman who developed Sharp’s syndrome
with exposure to chloracnegens has not been 5 years after diagnosis of acute silicosis due to
previously reported. inhalation of the scouring powder Ajax (Colgate
Dermatohistopathological changes, selected Palmolive Co.), containing 95% silica, 2%
as an example of highly organized connective alkylbenzosulphonate, and 3% trichlorocyanuric
tissue, were studied by eight different staining acid. MCTD due to PVC dust is mentioned above
and histochemical techniques in 896 biopsies (Panaszek et al. 1993).
5 Sjögren’s Syndrome heat, cold, and wind was cited in the past (Warde
1903). Sunlight was frequently considered an
Three cases of primary Sjögren’s syndrome were eliciting factor for the primary manifestations
described by Puisieux et al. (1994) in silicotic and the exacerbations as well (Baer and Harber
coal miners. All patients fulfilled the diagnostic 1965; Epstein et al. 1965; Diezel et al. 1977).
criteria for Sjögren’s syndrome recently However, among 236 patients examined, only
established by the European Community study six showed an improvement after the patients
group. One patient had cryoglobulinemia moved from an outdoor job to an indoor work-
and polyneuritis. Another had Raynaud’s place. In this study, no relationship between
phenomenon, arthralgia, purpura, and polyneu- occupation and LE could be confirmed
ritis. Capillary microscopy revealed normal (Nebe and Lenz 1971). In terms of association
findings in all three patients. ANA were detected with silicosis of the lung in the former German
only in one patient, who also had anti-SS-A Democratic Republic, 193 male infirmary
(RO) and anti-SS-B (LA) antibodies. Although patients were examined, with three cases of
the prevalence of SSc, RA, and probably coincidental silicosis among them (Ziegler
systemic LE is significantly higher after long- et al. 1987).
standing occupational exposure to silica, so Further reports exist about the association of
far no case of Sjögren’s syndrome has LE with silicosis (Hatron et al. 1982) or with
been described in the course of pulmonary occupational silica exposure (Ebihara and
silicosis. Kawami 1985). In addition, Mehlhorn and
Gerlach (1990) and Ziegler and colleagues
(1991) demonstrated several cases in the ura-
6 Lupus Erythematosus nium-mining industry in East Germany. The for-
mer author observed 37 patients with
Silica-induced LE is a chronic multiorgan LE exposed to quartz over many years
system autoimmune disease with frequent (Mehlhorn and Gerlach 1990). Thirty of them
exacerbations and remissions similar to the suffered from silicosis. In a survey of 877 male
natural course of mixed connective tissue LE patients (592 systemic LE, 279 discoid LE),
disease. The pathomechanism of LE is not yet Ziegler and colleagues (1991) only found seven
completely understood. Based on a genetic patients with silicosis out of 428 systemic
background, a major role seems to be played LE patients over 40 years of age. Recently,
by disturbances of immune regulation, such as Haustein (1998) reported of four additional
T-cell abnormalities, including T-cell cytokine male systemic LE patients with long-term silica
network, polyclonal B-cell stimulation, immune exposure (12–23 years) and silicosis. In 1996,
complex formation, defects in the clearance Wichmann et al. published a study of 16 sys-
of immune complexes, and dysregulation of temic LE patients among a group of 52 workers
apoptosis. Various environmental factors have occupationally exposed to silica (Wichmann
been discussed, such as drugs, solvents, and et al. 1996).
silica. In lupus-prone New Zealand mixed Siebels et al. (1993) presented case
mice, the exposure of silica induced significantly histories of five patients with silicosis
higher levels of immune complexes, antinuclear, who had developed systemic LE and micro-
as well as antihistone autoantibodies, increased scopic polyarteritis in two cases each, and
number of CD4+ T cells and B1a B cells, rapidly progressive glomerulonephritis (lim-
increased TNFa, thus altogether accelerating ited Wegener’s granulomatosis) in one case.
systemic autoimmune disease (Brown et al. Recently, a male patient who had worked
2003, 2004a, b). as a stonecutter and had developed silicosis
There is only scant knowledge with reference and systemic LE was also reported by Siebels
to occupational influences on LE. Exposure to et al. (1995).
Koeger et al. (1995) observed four patients must be included to assess the full potential
with systemic LE (three with silicosis) and one of occupational silica exposure. Thus, in the
with discoid LE among 24 cases of silica-associ- assessment of all work at least 2 weeks 9% of
ated CTD. SLE patients were classified as medium or
Conrad et al. (1996) described 28 definite high silica exposed (odds ratio 2.9), whereas,
and 15 likely systemic LE patients among in contrast, at least 12 months occupational
15,000 heavily silica-exposed miners, probably exposure provided a much lower risk
part of the same group analyzed by Mehlhorn among the same group of patients (odds ratio
and Gerlach (1990). Therefore, the prevalence 0.4) (Parks et al. 2004). OR 4.3 has been
of systemic LE in the population of highly calculated by Finckh et al. (2006), while Cooper
quartz-dust-exposed uranium miners may be et al. (2010) found an OR 2.1 after leisure
estimated at up to 93 of 100,000. ANA could activities!
be detected in all definite and in 72.9% of prob- Certain chemical contaminants in well water
able patients having systemic LE. Middle-to- have been implicated in the etiology of rheu-
high-titred ANAs were present in 94.4% of def- matic disorders. Kilburn and Warshaw (1992)
inite and in 54.7% of probable patients found an association between the prevalence of
having systemic LE. In patients exhibiting defi- symptoms of systemic LE and ANA with chronic
nite systemic LE, clear positive results were exposure to trichloroethylene and other
obtained for anti-dsDNA in 38.9%, anti-RO/ chemicals in well water in the Tucson, Arizona
SSA in 38.9%, and anti-LA/SSB in 11.1%. In area. Beer et al. (1994) presented two patients
uranium miners without systemic LE, the preva- with insecticide-induced LE after use of two
lence of ANA was significantly higher than “bug-bombs” containing 1,1,1-trichloroethane,
the age- and gender-related control group. Fur- propane, S-methoprene, and permethrin in the
thermore, an increase in ANA titers in heavily patients’ trailer home.
rather than slightly exposed uranium miners
could be detected. Table 11 comprises data of
patients with LE in association with silica 7 Dermatomyositis
exposure.
An ANA profile suggestive of Sjögren’s Few reports are available on dermatomyositis
syndrome or systemic LE without symptoms after occupational exposure. Koeger et al.
of either disease occurred in a patient (1991) described dermatopolymyositis in two
with chronic obstructive pulmonary disease. men and one woman after 5, 16, and 21 years
He worked for less than 5 years as a main- of occupational exposure to silica. Pulmonary
tenance mechanic in a plant in South Carolina involvement was present as diffuse interstitial
manufacturing silica flour and industrial fibrosis in two patients whose lung biopsies
sand (Johnson and Busnardo 1993). Excessive revealed high particulate silica contents. Another
occupational exposure to free silica by patient with polymyositis among 52 workers
inhalation was documented. An open-lung from a factory producing scouring powder with
biopsy revealed an early stage of silicosis an increased silica content (70–90% powdered
characterized by perivascular and peribronchial quartz) was described by Wichmann et al.
accumulation of macrophages, as well as (1996). Among 24 patients with silica-associated
early granuloma formation. CTD, three patients have been diagnosed with
In a population-based case-control study, dermatomyositis and Sjögren’s syndrome
Parks et al. (2002) calculated the risk for (Koeger et al. 1995).
SLE after medium silica exposure as 2.4 Yang et al. (2001) reported seven patients (one
(odds ratio) and after high exposure 4.6, female, six male) suffering from polymyositis/
respectively (n = 19 of 265 SLE patients). dermatomyositis associated with silicosis in a ret-
However, specific task-based questions rospective review.
Table 11 Lupus erythematosus (LE) in association with silica exposure

Author Cases Diagnosis Exposure (occupation)
Ziegler et al. (1987) 3 Systemic LE and silicosis Silica
Mehlhorn and Gerlach 37 Twenty-five systemic LE and Silica (36 ore miners, 1 foundry
(1990) silicosis, 5 discoid LE and worker)
silicosis, 4 systemic LE, 3
discoid LE
Ziegler et al. (1991) 30 LE, five with silicosis Silica (16 ore miners, 3 foundry
workers, 2 underground workers, 2
enamellers, 1 sandblaster, quarry
worker, stove bricklayer,
grindstone maker, well driller, glass
industry worker)
Siebels et al. (1993) 2 Systemic LE and silicosis Silica
Siebels et al. (1995) 1 Systemic LE and silicosis Silica (stonecutter)
Koeger et al. (1995) 5 Four systemic LE (three with Silica (mason, miner,
silicosis), one discoid LE dental prosthetist,
scouring and tooth
powder worker)
Wichmann et al. (1996) 16 Systemic LE Silica (scouring powder
factory)
Haustein and Albrecht 1 Systemic LE and silicosis Silica (uranium hewer)
(1996)
Conrad et al. (1996) 43 Twenty-eight systemic LE, Silica (uranium miners)
(partially the same group as 15 probable systemic LE
analyzed by Mehlhorn and
Gerlach 1990)
Haustein (1998) 4 Systemic LE and silicosis Silica (uranium hewer, cast
polisher, stone mason, uranium
driller)
Ueki and Omori (2001) 1 Discoid LE, left cheek Fine fragments of windshield
glass embedded
after automobile accident
8 years before
Parks et al. (2002) 19 of 265 (case SLE Medium (OR 2.1) or high (OR 4.6)
control) exposure
Finckh et al. (2006) Of 95 (case SLE OR 4.3
control)
Boston
hospital
database
Cooper et al. (2010) Of 258 (case SLE Pottery, ceramics in leisure activity!
control) 11 OR 2.1
Rheumatol
centers Canada
pulmonary hypertension, lung cancer, obstructive

8 Rheumatoid Arthritis
lung disease, and connective tissue disease
among both male and female patients. In an updated
Rosenman and Zhu (1995) found an assoc-
multivariate analysis of 3328 gold miners who
iation between silicosis and RA using hospital
worked underground for at least 1 year in
discharge data from Michigan between the
South Dakota between 1940 and 1965, an extended
years 1990 and 1991, examining potential
follow-up from 1977 to 1990 revealed significant
associations between pneumoconiosis and
Table 12 Exposure to crystalline silica or organic solvents and the risk of systemic sclerosis (according to Kettaneh et al.
2007), updated
(Confidence
Study Exposure Controls N Odds ratio interval)
Haustein (1998) Silica HC 111 5.7 (1.72–8.54)
Silicosis HC 57 12.0 (5.23–19.29)
Englert et al. (2000) Silica CC 60 3.93 (1.84–8.54)
Diot et al. (2002) Silica Cc? 10 3.74 (1.06–13.18)
Smith et al. (2008) Silica BNIS 10 Tenfold Higher prevalence
McCormic et al. (2010) Silica Meta-
analysis
Males 3.02 1.24-7.35
Females 1.03 0.74-1.44
Cohort 15.49 4.54-52.87
studies
Marie et al. (2014) Silica CC 100 5.32 2.25-13.09
Males 15 9.63 2.49-43.01
Marie et al. (2015) Silica + solvents Prosp. 142, 19.31 15.34-69.86
study 31males
Czirjak et al. (1989) Solvents CC 51 23.18 (2.97–180.79)
Silman and Jones (1992) Solvents CC 56 2.23 (1.04–4.80)
Bovenzi et al. (1995) Solvents HC 21 9.65 (1.00–92.73)
Goldman (1996) Solvents CD 33 5.82 (2.53–13.39)
Zachariae et al. (1997) Solvents HC 28 3.18 (0.99–10.23)
Nietert et al. (1998) Solvents HC 178 1.28 (0.65–2.50)
Diot et al. (2002) Solvents HC 80 2.66 (1.35–5.23)
Czirjak and Kumanovics Solvents HC 63 2.60 (1.11–6.06)
(2002)
Garabrant et al. (2002) Solvents CC 623 1.53 (1.24–1.89)
Bovenzi et al. (2004) Solvents HC 55 2.13 (0.93–4.83)
Maitre et al. (2004) Solvents (in CC 28 3.23 (1.58–6.63)
general)
Cleaning 32 1.66 (0.90–3.08)
products
Overall for solvents 1281 2.41 (1.73–3.37)
Marie et al. (2014) 7 solvents in CC 100 Between 1.56 and 0.14-11.06 and
detail 8.17 2.25-36.5
CC community controls, HC hospital controls, CD patients with other connective tissue diseases, confidence interval
95%, BNIS Belgian National Institute occupational list
excesses of arthritis, musculoskeletal diseases, and (2004) found a twofold increased risk of
skin conditions including systemic LE and SSc, rheumatoid arthritis among male metalworkers or
in addition to silicosis and tuberculosis, but in jobs that involved cleaning metal from Sweden.
without lung cancer (Steenland and Brown 1995).
The study of Koeger et al. (1995) presented five
patients with RA (four in association with Sjögren’s 9 Conclusion
syndrome). Calvert et al. (2003) calculated a mor-
tality odds ratio of 1.19 for rheumatoid arthritis after Connective tissue disorders such as SSc,
silica exposure (among 18,335 patients in total) LE, Sjögren’s syndrome, dermatomyositis, and
and a mortality odds ratio of 3.75 for RA RA can be induced by occupational exposure
patients with silicosis (n = 15). Olsson et al. to silica, solvents, and other chemical
offenders. An enhanced genetic susceptibility Anderegg U, Vorberg S, Herrmann K, Haustein UF (1997)

seems to favor these disorders. SSc is the most Silica directly induces intercellular adhesion molecule
1 (ICAM-1) expression in cultured endothelial cells.
frequent and best-studied disease. While Eur J Dermatol 7:27–31
silica precipitates SSc, the other offenders Arnett FC, Fritzler MJ, Ahn C, Holian A (2000) Urinary
induce scleroderma-like diseases with mercury levels in patients with autoantibodies to U3-
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Systemic Diseases by Absorption
Through the Skin 30
Hans Drexler and Sonja Kilo
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
3 Characterization of Dangerous Substances Absorbable Through
the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
4 Factors Influencing Dermal Exposure and Absorption . . . . . . . . . . . . . . . . . . . . . . . 429
5 Systemic Effects Following Percutaneous Absorption . . . . . . . . . . . . . . . . . . . . . . . . 430
5.1 Acute Systemic Illnesses from Percutaneous Absorption . . . . . . . . . . . . . . . . . . . . . . . . 430
5.2 Chronic Systemic Illnesses from Percutaneous Absorption . . . . . . . . . . . . . . . . . . . . . . 432
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433

Acetylcholinesterase poisoning · ACGIH ·
Amphiphilic · Aromatic amines · Benzene · • The relevance to health of percutaneous
Bladder cancer · Dimethylformamide · absorption of hazardous substances is often
Dinitrotoluene · Internal exposure · MAK · underestimated.
Mercury · Pesticides · Skin notation · Skin- • The transdermal absorption of hazardous sub-
absorbable substances · Transdermal · Warfare stances or pharmaceuticals usually requires
agents exposure to just a few square centimeters of
the skin in order to administer an effective dose
to the body.
• Skin contamination can occur in the workplace
or in the general environment.
• The systemic effects (acute intoxication,
chronic intoxication, cancer) of substances are
in principle independent of the uptake path.
H. Drexler (*) · S. Kilo
Institute and Outpatient Clinic for Occupational,
Social and Environmental Medicine, Friedrich-Alexander-
University, Erlangen-Nürnberg, Erlangen, Germany
e-mail: Hans.Drexler@fau.de;
Hans.Drexler@rzmail.unierlangen.de; Sonja.Kilo@fau.de

https://doi.org/10.1007/978-3-319-68617-2_30
428 H. Drexler and S. Kilo
2 Introduction esters, tensides, essential oils, amides, and vari-

ous alcohols (Wellner et al. 2006). Their
The relevance of percutaneous absorption of penetration-enhancing effect is mainly due to
hazardous substances to health is often temporary disruption of the stratum corneum
underestimated. Contaminants can be inhaled like changes in intercellular lipid layers (defor-
and enter the body through the respiratory tract mities, alterations, etc.) or interaction with des-
and ingested and enter through the gastrointesti- mosomes, proteins, and keratin fibers in the
nal tract and/or enter the body via absorption corneocytes. Significant amounts of many sub-
through the skin. Only two of these routes are stances at the workplace as well as from con-
controlled sensorily by the body. Olfaction sumer products and the environment can be
(smelling) and gustation (tasting) are the two absorbed through the skin. The systemic effects
senses monitoring the ambient chemical compo- (acute intoxication, chronic intoxication, cancer)
sition with the nose being as sensitive as a gas of these substances are in principle independent
chromatograph. Both senses enable people to of the uptake path. However, if the amount of a
notice and to avoid exposure to hazardous sub- potentially hazardous substance absorbed
stances. However, no sensory modality monitors through the skin contributes significantly to the
the chemical composition of substances internal exposure, i.e., to the overall body bur-
absorbed by the skin (percutaneous absorption) den, these effects are caused most likely by
as this used to play only a subordinate role in uptake via this exposure route.
nature. In case of dermal contamination of skin
by toxic substances, the skin can function as a
sensory organ and notice a substance on the skin 3 Characterization of Dangerous
which might be absorbed by the skin, but usually Substances Absorbable
awareness of danger is absent. Additionally, in Through the Skin
percutaneous absorption, as opposed to inges-
tion, the first-pass effect by the liver is missing, The extent of percutaneous absorption through an
which is why in case of certain hazardous sub- intact epidermis depends on:
stances, the onset of detoxification may be
delayed. • The lipophilicity and water solubility of the
Looking at transdermal therapeutic systems penetrating molecule
(TTS) reveals the significance of absorption • The molecular size and structure
through the skin. The transdermal absorption of • The aggregate state and the concentration of
pharmaceuticals requires exposure to just a few the substance
square centimeters of the skin in order to admin- • The characteristics of the skin (area of the
ister a pharmacologically effective dose to the body, skin disease, etc.)
body. For example, a transdermal contraceptive • And the exposure period
patch, covering just about 0.125% of the body
surface, releases enough estrogen and progestin Roughly speaking, the ability of a molecule
hormones to be as effective as oral contraception to permeate the skin increases with its lipophilicity
in preventing pregnancies. Transdermal delivery and diminishes with its molecular size. Since
systems often employ penetration-enhancing the skin is composed of layers with both lipophilic
methods to facilitate absorption. Improvement and hydrophilic properties, in particular small
in solubility of the active substance and therefore amphiphilic molecules penetrate the skin easily.
its distribution in the stratum corneum (kerati- These substances can be solid, liquid, or gaseous,
nous layer) facilitate absorption as well as phys- the latter being significant when respiratory protec-
ical procedures like iontophoresis and rise in tive masks are worn. To draw attention to the
temperature. Typical chemical penetration danger of absorption through the skin at the work-
enhancers are dimethylsulfoxide, fatty acid place, hazardous substances which are absorbable
30 Systemic Diseases by Absorption Through the Skin 429
through the skin are labeled as such (S=Skin, – Determination of the “flux” through skin
H=Haut, Huid). However, the criteria for explants or artificial skin membranes.
assignment of a skin notation vary. For example, – The permeability constant was calculated or
the American Conference of Governmental Indus- can be calculated.
trial Hygienists (ACGIH) in the USA uses the der- – Data available on the percentage absorption
mal LD50 as a criterion for assigning the “skin” of the applied dose (% absorbed per unit of
notation (Kennedy et al. 1993). The problem is that time and surface area).
carcinogenic and long-term effects are not IV. Classification on the basis of theoretical
sufficiently considered thereby. When labeling a (in silico) models
substance as absorbable through the skin, the
toxic potential of the compound must be consid- • Relevant percutaneous absorption can be
ered along with its permeability through the skin. assumed on the basis of analogy or mathemat-
The German Permanent Senate Commission ical model calculations.
for the Investigation of Health Hazards of Chemi-
cal Compounds in the Work Area (MAK Commis- Criteria I–IV are arranged in order of signifi-
sion) labels a substance as absorbable through the cance for classification with the data from humans
skin when the skin contamination endangers the being the most important (Drexler 1998).
person exposed to it. The percutaneous absorp- According to these criteria, about one-third of all
tion becomes relevant when adherence to the MAK listed substances are classified as absorb-
stipulated MAK value (maximum permissible able through the skin.
concentrations in air at the workplace) alone no
longer sufficiently protects the worker against
damage to health.
A substance is classed as absorbable by the 4 Factors Influencing Dermal
skin if the exposure to the substance in question Exposure and Absorption
can lead to toxic effects and one of the following
criteria is fulfilled: Skin contamination and absorption of a poten-
tially hazardous substance can occur in the work-
I. Classification on the basis of investigations in place or in the general environment as the result
man (in vivo) of an accidental exposure (i.e., contamination of
skin or clothing by leakage from or explosion of
• Contact with the substance in question and its a container) or incidental exposure (like with
potential percutaneous absorption is of practi- inadequate protective clothing, holes in gloves,
cal relevance (on the basis of scientifically etc.). Large-scale contamination is more easily
based field or case studies). noticed than small-scale contamination, like
• And the percutaneous absorption acco- from a splash.
unts without doubt for part of the internal There is always the danger of contamination
exposure. and absorption through the skin where skin-
II. Classification on the basis of investigations in absorbable substances are employed. Skin con-
animals (in vivo) tact can occur directly, for example, from a
splash, an aerosol, seepage through clothing, or
• Proof of percutaneous absorption in animals indirectly by touching contaminated surfaces
III. Classification on the basis of ex vivo or or soiled clothes. The extent of the dermal expo-
in vitro investigations sure is determined by the area of the body
part involved, the frequency, and the intensity
• Proof of relevant percutaneous absorption of the contact. The time course of absorption is
using recognized methods. also significant. The fact that the skin might
• Quantification of penetration: act as a reservoir for many foreign substances
allows systemic uptake to take place even 5 Systemic Effects Following

hours after cessation of exposure. Additionally, Percutaneous Absorption
highest internal doses develop sometimes after
a substantial time lapse. Furthermore, a series Basically, the systemic effects of a substance
of physical and chemical factors can change are independent of its route of entry; with the
the condition of the skin and thus influence exception that oral ingestion is followed by hepatic
percutaneous absorption. During or following first-pass metabolism, which can lead to poisoning
an activity, which is known to cause micro- or detoxification of the substance. When inhaled,
lesions to the skin, increased uptake through the the foreign substances enter the bloodstream
skin must be assumed. The simultaneous impact quickly and non-metabolized. In percutaneous
of corrosive, sensitizing, or irritating substances absorption, dermal metabolism can take place.
or preparations, which influence or damage the The skin is a metabolically active organ like the
skin directly, can increase the dermal uptake liver, but the enzyme activity is lower.
of systemically active substances as loss of In acute intoxication, the uptake path can usu-
skin integrity favors absorption. This applies ally be described unequivocally, for example,
among others to solvents such as acetone, meth- absorption primarily through the skin or primarily
anol, diethyl ether, and hexane. Detergents such by inhalation. In case of chronic intoxication or
as soap can also destroy the integrity of the skin cancer, simultaneous inhalation and absorption
and act as a penetration enhancer. Raising the through the skin can generally be assumed. Even
epidermal water content (i.e., by occlusion) can with “pure” airborne exposure to substances able
cause swelling of the corneal layer of the skin, to penetrate the skin, the percutaneous absorption
which can also favor percutaneous absorption of is paramount. The gaseous substance is rather
substances. Wearing gloves can facilitate direct absorbed into the body through the skin than
skin contact of substances to a supposedly pro- through the lungs (Bader et al. 2008; Johanson
tected area, firstly because of permeation through and Boman 1991; Weschler et al. 2015).
the glove material and secondly because of If absorption through the skin could have been
unintentional collection of sweat and/or liquid the cause of an illness, then first of all, it must be
substances running down from unprotected proved whether the symptoms of the illness fit the
areas (e.g., sweat from lower arms) into the toxic profile of the substance in question and
gloves opening (Kilo et al. 2015). As for the whether the substance is able to penetrate the
parts of the arm and hand inside the gloves, skin to a sufficient extent. Examples of systemic
increased dermal penetration must be taken illnesses due to percutaneous absorption are
into account under these occlusive conditions. shown below.
The protective effect of any gloves, i.e., their
resistance to the chemicals used, must be
checked carefully before they are recommended. 5.1 Acute Systemic Illnesses from
Substances or physical factors which are Percutaneous Absorption
capable of enhancing blood circulation can
facilitate dermal absorption, which is why an 5.1.1 Acute Intoxication Following
increased health hazard must be assumed for Dermal Absorption
these. in an Industrial Accident
Besides accidental or operational contamina- N,N-Dimethylformamide (DMF) is an organic
tion, intentional contamination of the skin with solvent which is produced in large quantities
substances which are absorbable through the worldwide. It is used industrially as a solvent, a
skin is common. The use of cosmetics and trans- chemical intermediate, and an additive. In many
dermal therapeutic systems and, in particular, the cases, dermal exposure happened accidentally to
military deployment of warfare agents must be workers when their clothes were soaked with
mentioned here. dimethylformamide due to a technical fault.
Within hours, the affected workers developed during military action with a desired toxic
abdominal pain as the first sign of toxic hepatitis. effect. Warfare agents such as the organophos-
They also suffered from dizziness, nausea, phorus compound “VX” are viscous fluids with
anorexia, vomiting, and alcohol intolerance. low vapor pressure whose preferred uptake path
Liver dysfunction could be verified by liver func- is through the skin.
tion tests. The affected persons recovered within In transdermal therapeutic systems, the per-
2–3 weeks (IPCS 1991). Dimethylformamide can cutaneous introduction of foreign substances
be absorbed almost completely through intact leads to effects which are pharmacologically
skin, so the high internal contamination, which desired, but inappropriate use of these systems
caused the clinical symptoms, was primarily due can lead to acute intoxication. A 69-year-old
to absorption of DMF through the skin. The chronic smoker placed two transdermal nico-
impairment of liver metabolism and alcohol intol- tine patches (TNPs) on her body for 2 weeks
erance are the typical symptoms of intoxication causing confusion and hypertension. Symp-
with dimethylformamide (Kilo et al. 2016; toms resolved within 4 h after removal of the
Schaller and Drexler 1995). patches and cleaning of the skin (Woolf et al.
1996).
5.1.2 Acute Intoxication Following Cosmetics too can contain substances which
Dermal Absorption Due are absorbed through the skin. Of particular
to Inadequate Safety Procedures toxicological significance with ensuing clini-
Many pesticides, primarily the organophosphates, cally obvious intoxication are preparations for
penetrate human skin quickly. Poisoning by pes- external use which contain mercury. Mercury
ticides frequently affects agricultural workers, preparations have been applied to the skin for
particularly in Third World countries. Poisoning almost 500 years in order to bleach it. A raised
through percutaneous absorption of pesticides is a level of mercury contamination is detectable in
major health problem in these countries the user (Sin and Tsang 2003), but used cor-
(Kesavachandran et al. 2009). The danger of per- rectly, concentrations which would cause acute
cutaneous absorption of pesticides, which are not intoxication are never reached. However fol-
being used professionally, is not sufficiently lowing accidental use of too much mercury dur-
heeded, as the following case report from Wu ing manufacturing, lethal doses of mercury can
and Deng (2009) shows. A 54-year-old man be absorbed percutaneously. A 77-year-old
treated his dog with trichlorfon. Trichlorfon is woman applied a gel on her breast to treat
used as an insecticide in agriculture, in veterinary eczema. This gel contained a high concentration
medicine, and in the household. The dog was of mercury bromide, since during the prepara-
supposed to be cleared of parasites. Half an hour tion mercury bromide was used instead of
after the treatment the dog died. The description of talcum powder. Two days into the treatment
the symptoms indicated acetylcholinesterase poi- with the product, clinical intoxication
soning. The man suffered from cramping stomach manifested itself. Locally the skin became
pains. A little later, he developed severe nausea, necrotic and systemically retention of urine
vomiting, shivering, a high temperature, and cold resulted from acute renal failure. The patient
sweats. This was followed by hemolysis with was disoriented and agitated. Four days after
renal impairment. At a follow-up half a year admission to hospital, an extremely high level
later, he was fully recovered. of mercury was detected in the blood (4836 mg/
l), which corresponds to about 80,000–500,000
5.1.3 Acute Intoxication Following times the concentration of mercury which is
Intentional Application reported to be normal (Sin and Tsang 2003;
to the Skin Triunfante et al. 2009). Despite hemodialysis,
Intentional contamination of the skin with skin- the patient died 9 days after first application of
absorbable dangerous substances can happen the product (Triunfante et al. 2009).
5.2 Chronic Systemic Illnesses from several substances, particularly those with low
Percutaneous Absorption vapor pressure or solid substances whose absorp-
tion through the skin is paramount in causing
5.2.1 Chronic Intoxication Following internal contamination. Dinitrotoluene, for exam-
Accidental Exposure ple, has been used in munitions manufacturing
A 48-year-old professor of chemistry was admit- since the nineteenth century and thereby repeat-
ted to hospital complaining of increasing loss of edly leads to poisoning. The absorption through
balance, unsteady gait, and speech disorder. She the skin via soiled clothing and dusty skin can be
had lost 6.8 kg weight within 2 months without substantial. Besides more acute symptoms like
dieting. The patient remembered that 5 months discomfort, loss of appetite, and gastrointestinal
prior to hospitalization, while working in the lab- disorders, symptoms of chronic intoxication range
oratory, transferring dimethylmercury from a con- from cardiovascular (i.e., ischemic heart disease)
tainer to a capillary tube using a pipette, she got a to neurological and hematopoietic (i.e., anemia)
few drops of the liquid on the back of her hand and finally to irreparable damage resulting in
which was protected by a latex glove. She said death (Letzel et al. 2003).
that she had removed the drops and changed the
protective gloves. The neurological symptoms 5.2.3 Cancer Following (Long-Term)
were paramount. Otherwise she appeared healthy. Handling of Skin-Absorbable
The routine blood counts were within normal Carcinogens
parameters. Because of the history of potential Cancer occurs mostly with a latency of many
methylmercury contamination, blood and urine years. To gather data retrospectively on previous
were tested for mercury. On day 154 after con- exposure to the substance which caused the can-
tamination, a concentration of over 1000 μg/l cer is exceedingly difficult. If records quantify-
mercury was still detectable. Despite intensive ing the contamination by dangerous substances
treatment including chelation therapy to bind exist at all, they refer primarily to air monitoring.
and remove the mercury from the body, the neu- Therefore, the cancer risk of a product is calcu-
rological symptoms were clinically progressive. lated in epidemiological studies from the air
The patient died 298 days after this single con- concentration (in mg/m3 or ppm) and the
tamination. A postmortem showed 1000 times the duration of exposure in years. The additional
normal concentration of mercury in the brain. absorption through the skin, which contributes
Dimethylmercury’s metabolite methylmercury as significantly to internal contamination and thus
many other organic metallic compounds is able to to the cancerogenesis, has only in recent years
easily penetrate the blood-brain barrier. Once in been taken into consideration. This influence of
the brain, the organic methylmercury can be dermal exposure is demonstrated by two exam-
demethylated. The resulting inorganic mercury is ples of carcinogenic substances relevant to
trapped in the brain since it does not penetrate the industrial medicine.
blood-brain barrier well, so that even after a single Aromatic amines are a group of chemicals used
exposure, chronic intracerebral contamination in a variety of ways as a base or intermediate
results (Nierenberg et al. 1998). material, particularly in the manufacture of dyes,
pigments, and insecticides. Several exponents
5.2.2 Chronic Intoxication Following have been identified as human carcinogens. The
(Long-Term) Dermal Absorption main organ affected by the carcinogenic effect of
If a worker falls ill years after contact with a skin- aromatic amines in humans is the urinary bladder.
absorbable substance, then in general, uptake Aromatic amines have a low vapor pressure and
through the skin and the lungs has taken place. penetrate the skin easily. The extent of absorption
Compounds with low vapor pressure can be of aromatic amines through the skin is influenced
inhaled as dust-borne particles and thus contribute by the condition of the skin. A field study showed
to toxic contamination. There are, however, increased levels of internal contamination in
persons with a damaged skin barrier caused by opposed to percutaneous absorption of airborne
skin disease and in workers using skin barrier benzene, percutaneous absorption by dermal con-
creams at work (Korinth et al. 2007). Acceleration tact with liquid benzene can no longer be ignored.
of the penetration of aromatic amines could – In this context, it was calculated that internal
experimentally – be affected by using hand benzene exposure is similar for both, 3 min
cream (Wellner et al. 2008). Therefore, an inves- handwashing with an organic solvent containing
tigation establishing the cause of bladder cancer 0.5% benzene and 8 h inhaling air with an average
which concentrates solely on air contamination airborne benzene concentration of 0.05 mg/m3
significantly underestimates the occupational haz- (Nies et al. 2005).
ard. The significance of absorption through the
skin in occupational carcinoma of the bladder
caused by aromatic amines has been acknowl-
edged for a long time and is generally accepted.
References
For substances with a high vapor pressure, Bader M, Wrbitzky R, Blaszkewicz M, Schaper M, van
such as benzene, generally only the inhaled con- Thriel C (2008) Human volunteer study on the inha-
taminant is taken into consideration. Benzene lational and dermal absorption of N-methyl-2-
itself is a hemotoxic solvent causing malignant pyrrolidone (NMP) from the vapour phase. Arch
Toxicol 82(1):13–20. https://doi.org/10.1007/s00
disease of the blood-forming organs. The connec- 204-007-0230-5
tion between exposure to benzene and leukemia Drexler H (1998) Assignment of skin notation for MAK
has been known since the beginning of the twen- values and its legal consequences in Germany. Int Arch
tieth century. In addition, exposure to benzene is Occup Environ Health 71(7):503–505
IPCS (1991) Environmental health criteria 114
regarded as a cause of malignant non-Hodgkin’s dimethylformamide. WHO, Geneva
lymphoma (NHL). Several epidemiological stud- Johanson G, Boman A (1991) Percutaneous absorption of
ies have proved this risk. The exposure assess- 2-butoxyethanol vapour in human subjects. Br J Ind
ment is always carried out using the results of air Med 48(11):788–792
Kennedy GL, Brock WJ, Banerjee AK (1993) Assignment
monitoring and duration of the exposure (known of skin notation for threshold limit values chemicals
as ppm-years). Thereby, dermal exposure is not based on acute dermal toxicity. Appl Occup Environ
taken into consideration, but ought to be, not only Hyg 8(1):26–30. https://doi.org/10.1080/1047322x.
for retrospective estimation of exposure after the 1993.10388112
Kesavachandran CN, Fareed M, Pathak MK, Bihari V,
illness has broken out but also because it might Mathur N, Srivastava AK (2009) Adverse health effects
have significant implications on future preventive of pesticides in agrarian populations of developing
efforts. For example, the extent of absorption of countries. Rev Environ Contam Toxicol 200:33–52.
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Kilo S, Zonnur N, Uter W, Göen T, Drexler H (2015) Effect
and Korinth 2008). It is agreed that benzene can of skin protection and skin irritation on the internal
penetrate the skin, but its respiratory absorption exposure to carbon disulfide in employees of the vis-
is usually clinically more relevant. Overall, cose industry. Ann Occup Hyg 59(8):972–981. https://
absorption of airborne benzene through the skin doi.org/10.1093/annhyg/mev032
Kilo S, Göen T, Drexler H (2016) Cross-sectional study on
plays a subordinate role even when respiratory N,N-dimethylformamide (DMF); effects on liver and
protection is worn. Percutaneous absorption, alcohol intolerance. Int Arch Occup Environ Health
however, becomes significant when there has 89(8):1309–1320. https://doi.org/10.1007/s00420-
been direct or indirect skin contact. For example, 016-1164-0
Korinth G, Weiss T, Penkert S, Schaller KH, Angerer J,
direct skin contact with liquid benzene or benzene Drexler H (2007) Percutaneous absorption of aromatic
mixtures can occur when painters or car mechan- amines in rubber industry workers: impact of impaired
ics clean their greasy hands with benzene or by skin and skin barrier creams. Occup Environ Med 64
contact with workpieces wetted with benzene (6):366–372. https://doi.org/10.1136/oem.2006. 027755
Letzel S, Göen T, Bader M, Angerer J, Kraus T (2003)
(e.g., when servicing cars or planes). Indirect Exposure to nitroaromatic explosives and health effects
skin contact with liquid benzene occurs when during disposal of military waste. Occup Environ Med
clothing or gloves are wet with benzene. As 60(7):483–488
Nierenberg DW, Nordgren RE, Chang MB et al (1998) 184(1–3):e1–e6. https://doi.org/10.1016/j.forsciint.

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through human abdominal skin in vitro”. Toxicol Korinth G (2008) Percutaneous absorption of aromatic
In Vitro 22(1):275–277. https://doi.org/10.1016/j. amines – a contribution for human health risk assess-
tiv.2007.04.015 ment. Food Chem Toxicol 46(6):1960–1968. https://
Nies E, Barrot R, Drexler H et al (2005) Perkutane doi.org/10.1016/j.fct.2008.01.036
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intoxication: two case reports. Forensic Sci Int 4901(09)70058-9
Occupational and Environmental Acne
31
Penpun Wattanakrai and James S. Taylor
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3 Oil Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
4 Pitch or Coal-Tar Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
5 Acne Cosmetica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
6 Acne Aestivalis (Mallorca Acne) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
7 Acne Mechanica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
8 Tropical Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
9 Drug-Induced Acne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
10 Environmental Heavy Metals Associated with Acne Vulgaris . . . . . . . . . . . . . . 440
11 Chloracne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
11.1 Chloracne-Producing Chemicals and Sources of Exposure . . . . . . . . . . . . . . . . . . . . . 441
11.2 Occupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
11.3 Nonoccupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
11.4 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
11.5 Noncutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
P. Wattanakrai (*) Abstract

Division of Dermatology, Department of Medicine, Occupational and environmental acne is an
Ramathibodi Hospital, Mahidol University, Bangkok,
acneiform disorder, resulting from various chem-
Thailand
e-mail: penpun.wat@mahidol.ac.th ical exposures and from a variety of environmen-
tal, physical, and mechanical factors, usually
J. S. Taylor
Department of Dermatology, Desk A-61, Dermatology- encountered in the workplace but occasionally
Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, seen in nonoccupational settings. Occupational
USA and environmental acne comprises oil acne, coal-
Cleveland Clinic Lerner College of Medicine of Case tar and pitch acne, acne cosmetica, acne
Western Reserve University, Cleveland, OH, USA aestivalis (from sun), acne mechanica, tropical
e-mail: taylorj@ccf.org

https://doi.org/10.1007/978-3-319-68617-2_31
436 P. Wattanakrai and J. S. Taylor
acne, drug-induced acne, and chloracne. Chlor- • Although chloracne is rare, it is a sensitive
acne, although rare, is a sensitive indicator of indicator of chemical exposure to certain poly-
chemical exposure to certain polyaromatic halo- aromatic halogenated hydrocarbons, which
genated hydrocarbons and is often associated may be associated with internal poisoning.
with systemic involvement that should be recog- Patients with the cutaneous manifestations of
nized by physicians treating occupational skin chloracne should be carefully investigated for
disease. Diagnosis of occupational and environ- systemic complications, e.g., hepatic, ophthal-
mental acne requires a detailed medical history mic, neurologic, lipoprotein, and endocrine
including possible physical, chemical, and envi- abnormalities.
ronmental causative agents, a compatible clinical • Putative chloracnegens should be identified by
and histologic picture and distribution usually environmental measurements and also may be
beyond the typical locations of acne vulgaris. assessed in serum and various tissues by direct
Putative chloracnegens should be identified by chemical analysis or biological assay.
environmental measurements and also may be
assessed in serum and various tissues by direct
chemical analysis or biological assay. Manage- 2 Introduction
ment of occupational and environmental acne
involves removing or limiting exposure to the Occupational and environmental acne is an
putative chemical agent, wearing chemical pro- acneiform disorder resulting from various chemi-
tective equipment, worker education, and topical cal exposures and from a variety of environmen-
and systemic pharmaceutical therapy as tal, physical, and mechanical factors, usually
indicated. encountered in the workplace but occasionally
seen in nonoccupational settings. The eruption
Keywords may be mild, involving localized exposure or
Occupational acne · Environmental acne · covered areas of the body, or severe, explosive
Acneiform disorder · Oil acne · Coal-tar acne · and disseminated with the involvement of almost
Pitch acne · Acne cosmetica · Acne aestivalis · every follicular orifice. Additionally, chloracne
Acne mechanica · Tropical acne · Drug- almost always represents a cutaneous sign of sys-
induced acne chloracne · MADISH · Dioxin temic exposure to highly toxic chemicals. Occu-
pational and environmental acne comprises oil
acne, coal-tar and pitch acne, acne cosmetica,
1 Core Messages acne aestivalis (from sun), acne mechanica, trop-
ical acne, drug-induced acne, and chloracne
• Occupational and environmental acne includes (Table 1). This listing serves as a useful paradigm
oil acne, coal-tar and pitch acne, acne cosmetica, and includes the most common causes of occupa-
acne aestivalis (from sun), acne mechanica, tional and environmental acne (Plewig and
tropical acne, drug-induced acne, and chloracne. Kligman 1993) (Fig. 1).
Diagnosis requires a detailed medical history,
listing of associated physical, chemical, and
environmental agents and a compatible clinical 3 Oil Acne
and histologic picture.
• Chloracne, recently renamed “metabolizing Oil acne or oil folliculitis is the most common
acquired dioxin-induced skin hamartomas” form of occupational acne and consists of numer-
(MADISH), is a refractory acneiform eruption ous follicular papules and pustules occurring in
clinically characterized by comedones and areas with heavy oil exposure, such as the thighs
straw-colored cysts, typically affecting the and forearms. Oil acne is most commonly
malar region of the cheeks and the observed in machine tool operators, mechanics,
retroauricular areas. refinery workers, and other employees of
31 Occupational and Environmental Acne 437
Table 1 List of types and etiologies of occupational and environmental acne

Type Etiology Occupations/other sources
Oil acne Cutting oils, semisynthetic coolants, grease, fat, Machinists working with oil-based cutting fluids;
lubricating oils, and kerosene auto, airplane and truck mechanics; roofers; oil
well drillers; petroleum refiners; rubber workers;
textile mill workers; and road pavers
Pitch/ Coal-tar oils, creosote, and pitch Coal-tar plant, road maintenance and construction
coal-tar workers; roofers
acne
Cosmetic Greasy, oily makeup or grooming substances, Actors, actresses, models, and cosmetologists
acne pomade
Acne Sun exposure; ultraviolet and fluorescent lighting; Performing artists; occupations with heavy sun
aestivalis and ionizing radiation exposure; and those who work under florescent
lighting
Acne Pressure; friction on dependent areas; repeated or Truck drivers; professional/amateur athletes;
mechanica prolonged physical insults to the skin; and tight- fiddlers/violinists; those who wear face masks,
fitting work clothes hats or helmets and use telephones
Tropical Hot or humid environments Soldiers stationed in tropical climates
acne
Drug- Anabolic steroids (e.g., danazol, testosterone); Exposure to certain medications, supplements, or
induced corticosteroids, corticotropin, phenytoin, lithium, medical procedures
acne isoniazid, iodides, bromides, CNS agents, TNF- α
inhibitors, and tyrosine kinase and multikinase
inhibitors
Chloracne Specific halogenated aromatic hydrocarbons; Chemical production and agricultural workers;
wood preservatives, fungicides, herbicides, and manufacture of pesticides and wood preservatives;
pesticides; pollutants of industrial production accidental industrial or laboratory exposures;
processes and during waste incineration deliberate poisoning or undetermined exposures;
(skin contact, ingestion and possibly inhalation
exposure sources)
Cutting oils, especially insoluble (straight) oils,

and semisynthetic coolants have been the most com-
monly incriminated oil acnegens (Taylor 1987). In
mechanics, prolonged exposure to grease, lubricat-
ing oils, and kerosene may induce oil acne (Upreti et
Fig. 1 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) – a al. 1989). An anecdotal report of acne observed in
halogenated aromatic compound – is highly toxic and young fast-food workers exposed to grease and fat
causes chloracne while frying hamburgers has been termed
“McDonald’s acne” (Litt 1974), although there is
petroleum-based industries who encounter no other evidence that this is a separate entity.
greases or cutting oils that contain a high percent- Prolonged oil exposure produces a reactive fol-
age of mineral oil (Ancona 1986). Other workers licular hyperkeratosis and results in sebum retention.
likely to be affected may include machinists, auto, This manifests clinically as multiple open comedo-
airplane and truck mechanics, roofers, oil well nes, inflammatory folliculitis, follicular papules/pus-
drillers, petroleum refiners, rubber workers, tex- tules, and microcystic lesions caused by the oil itself
tile mill workers, and road pavers. The incidence (Ancona 1986). Lesions are distributed primarily
of oil acne has declined in recent years because of over exposed areas, such as the dorsal hands and
decreased use of pure cutting oils and improved extensor forearms. Oil-soaked clothing may pro-
industrial and personal hygiene practices duce lesions on the thighs, lower abdomen, and
(Kokelj 1992). buttocks (Kokelj 1992). The face may be involved
from wiping the brow with an oil-contaminated uniforms, protective coverings, and exhaust
sleeve. Although the lesions are commonly referred ventilation systems (Adams et al. 2000).
to as oil boils, they usually do not develop from
bacteria present in the oils (Taylor 1986). The
inflammatory lesions, larger furuncular and carbun- 5 Acne Cosmetica
cular lesions may form, are more prominent than in
chloracne, and may mimic conglobate cystic acne. In 1972, Kligman and Mills described acne
Acquired perforating (transepidermal elimina- cosmetica consisting chiefly of small, scattered
tion) disease has been reported in oil field workers comedones occurring mainly in women in the
exposed to drilling fluids. The fluids contain many age range 20–50 years. These women, who were
additives, including calcium chloride. Histopath- using a variety of cosmetics for prolonged periods
ologic examination revealed transepidermal elim- of time, developed comedonal lesions exclusively
ination of calcium with minimal involvement of on the face, predominantly on the chin. Acne
hair follicles (Knox et al. 1986). cosmetica may develop in actors and models
Oil acne is treated with the usual acne vulgaris who are often required to wear heavy, greasy
modalities, such as topical benzoyl peroxide and makeup; cosmetologists may also be affected.
retinoic acid. Systemic treatment is often needed Clinically acne cosmetica consists of essentially
with tetracycline, erythromycin or minocycline, noninflammatory, small, closed comedones and a
or with isotretinoin in severe cases. The key factor few intermittent papules, and pustules. When
is avoiding contact with oils and grease and the superimposed upon acne vulgaris, the clinical pic-
practice of good hygiene. Work clothes should be ture may be obscured (Kligman and Mills 1972).
changed daily and frequent cleansing of the skin Animal models were originally used to determine
with soap and water is advised. the comedogenic potential of raw materials with
the assumption that finished formulations
containing these ingredients would also be
4 Pitch or Coal-Tar Acne comedogenic. Cosmetic ingredients found exper-
imentally to be comedogenic include isopropyl
Coal-tar oils, creosote, and pitch can produce a palmitate, isopropyl myristate, butyl stearate, iso-
comedonal type of acne, which shows a predi- propyl isostearate, decyl oleate, isostearyl neo-
lection for exposed areas, particularly the malar pentanoate, isocetyl stearate, myristle myristate,
regions (Bartolini 1989) and periorbital areas in cocoa butter, cetyl alcohol, paraffin, stearyl alco-
individuals exposed to pitch tar (Adams et al. hol, sodium lauryl sulfate (SLS), and petrolatum
2000). Coal-tar plant workers, roofers, road (Nguyen et al. 2007). Despite the fact that finished
maintenance workers, and construction products using comedogenic ingredients are not
workers are among those at risk. Coal-tar deriv- necessarily comedogenic (Draelos and DiNardo
atives have been reported to be not only 2006), many of these substances are avoided or
acnegenic, but also carcinogenic and photo- modified by cosmetic manufacturers and cos-
sensitizing (Adams et al. 2000). Therefore coal- metics are frequently advertised as noncomedo-
tar acne may be complicated by phototoxic reac- genic. Still a recent study reported that use of full-
tions affecting both the skin and the eyes and coverage foundations was one of the factors that
resulting in hyperpigmentation known as coal- increased the severity of acne in adult acne
tar melanosis. Late complications include the patients (Chlebus and Chlebus 2017). Acneiform
development of pitch and tar papillomas, kerato- eruptions with predominantly deep-seated nod-
ses, and acanthomas (Taylor 1987). Pitch acne ules and a few comedones situated mainly on the
responds to treatment much better than chlor- cheeks can occur after facial massage beauty treat-
acne. Prevention of pitch acne includes showers ment. This eruption is unlike classic acne
and available cleansers at work facilities, clean cosmetica in being inflammatory, indolent, and
often occurring a few weeks after facial massage occurs in truck drivers. Acne mechanica is specif-
(Khanna and Gupta 1999). ically related to sporting activities. Occupational
causes of acne mechanica include the use of face
masks (as in hospital workers or clean-room
6 Acne Aestivalis (Mallorca Acne) workers in the semiconductor industry), belts,
straps, tight-fitting work clothing, football shoul-
Acne aestivalis is a rare, infrequently described, der pads, football helmets, hats, and telephones
generally, nonoccupational eruption, which can (Mills and Kligman 1975). Fiddler’s neck (Brun
also affect performing artists. Typically, it affects and Baran 1984) and violinists neck is also a
women in the age range of 25–40 years and variant of acne mechanica (Omohundro and Tay-
involves the cheeks, sides of the neck, chest, lor 1998). In 2012 a form of exogenous inflam-
shoulders, and upper arms. Typical lesions are matory acne due to combined application of
monomorphic papular, round, hard, and small cosmetics and facial rubbing affecting young
lesions reported to develop after sun exposure. women without personal history of acne was
Comedones and pustules are absent or scarce. reported (Seneschal et al. 2012).
Lesions involute in the fall without scar Clinically, crops of inflammatory papules and
formation. pustules appear in affected areas of skin. Deep,
The eruption is due to sun exposure, ultraviolet inflammatory nodules may result from prolonged
radiation, mainly UVA, and florescent light expo- pressure. It has been emphasized that acne
sure (Plewig and Jansen 1998; Zugerman 1990). mechanica is a complication of acne vulgaris and
PUVA therapy and ionizing radiation are also that external physical forces merely exacerbate
potentially acnegenic. Acne aestivalis responds the underlying disease focally (Mills and Kligman
to topical retinoic acid or benzoyl peroxide but 1975). Improvement of mechanical acne may
not to antibiotics (Hjorth et al. 1972). Prophylactic occur promptly after removing the source of
treatment has been reported by gradually increas- mechanical and physical factors. Skin washing
ing exposure to artificial UV radiation (UVB, and use of topical cleansing agents may reduce
UVA, or PUVA) prior to the first exposure to the risk of acne mechanica.
natural sunlight (Plewig and Jansen 1998).
Actinic follicuitis a rare photodermatosis pre-
senting with recurrent pustular facial eruptions, 8 Tropical Acne
typically appearing 4–6 h after exposure to sun-
light falls into the same spectrum as acne Tropical acne may result from exposure to exces-
aestivalis and actinic superficial folliculitis sively hot or humid environments and, when such
(Veysey and George 2005). exposure is required in the performance of the
patient’s job, may be considered to be a form of
occupational acne. Tropical acne has been observed
7 Acne Mechanica most commonly in soldiers stationed in tropical
climates, but variants may result from chronic
In 1975, Mills and Kligman defined acne exposure to other hot and/or humid environments
mechanica as a process in which mechanical fac- as can be found in foundries (Mathias 1994).
tors such as pressure, occlusion, friction, rubbing, Onset is explosive in nature and typically
or heat provoke acne lesions by inducing the occurs several months after entering the hot,
rupture of microcomedones. Repeated or pro- humid environment. This is a severely inflamma-
longed physical insults to the skin may produce tory condition, with the development of papules,
an acneiform eruption that can be strikingly pustules, nodules, and draining sinuses as in acne
inflammatory in nature. An example is the local conglobata. Patients often feel quite ill, and acute-
pressure and rubbing against seat covers which phase reactants may be elevated. There is
characteristic involvement of the buttocks and Tumor necrosis factor alpha (TNF-α) inhibitors:
upper thighs, but lesions may be extensive, with adalimumab (Fernández-Crehuet and Ruiz-
the neck, arms, and trunk being affected. The face Villaverde 2015), etanercept (Kashat et al. 2014).
is usually spared (Sperling 1994). Tyrosine kinase inhibitors: The most common
Cultures have not identified a consistent path- cutaneous side effects of epidermal growth
ogen, and the role of bacterial infection is felt to be factor receptor tyrosine kinase inhibitors
unimportant. Antibiotic therapy is without signif- (EGFR-TKIs) are skin lesions that are charac-
icant benefit. The only effective therapeutic mea- terized by papulopustules with lack of come-
sure is to remove the patient from the precipitating dones presenting in seborrheic areas.
environment (Sperling 1994). Acneiform eruptions may occur during treat-
ment with inhibitors of the epidermal growth
factor receptor (EGFR), such as erlotinib,
cetuximab, panitumumab (Osio et al. 2009),
9 Drug-Induced Acne and gefitinib (Jalalat and Cohen 2013).
Eruptive acneiform lesions or acneiform folliculitis Other tyrosine kinase and multikinase inhibitors
can be seen as a side effect of a number of systemic which have been developed and used for targeted
medications and topical corticosteroids. Commonly therapy including imatinib mesylate (Martín et al.
known culprits include anabolic steroids (e.g., dana- 2006; Demirci et al. 2011), sunitinib, lapatinib,
zol, testosterone), corticosteroids (e.g., corticotropin sorafenib (Cohen 2015), dovitinib (Gracia-Cazaña
and other systemics: enteral, parenteral and inhala- et al. 2014), BRAF kinase inhibitor vemurafenib
tion; and topical corticosteroids), phenytoin, lith- (Petukhova et al. 2013), MEK inhibitor trametinib
ium, isoniazid, iodides, and bromides (Plewig and (Uribe et al. 2014), and HER2 inhibitor
Jansen 1998). Less often, azathioprine, cyclospor- trastuzumab (Sheu et al. 2015) have been reported
ine, tetracyclines, vitamins B1, B6, B12, and D2, to cause acneiform eruptions. The clinical presen-
phenobarbital, PUVA, propylthiouracil, disulfiram, tations are various including classic papules and
or quinine have been incriminated (Plewig and pustules, open and/or closed comedones, similar
Kligman 1993). Clinically drug-induced acne pre- appearance, and distribution as chloracne.
sents as an abrupt onset of monomorphous inflam- This acneiform “EGFR-inhibitor like” cutane-
matory papules or pustules in contrast to the ous side effect has also been reported with other
heterogeneous morphology of lesions of acne drugs including tacrolimus (Formicone et al.
vulgaris (Zaenglein and Thiboutot 2008). Drug- 2005), sirolimus, thalidomide, lenalidomide
induced acneiform eruptions occur in more wide- (Michot et al. 2010), and bevacizumab, a recom-
spread unusual locations, beyond typical acne age binant, humanized monoclonal antibody against
and clear after the offending drug has been vascular endothelial growth factor (VEGF)
discontinued (Plewig and Jansen 1998). (Molina-Ruiz et al. 2013).
Other drug categories causing acneiform erup-
tions include the following:
Central nervous system agents: such as anti- 10 Environmental Heavy Metals

epileptics: lamotrigine, valproate; specific Associated with Acne Vulgaris
serotonin reuptake inhibitor (SSRI) antide-
pressants: escitalopram oxalate (Khanna et al. Cadmium and lead Patients with acne vulgaris in
2012), sertraline (Sinha et al. 2014); tricyclic Nigeria were found to have significantly higher
antidepressant (TCA): amineptine (De Gálvez blood levels of the heavy metals; cadmium and
Aranda et al. 2001); antipsychotic drugs: lead and nonsignificantly different blood levels of
aripiprazole haloperdidol quetiapine (Kansal trace elements; and copper and zinc compared to
and Sharma 2013). controls. There were also significant progressive
increases in blood levels of cadmium and lead from environmental pollutions and in food contamina-
mild to moderate and severe acne. It is possible that tions. A decreasing incidence of chloracne may be
increases in blood of environmental toxic heavy attributed to the advent of plastics, the substitution
metals-cadmium and lead may be a contributing of chlorinated hydrocarbons with synthetic resins,
factor in the pathogenesis/severity of acne compared and the restriction of the use of polychlorinated
to copper and zinc (Ikaraoha et al. 2017). Yet the biphenyls to only closed-system formulations
mechanism of cadmium and lead toxicity in the (Kokelj 1992). However, the attempt to poison
development of acne vulgaris was unclear. Ukrainian president Viktor Yushenko with
dioxins in 2004 raised the public attention regard-
ing these toxic chemicals (Sterling and Hanke
11 Chloracne 2005; Sorg et al. 2009; Saurat and Sorg 2010;
Saurat et al. 2012).
Chloracne is an acneiform dermatosis often Chloracnegenic compounds are structurally
refractory to treatment, which results from envi- similar (Table 1), sharing relative molecular pla-
ronmental exposure to certain halogenated aro- narity and containing two benzene rings with hal-
matic hydrocarbons. It is characterized by ogen atoms occupying at least three of the lateral
numerous comedones with pale yellow cysts pre- ring positions. The degree of halogenation does
dominantly affecting the malar region of the cheek not necessarily determine toxicity, whereas the
and the retroauricular areas. In more severe cases, position of halogen atoms on the outside of the
lesions may spread to the trunk and genitalia and molecule seems to be crucial as reduced biologi-
inflammatory lesions are found. Skin involvement cal activity results from halogen substitution into
in chloracne is considered one of the most sensi- positions that lead to molecular nonplanarity
tive indicators of biological response to these (Crow 1981; Kokelj 1992). The main groups of
chemicals, and it occurs regardless of whether chloracnegens include dioxins, naphthalenes,
chemical exposure has occurred via skin contact biphenyls, dibenzofurans, azobenzenes, and
– the usual route, inhalation, or ingestion (Crow azoxybenzenes, with the chloracnegenic potential
and Puhvel 1991). being closely correlated with the chemical’s
Chloracne was first reported by Von Bettman potential to induce the enzyme aryl hydrocarbon
in 1897. In 1899 Herxheimer used the term chlor- hydroxylase (Poland et al. 1976; Sorg 2014;
acne to describe four cases of severe acne Schäfer et al. 2014).
resulting from environmental contact with elec-
trolytically produced potassium hypochlorite
(Herxheimer 1899). Since that time, various 11.1 Chloracne-Producing Chemicals
chloracnegenic chemicals have been identified. and Sources of Exposure
Chloronapthalenes and polychlorinated biphenyls
(PCBs) were the causative agents in the pre-World Table 2 classifies the chemical causes of chlor-
War-II era. Since then, trace contaminants formed acne. Of related interest, Table 3 provides a partial
during the manufacture of PCBs and other poly- list of past and present sources of the various
halogenated compounds, especially herbicides chloracnegens. The majority of chloracne cases
and insecticides, have been the major causes of have resulted from occupational exposure during
chloracne. These include polyhalogenated diben- chemical manufacturing or rarely from end-prod-
zofurans, polychlorinated dibenzo-p-dioxins, and uct use.
chlorinated phenols, azo- and azoxy benzenes.
When it occurs, chloracne tends to be sporadic.
It is caused primarily by exposure to 11.2 Occupational Exposure
chloracnegenic agents in industrial or agricultural
settings. Chloracne has also been caused by non- Selected outbreaks will be discussed as classified
occupational exposures via accidental by chemical cause.
Table 2 Chloracne-producing chemicals Table 3 Partial list of past and present sources of
chloracnegens
Polyhalogenated naphthalenesa
Polychloronaphthalenes Chloracnegen Source
Polybromonaphthalenesb,c Polychloronaphthalenes Electrical insulators; fire-
Polyhalogenated biphenyls resistant materials; wood
preservative; boat hull
Polychlorobiphenyls (PCBs)
coatings (antimagnetic
Polybromodiphenyls (PBBs) properties); and high-
Polyhalogenated dibenzofuransa pressure additives for
Polychlorodibenzofurans (PCDF), especially tri-, lubricants
tetra-, penta-, and hexachlorodibenzofuran Polychlorobiphenyls Hydraulic fluids; plastics;
Polybromodibenzofurans, especially (PCBs) adhesives; fire retardants in
tetrabromodibenzofuran transformers; and sealants
Contaminants of polychlorophenol compounds, Polychlorodibenzofurans Contaminants of PCBs and
especially herbicides (2,4,5-T and pentachlorophenol) (PCDFs) various chlorinated
and herbicide intermediates (2,4,5-trichlorophenol) phenols
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Polyclorinated phenols, Wood preservatives;
Hexachlorodibenzo-p-dioxin Pentachlorophenols leather; paper industry
(PCP) applications; herbicides;
Tetrachlorodibenzofuran
pesticides; fungicides;
Contaminants of 3,4-dichloroaniline and related algicides; insecticides; and
herbicides disinfectants
3,4,3,4,-Tetrachloroazoxybenzene (TCAOB) Dioxins Contaminant of Agent
3,4,3,4-Tetrachloroazobenzene (TCAB) Orange, formed during
Other production of chlorinated
Dihydrotrifluoromethylphenylbenzothiopyrazolone organic solvents
(Scerri et al. 1995) (hexachlorophene and the
1,2,3,4-Tetrachlorobenzene (experimental) herbicide 2,4,5-T); and
products of combustion
Dichlobenil, a herbicide (clinical only)
Azo- and azoxybenzenes Herbicide intermediates
DDT (crude trichlorobenzene)
Triazoloquinoxalines Intermediates discovered
Triazoloquinoxalines (Gawkrodger et al. 2009)
during novel drug
Sodium 3,5,6-trichloropyridin-2-ol (STCP)c,d (Wu et synthesis by
al. 2012; Niu et al. 2014) pharmaceutical discovery
a
The polychlorodibenzofurans and hexachlonaphthalenes chemists
may occur as contaminants in some PCBs Sodium 3,5,6- Main intermediate for
b
The polybromonaphthalenes may occur as contaminants trichloropyridin-2-ol synthesizing
in some PBBs (STCP) (Not confirmed as organophosphate
c
Not confirmed as chloracnegens chloracnegen) insecticide chlorpyrifos
d
Intermediate for insecticide (chloropyrifos) synthesis
11.2.1 Dioxins Dioxins may also appear during natural phenom-

Dioxin is the common name for dibenzo-p- ena such as volcanic eruptions or forest fires and
dioxins, polychlorinated dibenzodioxins in residential wood burning (Fabbrocini et al.
(PCDD), and polychlorinated dibenzofurans 2015). Trace levels are detectable in emissions
(PCDF). Dioxins are mainly produced as undesir- from motor vehicles using leaded gasoline or die-
able by-product pollutants of manufacturing pro- sel fuel. Dioxins contaminate polychlorophenols,
cesses that utilize chlorine, such as in the especially the herbicides 2,4,5-T and pentachloro-
manufacturing of herbicides, paper, and pulp phenol (PCP) and herbicide intermediates (2,4,5-
bleaching, in industrial production processes and trichlorophenol).
during incineration (e.g., of waste). High levels of Of the hundreds of dioxins, 2,3,7,8-tetra-
dioxins are also emitted from metallurgical indus- chlorodibenzo-p-dioxin (TCDD) is the paradigm
tries including copper smelters, electric furnaces for chemicals causing chloracne and also for the
in steel mills, and wire reclamation incinerators. biological importance of trace industrial
contaminants. TCDD is one of the most toxic accident. Thus, a body burden of 9.7 μg, as mea-
small molecules known to man. It is also one of sured in adipose tissue, may be the lowest observ-
the best-studied toxic chemicals, largely after able effect level for TCDD-related chloracne in
intense scrutiny over its use as the main compo- humans. Thirty-two years after exposure, these
nent in the herbicide Agent Orange used during German workers still had detectable levels of
the Vietnam War and more recently in the TCDD TCDD in adipose tissue, and one still had chlor-
poisoning of former Ukrainian President Victor acne (Agency for Toxic Effects of Chemical Sub-
Yushchenko in 2004 (Saurat et al. 2012). The stances 1993). In a follow-up study after the
elimination half-life of 2,3,7,8-tetra- Seveso accident in 1976, which resulted in one
chlorodibenzo-p-dioxin (TCDD) in humans is of the largest ever-reported environmental out-
approximately 7–11 years (Mukerjee 1998). breaks of chloracne, residents of communities
TCDD currently serves no commercial purpose. contaminated with TCDD still had elevated levels
Pure TCDD must be manufactured in a laboratory. of plasma TCDD up to 20–30 years after exposure
It is made in labs in Europe, Russia, and the (Baccarelli et al. 2005).
United States for use as a control for measuring A case of palmoplantar keratoderma, sclero-
dioxin levels (Sterling and Hanke 2005). In 1949, derma, and chloracne was reported in an agricul-
the first descriptions of human exposure to tural worker who had been a weed sprayer for
2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8- 5 years. He had used 2,4,5-trichlorophenoxyacetic
TCDD)-contaminated chemicals were reported acid and/or 2,4 dichlorophenoxyacetic acid, both of
after a trichlorophenol reactor explosion in Nitro, which may contain chlorinated dibenzodioxins as
West Virginia, United States (Sweeney and impurities. He also had been chronically exposed
Mocarelli 2000). More than 20 outbreaks of to multiple other, nonchloracne-associated herbi-
dioxin chloracne, as well as its other health cides, some of which have been associated with
effects, have been reviewed (Taylor et al. 1977; scleroderma. Safety equipment was not utilized
Tindall 1985; Mukerjee 1998). Follow-up studies (Poskitt et al. 1994).
have shown persistence of chloracne up to Pentachlorophenol (PCP) is frequently used as
20 years from the exposure (Baccarelli et al. a wood preservative, herbicide, and fungicide. It
2005). These studies identified an increased risk has additional uses in the leather and paper indus-
of soft-tissue sarcoma from end-product use in try and an estimated 17,000 workers are exposed
Sweden, occupational exposure in the United to PCP in the United States (O’Malley et al.
States and nonoccupational environmental expo- 1990). Pentachlorophenol (PCP) is a stable and
sure in Seveso, Italy. persistent compound. In humans, it is readily
Occupational exposures to TCDD in herbicide absorbed by ingestion and inhalation but is less
and chemical plants were much greater than from well absorbed dermally. Severe exposure by any
most other nonoccupational exposures. Exposure route may result in an acute and occasionally fatal
would sometimes begin as a caustic chemical burn illness that bears all the hallmarks of being medi-
when the trichlorophenol reactors would over ated by uncoupling of oxidative phosphorylation.
heat. These workers showed the earliest and most Tachycardia, tachypnea, sweating, altered con-
severe chloracne (Taylor 1979; Tindall 1985). sciousness, hyperthermia, convulsions, and early
Chloracne is the hallmark of dioxin exposure onset of marked rigor (if death occurs) are the
in man; however, its absence does not exclude most notable features. Pulmonary edema, intra-
dioxin exposure. There is no apparent dose- vascular hemolysis, pancreatitis, jaundice, and
response model for chloracne in exposed human acute renal failure have been reported. There is
populations and lesions may develop weeks or no antidote and no adequate data to support the
months after exposure. In Germany, six workers use of repeat-dose oral cholestyramine, forced
who developed chloracne after an industrial acci- diuresis, or urine alkalinization as effective
dent had an estimated mean TCDD body burden methods of enhancing PCP elimination in poi-
of 44 μg (range 9.7–124 μg) shortly after the soned humans. Supportive care and vigorous
management of hyperthermia should produce a carpenter who assembled piers for small boat
satisfactory outcome. Chronic occupational expo- marinas using PCP-treated lumber. The worker,
sure to PCP may produce a syndrome similar to wearing only shorts and shoes, took measure-
acute systemic poisoning, together with conjunc- ments for extended periods of time while laying
tivitis and irritation of the upper respiratory atop the treated lumber. After 9 months of this
and oral mucosa. Long-term exposure has also activity, he noted the onset of a papular acneiform
been reported to result in chronic fatigue or eruption. Multiple small yellow-white papules
neuropsychiatric features in combination with were present involving the malar regions of the
skin manifestations (including chloracne), face, postauricular area, trunk, buttocks, thighs,
chronic respiratory symptoms, neuralgic pains and lower legs. Samples of treated lumber were
in the legs, and impaired fertility and hypo- tested for octachlorodibenzodioxin (OCD) and
thyroidism secondary to endocrine disruption contained 1040 times the amount of OCD than
(Proudfoot 2003). untreated wood. The yellow residue from treated
A retrospective review of 648 medical and wood contained 400 ppm OCD compared with
personnel records from individuals manufacturing technical grade PCP which contained 1600 ppm
PCP between 1938 and 1978 demonstrated 47 OCD. This case is unusual because the only
cases of chloracne occurring in a 25-year period. source of PCP exposure was pressure-treated lum-
These workers were exposed only to PCP for ber; chloracne developing from this type of expo-
2 years prior to their diagnosis. PCP was produced sure is unusual. In the United States, the
by direct chlorination of phenol, mono- Environmental Protection Agency oversees the
chlorophenol, dichlorophenol, and/or 2,4,6-tri- use of wood preservatives. In 1986, the agency
chlorophenol in the presence of an aluminum proposed a level of hexachloro-p-dioxin no
catalyst. During the commercial synthesis of greater than 15 ppm, which was to be reduced to
PCP, varying amounts of polychlorinated aro- 1 ppm within 18 months (Cole et al. 1986).
matic by-products, including dioxins, are pro-
duced (O’Malley et al. 1990). Russian workers 11.2.2 Polyhalogenated Naphthalenes
who manufactured phenoxy herbicides and (PCNs)
related compounds in the 1960s in the city of Polychlorinated naphthalenes (PCNs) have a
Ufa, Bashkortostan, a republic of the former wax like consistency and have been used since
Soviet Union, were studied for exposure to poly- the early 1900s in the electronics industry, as a
chlorinated dibenzo-p-dioxins (PCDDs) and dielectric material for condensers, as wire insu-
dibenzofurans. The patterns of the PCDDs and lation, on boat hulls, as a lubricant, and as a
dibenzofurans (as defined by the specific conge- wood preservative. Chloronaphthalenes were
ners and their relative amounts) were distinctive sold under the trademark Halowax by Koppers
for the type of chemical produced, with notable Company until the 1970s, but many potential
contributions to the TCDD toxic equivalents from uses have now been taken over by plastic and
the 2,3,7,8-TCDD and 1,2,3,7,8-pentachloro-p- silicone. Their manufacture has been greatly
dioxin (PnCDD) congeners. No correlation was curtailed (Zugerman 1990).
found between chloracne status in 1965–1967 and Industrial use of the polyhalogenated naphtha-
TCDD or toxic equivalent blood lipid concentra- lenes (PCNs), occupational chloracne outbreaks,
tions in 1992. These Russian phenoxy herbicide and experimental human and animal studies
and related chemical producers have some of the have been reviewed. No occupational cases
highest occupational exposure to dioxins of any of PCN chloracne have been reported since
cohort studied to date and seem to be unique with 1972. Trace contamination of polychlorinated
respect to the presence of appreciable amounts of biphenyls (PCBs) with hexachloronaphthalenes
1,2,3,7,8-PnCDD (Ryan and Schecter 2000). and of polybrominated biphenyls (PBBs) with
Cole et al. (1986) reported an unusual case of polybromonaphthalenes are potential current, but
occupational chloracne that developed in a unlikely, sources of exposure (Taylor 1979).
11.2.3 Polyhalogenated Biphenyls 11.2.5 Azo and Azoxybenzenes

(Polychlorinated Biphenyls We first documented cases of chloracne from
(PCBs) and Polybrominated a chlorobenzene compound tetrachloroa-
Biphenyls (PBBs)) zoxybenzene (TCAOB) in 1977. Tetra-
Chloracne has also been ascribed to exposure to chloroazobenzene (TCAB) was also produced
polychlorinated biphenyls (PCBs), but most during the synthesis of 3,4-dichloro aniline or
cases are probably due to a contamination of during its further conversion to herbicides. More
the PCBs with the above-mentioned dioxins and than 90% of 41 workers in a small chemical plant
dibenzofuranes. Polychlorinated biphenyls (PCBs) developed chloracne from direct skin contact, but
have been in use since 1929, and only over the last inhalation and ingestion were also possible routes.
few decades have been recognized as environmen- Family members of four workers, none of whom
tal contaminants. Their use has now been confined had been in the plant, also developed chloracne,
to closed-system applications, such as in electrical probably from exposure at home to contaminated
capacitors and transformers. Other previous uses, tools or work clothes (Taylor et al. 1977). No
such as in paints, in sealants, and in printing, have systemic reactions were found in any individuals.
been eliminated (Zugerman 1990). Chloracne from Eight years later, three of five workers with chlor-
PCBs has been demonstrated in reports in capacitor acne still had some evidence of chloracne and
workers (Taylor et al. 1977; Tindall 1985) and in scarring. Two children who had chloracne were
other workers (Longnecker et al. 1997). Cutaneous clear, except for mild scarring; one had acne
hyperpigmentation, eye discharge, and palpebral vulgaris when seen again (Taylor and Lloyd
edema have also been reported (Taylor et al. 1977). 1982). Similar episodes of chloracne have been
The greatest mass poisoning with PCBs reported in workers exposed to TCAOB from the
occurred in nonoccupation settings of “oil-poi- production of the pesticide-herbicide Proponil in
soning” in Yusho, Japan, 1968 and Yu-Cheng, Arkansas in 1977. A 38% incidence of chloracne
Taiwan, 1979 when thousands of persons were developed among the 102 workers in the plant and
affected after eating rice-based cooking oil that 11% were hospitalized for acute illness related to
had been contaminated with large amounts of chemical exposure. We are aware of other reports
PCBs as described in detail below. of TCAB and TCAOB chloracne in the United
In 1973, polybrominated biphenyls (PBBs) States and England in the 1970s and 1980s (Tay-
were accidentally introduced into cattle feed as a lor and Lloyd 1982). An outbreak of chloracne in
result of a shipping error in Michigan. Thousands 17 workers from a British plant manufacturing
of dairy animals died or were destroyed, and farm dichloro-aniline-derived herbicides was reported
workers were exposed to significant levels of in 1993. TCAB and TCAOB were the acnegens.
these chemicals. Three percent of the exposed Comedones evolved 6–12 weeks after exposure to
farm workers developed chloracne, but abnormal these chloracnegenic contaminants. Cutaneous
sweating and nonscarring alopecia were the more xerosis and folliculitis on the trunk, limbs, thighs,
common complaints (Zugerman 1990). and buttocks, previously uncommonly described,
were present in 50% of exposed workers. Affected
11.2.4 Polyhalogenated follicles were surrounded by a collarette of scale
Dibenzofurans (PHDFs) and frequently the hair shaft was twisted or bro-
Polychlorinated dibenzofurans were used as ken. The pathogenesis of these lesions is unclear
recently as 1974 in flame retardants; but due but may involve a disorder of keratinization. A
to their extreme toxicity they are no longer direct toxic effect on epidermal keratinocytes or a
manufactured. Since polyhalogenated secondary effect due to a perifollicular inflamma-
dibenzofuans (PHDFs) may occur as contami- tory reaction has been theorized (McDonough et
nants of PCBs and polyhalogenated phenols, al. 1993). They suggested that folliculitis and
their cutaneous effects are discussed under those xerosis should be included in the clinical spectrum
headings. of chloracne.
In 1996, nine workers from a Mexican chemi- were several times more chloracnegenic than
cal plant were evaluated for the effects of chronic dioxins on a weight for weight basis. Tri-
exposure to chlorobenzenes (mono-, ortho-, and azoloquinoxalines were synthetic intermediates
paradichlorobenzenes). They had a mean expo- in the project, being synthesized in small scale
sure of 24 working years and worked in all stages (mg g1) quantities. Triazoloquinoxalines were
of chemical production. Safety equipment was not not previously known as chloracnegens; however,
used, and direct contact with the chlorobenzenes they showed the basic structural features and
occurred via the skin and respiratory tract. The physiochemical properties that are typical of
nine workers had a polymorphic acneiform erup- chloracnegens, such as high metabolic stability, a
tion consisting mainly of comedones and cysts. polycyclic structure, a lipophilic nature, and the
All had comedones on the face, predominately in potential to be halogenated (Gawkrodger et al.
the malar area; lesions on the nose, axillae, chest, 2009). The chloracne in subjects mostly resolved
shoulders, arms, buttocks, and thighs were also within 18–24 months although on examination
present. Yellow cysts (2–5 mm in diameter) were about 3 years later, five of the seven still showed
found on the malar area of the face, eyelids, penis, minor changes of chloracne.
scrotum, chest, axilla, and ears. Abnormal hyper-
pigmentation of the face, oral cavity, or diffuse 11.2.7 Sodium 3,5,6-Trichloropyridin-
hyperpigmentation was also observed in all 2-ol (STCP)
patients. Chlorobenzenes were measured in the Sodium 3,5,6-trichloropyridin-2-ol (STCP) is a
water at a concentration of 15 ppm. All workers widely used intermediate for the production of
reported chronic conjunctivitis with thick secre- chlorpyrifos. Chlorpyrifos is an organophospho-
tions from meibomian glands similar to those seen rus insecticide developed by the US Dow
in Yusho. Hepatic involvement including elevated AgroSciences (DOW) Chemical Company com-
serum alkaline phosphatase and lower extremity monly used worldwide. In 2012 four male
peripheral neuropathy were also evident (Vazquez workers who worked in a STCP factory in
et al. 1996). China without proper protection developed
peripheral neuropathy with numbness and pain
11.2.6 Triazoloquinoxalines in the lower extremities and chloracne-like skin
In 2009, a new chloracnegen was reported from lesions on the whole body of varying degrees
the United Kingdom in an outbreak of chloracne (Wu et al. 2012). Patches of follicular skin erup-
among seven male pharmaceutical discovery tions (mainly blackheads, accompanied by fol-
chemists who synthesized novel polycyclic halo- licular orifice cornification occasionally
genated chemical compounds which were classi- accompanied by milia-like skin eruptions) were
fied as triazoloquinoxalines (Gawkrodger et al. found on the head and face, around the auricle,
2009). Comedones developed on the face, malar chest and back, abdomen, and scrotum. An
area, postauricular, periauricular, and preauricular almost identical report also from China pre-
areas with occasional inflammatory papules, pus- sented four male workers involved in the indus-
tules, and cysts. Other findings on examination trial manufacture of STCP who were affected
included dry skin on the back and papular follic- with different degrees of acne on the skin also
ulitis on the thighs. A clinical diagnosis of chlor- with pain and numbness in both the legs. Their
acne was made. One subject had slightly raised electromyography (EMG) showed peripheral
serum level of alanine aminotransferase. There neurogenic damage (Niu et al. 2014).
were no other signs of systemic toxicity. Toxico- STCP is a chlorophenol, and while chlo-
logical investigations of the synthesized com- rophenol manufacture and use has historically
pounds found that the triazoloquinoxalines, been associated with chloracne, this is believed
which showed high activity in the chemically to be the result of contamination by 2,3,7,8-tetra-
activated luciferase gene expression (CALUX) chlorodibenzo-p-dioxin (TCDD) and other
cell bioassay for estimation of dioxin-like activity, dioxin/benzofuran impurities. The occurrence of
these is highly dependent on manufacturing con- There was also a strong association between
ditions and degree of purification (Wu et al. 2012). plasma TCDD levels and chloracne occurrence,
STCP is a metabolite of chlorpyrifos, and which appeared related to younger age and light
chronic exposures to chlorpyrifos do not suggest hair color (Baccarelli et al. 2005). The Seveso
that STCP itself is responsible for chloracne cancer incidence was updated to cover the
(Burns et al. 2006). In both of the aforementioned 20 years period from 1977 to 1996 which con-
case reports of STCP toxicity, the authors did firmed an excess risk of lymphatic and hematopoi-
neither test the materials for dioxins/dibenzofu- etic tissue neoplasms in the most exposed zones.
rans or other neurotoxins nor look at the levels in There was also elevated risk of breast cancer in very
affected individuals. Wu et al. acknowledged that high contaminated zone females after 15 years
there may be a contaminate causing the nerve and since the accident. No cases of soft tissue sarcomas
skin damage rather than STCP. occurred (Pesatori et al. 2009).
Ingestion alone of PCBs and their thermally
degraded polychlorinated dibenzofurans (PCDFs)
11.3 Nonoccupational Exposure played a major role in two mass “oil-poisoning”
episodes Yusho in Japan in 1968 and Yu-Cheng in
Nonoccupational chloracne has resulted from Taiwan in 1979, the largest epidemics of chlor-
industrial accidents, contaminated industrial acne to date. In both countries, several thousand
waste, and poisoned food products. A well-publi- persons were affected after eating rice-based
cized example was the extensive accidental envi- cooking oil that had been accidentally contami-
ronmental contamination with by 2,3,7,8- nated with large amounts of tetrachlorobiphenyl.
tetrachlorodibenzo-p-dioxin (TCDD), which Most clinical manifestations were observed in
occurred on 10 July 1976, at the ICMESA chem- patients who had directly ingested the oil. Derma-
ical plant near Seveso, Italy. An explosion tologic manifestations in typical Yusho and
occurred during the manufacturing of tri- Yucheng cases having high PCB and PCDF con-
chlorophenol that resulted in the formation and centrations in blood included acneiform erup-
ultimate discharge into the atmosphere of an esti- tions, hyperpigmentation, fingernail
mated 2 kg of TCDD. The contaminated area abnormalities, and hypersecretion of conjunctival
encompassed more than 200 acres of land, and meibomian glands which recovered very slowly
135 cases of chloracne, mostly in children, were after several years. However, elevated serum tri-
confirmed among the 2000 area inhabitants. The glycerides and serum thyroxin, immunoglobulin
toxic cloud caused the death of hundreds of fowl disorders, goiter, decreased sperm mobility, dental
in the first days after the explosion; the develop- abnormalities joint inflammation, decreased IQ
ment of chloracne occurred after different time score in children, headache, and numbness were
periods. Aside from chloracne, some cases of persisting 30 years later (Masuda 2001).
subclinical neurological damage were reported PCBs and PCDFs can persist in human tissues
(Pocchiari et al. 1979). with the median half-life of 2.9 years in the first
In a long-term follow-up study of health status 15 years after onset and 7.7 years in the next stage
and plasma dioxin levels in chloracne cases of 15 years (Masuda 2001) (similar dioxins have
20 years after exposure, residents of the Seveso half-lives in humans of about 7 years).
communities contaminated with industrial effluent The offspring of exposed females are described
dioxin levels still had elevated levels of TCDD in as cola babies because of their dark color. Gener-
plasma and adipose tissues, particularly in females, alized hyperpigmentation, meibomian gland
in subjects who had eaten home-grown animals, enlargement with eye discharge, and nail defor-
and in individuals with older age, higher body mass mities occurred in congenitally exposed individ-
index, and residence near the accident site. How- uals. Severe chloracne scars were observed
ever, the health conditions of chloracne cases were 11 years postcongenital exposure in some affected
similar to those of controls from the Seveso area. individuals in Taiwan (Hsu et al. 1995).
Rogan et al. studied 128 children who were oil consumption ceased (Rodriguez-Pichardo et
transplacentally exposed to PCBs and dibenzofu- al. 1991).
rans in Taiwan, their parents and siblings who In 1981, an electrical transformer fire occurred
were directly exposed, and 115 control children. in Binghamton, New York. The fire began in the
Direct exposure of the mothers stopped in 1979 basement mechanical room of an 18-story office
and the children were born as late as 1985. At building. Approximately 180 gallons of Askarel, a
birth, the exposed children had increased rates of dielectric fluid composed of 65% PCBs (Aroclor
hyperpigmentation, eyelid swelling and dis- 1254) and 35% polychlorinated benzenes leaked
charge, deformed nails, acne, natal teeth, and from a transformer. The fire originated in the
swollen gums unlike controls. On cutaneous switch gear of the secondary electrical power dis-
examination in 1985, key findings were a much tribution system. Pyrolysis of the Askarel led to
higher rate of dystrophic fingernails and the formation of a fine oily soot containing PCBs,
pigmented or dystrophic toe nails than in controls. dibenzo-p-dioxins, and dibenzofurans, which
Increased rates of hyperpigmentation and acne spread to all areas of the building through venti-
were also seen in the exposed groups. The cuta- lation shafts. Three-year postexposure serum PCB
neous findings were part of a transplacental concentrations increased with the degree of poten-
neuroectodermal dysplasia, with dental abnormal- tial exposure, but 98% of samples tested had
ities, a growth deficit, developmental delay, and a values similar to those found in unexposed
behavior disorder. Transplacental dermatotoxins populations. One-third of the fire fighters and
are rare (minoxidil, phenytoin, carbamazepine, other persons who were in the building for 25 h
and hexachlorobenzene). This syndrome is one or more reported “rash” or itching. However, no
of very few documented to result from transpla- cases of chloracne, liver disease, or neurological
cental exposure to pollutant chemicals (Rogan et disorders were identified in the exposed individ-
al. 1988). On reexamination 6 years later, nail uals (Fitzgerald et al. 1989).
changes were still present and suggested prenatal In 2007, eight cases of chloracne were reported
injury to the nail matrix (Hsu et al. 1995). The which developed rapidly 3–4 months after spend-
findings in transplacentally exposed children dif- ing vacation at the same resort facility building in
fer from those seen in people directly exposed, the Apennines outside Bologna, Italy. Patients
particularly the higher prevalence of acne in the presented with numerous comedo-like lesions
latter group (Rogan et al. 1988; Gladen et al. and yellowish cysts of various severity on the
1990; Hsu et al. 1995). face, scalp, the V of the chest, and extremities.
In 1982, eight members of a Spanish family Other cutaneous findings associated were ery-
were poisoned by consumption of olive oil con- thematous-edematous eruption, grayish skin pig-
taminated with PCDDs and PCDFs. The entire mentation, hypertrichosis, and vermiculated
family had varying degrees of acneiform lesions, atrophy. Of the eight patients, seven were noted
including papules, pustules, cysts, comedones, to have augmented serum triglycerides, three had
and scars located on the face, axilla, neck, trunk, increased liver enzyme levels, one had altered sex
groin, and genitals. Hyperpigmentation of the face hormones, and one had signs of neuropathy. The
was also reported. These lesions are comparable concentrations of dioxin and polychlorinated
in severity to those described in the Yusho inci- biphenyls in the soil, water, and plant material
dent. The olive oil consumed was stored in a and the serum titers of dioxin were within the
plastic container, which had presumably stored normal range. The source of the environmental
hexachlorobenzene and pentachlorophenol prior contamination was not identified, but the hypoth-
to the oil. The causative agents were identified as esis was that someone contaminated foods that
PCDDs, PCDFs, and PCP, each of which was every week a farmer left for the inhabitants of
recovered from the cooking oil. There were high the building. Although the blood concentrations
serum levels of PCDDs and PCDFs, which of PCBs, PCDDs, and PCDFs were within the
returned to normal when measured 5 years after range for the general population, they were near
the maximum levels and highest in the two it can be generalized. Hyperpigmentation has also
patients with more serious skin lesions and affected the nails, mucous membranes, lips, and
major systemic alterations (Passarini et al. 2010). mouth in those involved in Yusho and Yucheng
Localized chloracne-like comedones resulting poisoning in Japan and Taiwan, respectively. Indi-
from occluded cigarette smoke exposure have viduals exposed to chlorobenzenes and industrial
been reported in a male patient with squamous polychlorinated biphenyl (PCB) poisoning may
cell carcinoma of the nasal septum. The lesions lead to similar pigmentation.
developed post rhinectomy after which the patient Eye involvement is relatively common and is
continued smoking. The patient’s smoking caused termed “ophthalmic acne” (Taylor 1974; Crow
direct local exposure to cigarette smoke via nasal and Puhvel 1991). Conjunctivitis with meibomian
exhalation and occlusion under his surgical site gland involvement may be seen in severe cases of
gauze dressing (Patterson et al. 2015). The distri- poisoning from chloracnegens, especially in the
bution of numerous black noninflammatory open Yusho poisoning. The Yusho victims demon-
comedones was exclusively in the bilateral strated extreme eye findings when their
nasolabial regions of direct gauze contact, thus meibomian glands were converted to squamous
presuming the etiopathological agent to be con- cysts filled with a cheesy keratinous substance;
centrated exposure to halogenated aromatic com- the unusual oral route of entry and absorption of
pounds from the tobacco smoke. PCBs may have been an essential part of the
syndrome (Tindall 1985).
Dermatologic observations associated with
11.4 Cutaneous Manifestations chloracne, which may lead to identification of
specific exposures, include hyperpigmentation of
Clinical features of chloracne include multiple the skin (PCBs, TCDD), mucous membrane and
comedones and yellowish straw-colored cysts dis- nail hyperpigmentation (PCBs), follicular hyper-
tributed primarily over the malar crescents and keratosis (PCBs, TCDD [Seveso]), conjunctivitis
retroauricular folds, typically sparing the nose. and meibomian gland changes (PCBs), facial ery-
This pattern of distribution is of significant diag- thema and edema (trichlorophenol), hyper-
nostic importance. Inflammatory lesions occur but trichosis (TCDD), hyperhidrosis of the palms
are less frequent than in other forms of acne. As and soles (TCDD, PCBs), folliculitis and xerosis
severity increases body areas are not usually (TCAB, TCAOB), and actinic elastosis (TCDD).
affected by acne vulgaris; the posterior neck, Erythema and edema of the exposed face and
trunk and extremities, buttocks, scrotum, and extremities associated with trichlorophenol pro-
penis may become involved. The axillae are duction was also seen in the Seveso cases. These
most likely to be involved in those who ingest “prechloracne” lesions were also accompanied by
chloracnegens, such as in Japan’s Yusho poison- vesiculobullous and necrotic lesions on finger tips
ing in 1968 or in those at Seveso, Italy, in 1976, and palms, and papulonodular lesions, all of
who were exposed in toxic cloud (Jirasek et al. which resolved within a few weeks. Hyperkera-
1973). totic, infiltrative erythematous granuloma
Associated with the classic lesions of chlor- annulare, or erythema elevatum diutinum-like
acne is a relatively dry appearance of the skin. lesions were also seen in association with chlor-
Metaplasia of sebaceous epithelium occurs, with acne 2 months after the explosion. Axillary
subsequent atrophy of sebaceous and meibomian involvement and follicular hyperkeratosis are
glands leading to xerosis of the facial skin, skin of linked with inhalation or ingestion of
the chest, and back and the reduction in sebum chloracnegens (Taylor 1979; Tindall 1985).
excretion seen in chloracne (Zugerman 1990; Hypertrichosis in association with chloracne
Gawkrodger et al. 2009). has been mainly confined to the temples and
Hyperpigmentation may also occur and is usu- may rarely be a sign of hepatic porphyria.
ally confined to the face, although in severe cases However, hypertrichosis has also been described
in chloracne patients with normal uropo- 11.5 Noncutaneous Manifestations

rphyrin levels (Jirasek et al. 1973; Crow and
Puhvel 1991). Chloracnegen exposures to humans have been
Punctate keratoderma-like lesions on the palms associated with increased risk of severe skin
and soles clinically and histologically indistin- lesions such as chloracne and hyperpigmentation,
guishable from keratosis punctata palmaris et altered liver function, hypertriglyceridemia,
plantaris (KPPP) was reported to occur in a female hypercholesterolemia, general weakness, weight
patient with dioxin intoxication (Geusau et al. loss, depression of the immune system, increased
2000). In addition to chloracne, she also exhibited risk for diabetes and cardiovascular disease, vari-
acral granuloma annulare-like lesions, distal ous hormonal alterations, nervous-system abnor-
onycholysis, hypertrichosis, and brownish-gray malities, effects on reproduction, impaired
hyperpigmentation of the face. developmental, neurological, and cognitive func-
Scarring may occur in the end stage of moder- tion in infants. It is a potent teratogenic and
ate to severe chloracne. It may appear as fine pits fetotoxic chemical in animals. Other systemic dis-
seen in atrophodermia vermiculata or may resem- orders reported with chloracne include bronchitis,
ble scars caused by severe acne vulgaris renal, and pancreatic involvement (Taylor 1987).
(Zugerman 1990). Patients with chloracne should have appropriate
Chloracne may occur in relatives of workers physical examination and laboratory evaluations
exposed at home to contaminated work clothing to exclude systemic involvement.
and tools (Taylor et al. 1977). Epidemiologic data suggesting that high-level
TCDD exposure appears to be associated with dioxin exposure causes liver function abnormali-
the development of nonmelanotic invasive skin ties and chloracne are incontrovertible
cancer. A retrospective study in 2014 reported (Longnecker et al. 1997). In Seveso, a transient
the incidence of nonmelanotic invasive skin can- rise in values of hepatic enzymes that reflected
cer was significantly higher among veterans who hepatocellular damage, that is, gamma-glutamyl
were exposed to 2,3,7,8-tetrachlorodibenzodioxin transferase and alanine amino transferase
than in an age-matched subset of the general pop- occurred. Alkaline phosphatase and serum biliru-
ulation. Patients involved directly with spraying bin levels were not elevated and jaundice or other
the agent and those with light eye and skin colors signs of hepatic injury were not appreciated. Crow
were most susceptible. In addition, the incidence and Puhvel (1991) suggested that the degree of
of nonmelanotic invasive skin cancer was signif- hepatic injury was dependent on the specificity of
icantly higher among exposed patients with chlor- the toxicant involved, rather than as a consistent
acne than among those who did not have consequence of all forms of chloracnegen
chloracne (Clemens et al. 2014). exposure.
Porphyria cutanea tarda (PCT) has been
11.4.1 Onset and Duration reported in humans following TCDD exposure
The clinical course of chloracne varies. After (Bleiberg et al. 1964). Both normal urine porphyrin
exposure to a chloracnegenic agent, there usu- levels have been observed from individuals with
ally is a delay of 2–4 weeks until the develop- severe chloracne (Strik 1979) and higher levels of
ment of chloracne. However, the onset can be urine porphyrins in workers exposed to pentachlo-
delayed up to months (Passarini et al. 2010). rophenol pesticide exposure (Hryhorczuk et al.
Dioxin-induced skin lesions progress over 1998). TCDD is a porphyrinogen in animal models
months while internal organs heal. Lesions and inhibits uroporphyrinogen decarboxylase, the
slowly decrease after a period of 3–5 years enzyme precipitating PCT in some patients
(Saurat et al. 2012) but tend to persist for decades (Mukerjee 1998).
even without additional contact and are refrac- Peripheral neuropathy with pain and numbness
tory to treatment (Crow and Puhvel 1991; Ster- may be observed, especially in persons severely
ling and Hanke 2005). exposed to chlorinated hydrocarbons (Thomke et
al. 1999). Neuropathy has been confirmed by Sandstrom 1979). Soft tissue sarcomas showed
delayed nerve conduction velocity. In the 1968 an increase in the largest, yet least exposed, expo-
Japanese epidemic of chloracne caused by inges- sure subcohort (Pesatori et al. 2003). Others con-
tion of contaminated cooking oil (Yusho), these cluded that there is no evidence to state that
neurologic symptoms were especially apparent. TCDD is a significant carcinogen in humans
The long-term health effects of dioxin expo- (Cole et al. 2003; Tuomisto and Tuomisto 2012;
sure in humans have not been conclusively Sorg 2014).
proven. Carcinogenesis, teratogenicity, and Because of the long-term persistence of TCDD
immunosuppressive effects of these compounds in the human body, atherosclerosis, hypertension,
are extremely controversial areas. Although ani- diabetes and various hormonal alterations, vascu-
mal studies with TCDD have strongly suggested lar, ocular changes, effects on reproduction, neu-
that this material is carcinogenic in animal sys- ral system damage, including neuropsychological
tems, these findings cannot necessarily be extrap- impairment, neurological, and cognitive impair-
olated to humans. Anecdotal information has ments in infants, can be present several decades
pointed to TCDD as being a human carcinogen. after exposure. Such chronic effects are non-
Based on animal data and on human epidemiol- specific and multifactorial and may be causally
ogy data, WHO and the US National Toxicologi- linked to TCDD (Sweeney and Mocarelli 2000;
cal Program has classified TCDD as a human Pelclova et al. 2006). It is also possible that people
carcinogen, but there is a strong matter of debate exposed to dioxins may also have been exposed to
regarding the carcinogen potential of TCDD to other pollutants; thus, it is feasible that a com-
humans. A completed report by the International bined action of these chemicals could induce can-
Agency for Research on Cancer (IARC 1997) on cer or any other health problems (Sorg 2014).
the evaluation of the carcinogenicity of PCDD Continuous long-term surveillance and follow-
and PCDF in humans, published at the time up is warranted to cover the long time period,
where TCDD was considered by WHO as a pos- even decades, often elapsing from exposure to
sible human carcinogen, was not conclusive. carcinogenic chemicals and occurrence of disease
Populations occupationally or accidentally (Table 4).
exposed to chemicals contaminated with dioxin
may have an increased incidence of soft-tissue 11.5.1 Mechanism
sarcomas, Hodgkin and non-Hodgkin lymphoma, The mechanism involved in the initiation of chlor-
and chronic lymphocytic leukemia (Mukerjee acne remains unknown. The interference of halo-
1998; Frumkin 2003). In a long-term cohort of genated biphenyls, dibenzo-p-dioxins,
2187 male workers exposed to dioxin, Bodner dibenzofurans, and azo and azoxybenzenes in
found no increased cancer risk from dioxin expo- vitamin A metabolism and function may offer an
sure and concluded that there is a wide range of explanation about the acnegenic effects of these
cancer rates and the lack of consistency across compounds on human skin (Chen et al. 1992; den
dioxin studies (Bodner et al. 2003). However, Besten et al. 1993; Coenraads et al. 1994).
mortality and morbidity findings during the 20- Coenraads and coworkers (1994) found that reti-
year period following the accident showed nol concentrations in skin biopsies from nine
increased risk of lymphatic and hematopoietic PCP-exposed workers with chloracne were much
tissue neoplasms, digestive system cancer (rectum lower in comparison with controls. This suggests
in males, and biliary tract among females, in par- that the chemicals may affect vitamin A metabo-
ticular), and respiratory system cancer (lung, lism and hence influence pilosebaceous units and
among males). There was also elevated risk of the epidermis.
breast cancer in females in very high contami- A reduction in sebum excretion (Suskind
nated zones (Pesatori et al. 2003, 2009). In the 1985) and loss of sebaceous glands (Suskind
incidence analyses, thyroid and pleural cancer 1985; Saurat and Sorg 2010; Passarini et al.
were suggestively increased (Hardell and 2010) is a hallmark of chloracne, and fewer
Table 4 Cutaneous and systemic manifestations from 2010; Guyot et al. 2013). The main known func-
exposure to dioxins or related halogenated aromatic tion of this receptor is to induce the metabolism of
compounds*
these compounds by phase I and phase II enzymes
Cutaneous manifestations in order to render them more hydrophilic and thus
Chloracne or MADISH (metabolizing acquired facilitate their elimination (Köhle and Bock 2007;
dioxin-induced skin hamartoma)
Abel and Haarmann-Stemmann 2010).
Hyperpigmentation: skin, nails
Erythema, edema
Hence dioxins are lipophilic AhR agonists
Dry skin, xerosis which exert their biological effects by binding to
Skin fragility and activating AhR with various potencies, as
Acne scars measured by their respective TCDD-equivalent
Scars resembling atrophoderma vermiculata factors (TEF) (Poland et al. 1976; Sorg 2014).
Conjunctivitis Thus, following AhR activation by exposure to
Hypertrichosis TCDD, the signaling pathway leads to the induc-
Folliculitis tion of phase I, e.g., cytochrome p450 1A1
Systemic manifestations (CYP1A1) enzymes (Saurat et al. 2012). Expres-
Liver involvement (altered liver function, porphyria sion of CYP1A1 in human skin is a key marker for
cutanea tarda, lipoprotein abnormalities) AhR activation (Sorg 2014). Clinically in humans
Peripheral neuropathy
this AhR activation induces acne-like lesions
Hormonal alterations (reproduction, sex, pancreatic)
known as chloracne which has been proposed to
Immunosuppression
be renamed “metabolizing acquired dioxin-
Possible carcinogen/increased cancer risk
induced skin hamartomas” (MADISH) (Saurat et
Increased diabetes and cardiovascular diseases
al. 2012; Saurat and Sorg 2010).
*Adapted from Passarini et al. (2010)
In cultures of normal human epidermal
keratinocytes, the aryl hydrocarbon receptor
Propionibacterium acnes organisms are present in AhR also mediates dioxin accelerated cell differ-
follicles of those with chloracne than of those with entiation, as measured by the formation of
acne vulgaris (Cunliffe et al. 1975). Dioxins, for cornified envelopes. Dioxin also increases the
example, TCDD have been shown to impede expression of several genes known to be regu-
androgen action possibly through interfering lated by Ah receptor nuclear translocator
with androgen receptors (Gawkrodger et al. (ARNT), which have critical roles in the cornifi-
2009). The biological mechanisms of chloracne cation and epidermal barrier function of the skin.
induction are still debated, but it was suggested It has been demonstrated that all of these
that dioxins have their chloracnegenic effect by responses are opposed by ligand-activation of
activating skin stem cells and shifting the differ- the Epidermal growth factor (EGF) receptor
entiation commitment of the stem cell progeny which is an important regulator of keratinocyte
(Panteleyev and Bickers 2006). cell fate. EGF represses the dioxin-mediated
The toxic effects of 2,3,7,8-tetra- gene transcription induction of CYP1A1 in cul-
chlorodibenzo-p-dioxin (TCDD) and dioxin-like tured normal human keratinocytes by inhibiting
compounds are mediated through binding to the the recruitment of the transcriptional coactivator
intracellular aryl hydrocarbon receptor (AhR), protein p300 to the CYP1A1 gene. EGF also
which is highly expressed in the human epider- inhibits the dioxin-dependent induction of cer-
mis, hair follicles, and sebaceous glands (Ju et al. tain parameters in keratinocytes that are reflec-
2011; Furue et al. 2014; Sorg 2014). This aryl tive of dioxin-induced chloracne. This epidermal
hydrocarbon receptor (AhR) is activated by a growth factor receptor signaling may modulate
variety of xenobiotic (exogenous) lipophilic com- the incidence and severity of chloracne and be of
pounds diffusing through plasma membranes, in potential therapeutic relevance to human poison-
particular those containing at least one aromatic ings by dioxin (Sutter et al. 2009; Hankinson
ring (Hahn 2002; Abel and Haarmann-Stemmann 2009).
However, although the biological effects of The study from Schäfer et al. (2014) showed
dioxins are mediated by the AhR signaling path- that prolonged genetic and pharmacological acti-
way (Bock and Kohle 2009; Sorg 2014), dioxin vation of Nrf2 in mouse keratinocytes leads to
toxicity cannot be explained only by AhR activa- sebaceous gland enlargement combined with
tion. Some AhR agonists do not induce chloracne hyperkeratosis and acanthosis of the hair follicle
such as some natural AhR agonists found in infundibula which caused dilatation of infundib-
vegetables, esomeprazole, 5,6-benzoflavone ula, hair loss, and development of large
rutacarpine, 6-formylidolo(3,2-b) carbazole, keratinized skin cysts in the mice. Sebaceous
indole-3-carbinol, 3,30 diindolylmethane, and sul- gland enlargement resulted from increased
foraphane (de Waard et al. 2008; Sorg 2014), expression of the novel Nrf2 target epigen
while other compounds induce similar chlor- (EPGN), which caused sebocyte proliferation.
acne-toxicities without activating AhR, for exam- Moreover, upregulation of EPGN, secretory leu-
ple, tetrachloro-benzene, trichloronaphthaline, kocyte peptidase inhibitor (SLPI), and small pro-
hexabromo-naphthaline, dichlorbenil, line-rich protein 2d (SPRR2D) are responsible for
amineptine, and the BRAF kinase inhibitor the hair follicle abnormalities and cyst formations.
vemurafenib (Sorg 2014). These findings observed upon Nrf2 activation in
Human keratinocytes also express nuclear fac- mice were very similar to the cutaneous abnor-
tor-erythroid 2-related factor-2 (Nrf2), which is a malities of patients with chloracne/“metabolizing
master switch for antioxidant signaling to minimize acquired dioxin-induced skin hamartomas”
oxidative stress. The transcription factor Nrf2 (MADISH) (Saurat and Sorg 2010). The same
induces the expression of antioxidant and phase II study treated human keratinocytes with TCDD
enzymes, i.e., detoxifying enzymes. When the resulting in upregulation of Nrf2 and its targets
dioxin receptor AhR is activated, it stimulates the SPRR2D, SLPI, and EPGN via activation of the
expression of detoxifying genes such as Cyp1A1 aryl hydrocarbon receptor (AhR receptor), which
and also functionally interacts with Nrf2 to enhance in turn stimulated its target genes CYP1A1 and
its signaling. There is fine-tuned crosstalk between CYP1B1. Furthermore, a strong expression of
AHR and NRF2, which mutually increase or SPRR2D, SLPI, EPGN, and the classical Nrf2
decrease their activation states. target, NAD(P)H:quinone oxidoreductase 1
It has been shown that TCDD-activated AHR (NQO1), was present in the epidermis and cysts
induced Nrf2 activation in different cell types in epithelium of MADISH patients. From these
vitro (Hayes et al. 2009). Recently the role of unique findings, it can be concluded that both
Nrf2, Nrf2 targets, and activation of an AHR- AhR and Nrf2 in a novel AhR-Nrf2 signaling
NRF2 axis in the pathogenesis of MADISH has axis are required for the TCDD-mediated Nrf2
been demonstrated by Schäfer et al. (2014). In the activation of SPRR2D, SLPI, and EPGN in the
pilosebaceous unit, Nrf2 activation stimulates pathogenesis of MADISH (Schäfer et al. 2014).
upregulation of the Nrf2 targets: Epigen,
SPRR2D, and SLPI. Epigen (EPGN) is a growth 11.5.2 Histopathology
factor and EGFR ligand that stimulates prolifera- Histologic changes in the skin may begin within
tion of infundibular keratinocytes via EGFR sig- 5 days of severe exposure to chloracnegenic
naling. SPRR2D (Small proline-rich protein 2d) chemicals (Hambrick 1957). The primary lesion
upregulation weakens the epidermal barrier which of chloracne appears to be keratotic plugging of
further leads to inflammation and enhanced the hair follicle with collection of keratinous
keratinocyte proliferation that results in sebaceous material in the follicular orifice. The follicular
gland enlargement and acanthosis. The SLPI epithelium thickens, followed by atrophy of seba-
(secretory leukocyte peptidase inhibitor) ceous glands and their replacement by keratinous
upregulation leads to decreased desquamation, cysts. Inflammation is minimal or absent
which contributes to hyperkeratosis (Tan and (Coenraads et al. 1994). Biopsies from Seveso
Wahli 2014). showed eccrine duct metaplasia with possible
acrosyringeal cyst formation. Foreign body gran- dioxin concentration, focal expression of the
ulomas around detached walls of eccrine gland dioxin-metabolizing cytochrome P450
excretory ducts may also be present (Omohundro CYP1A1 enzymes, and reduced lipogenesis
and Taylor 1998). (Saurat et al. 2012; Saurat and Sorg 2010).
Hyperpigmentation of the lesions in chloracne
has been demonstrated to result from hyper- 11.5.3 Diagnosis
production of melanin by a normal number of In 1984, a diagnostic criterion for chloracne was
melanocytes along the basal layer of the epidermis established by the Veterans Administration
and infundibular epithelium. Masson-Fontana Chloracne Task Force including (1) exposure to
staining has demonstrated numerous fine melanin a chloracnegen; (2) aggravation or onset within
granules in the stratum corneum correlating to weeks to 2 months of exposure; (3) predomi-
hyperpigmented stratum corneum seen in the his- nance of open comedones and straw-colored
topathology (Passarini et al. 2010). cysts; (4) atypical distribution, that is, malar
Histopathology from 52 skin specimens from crescent and “crow’s-foot” area of the face; (5)
a victim of massive TCDD poisoning (Victor compatible histology; and (6) inflammatory
Yushchenko) determined the skin lesions were cysts and abscesses on the face, behind the
harmatomas with the key features of “structure ears, and on the neck, buttocks, scrotum, and
loss” and “structure gain.” The structure loss was thighs (Veterans Administration Chloracne
the disappearance of the sebaceous glands. The Task Force 1984). The diagnosis of chloracne
structure gain was the appearance of cystic entails a compatible clinical picture with distri-
lesions with epithelial walls showing epider- bution of comedones and noninflammatory cysts
mal-like differentiation (Saurat et al. 2012). beyond the typical locations of acne vulgaris. It
The lesions were either superficial with an open is characterized by open and closed comedones
comedo-like aspect or extending much deeper in with straw-colored cysts found predominantly in
the dermis, resembling infundibular cysts, but the malar region, postauricular area, axilla, and
with the following distinct characteristics: (1) scrotum. Documentation of significant exposure
mantle-like columnar epithelial downgrowths, to known chloracnegens and the absence of other
showing high proliferative activity (Ki67-posi- external causes is also required. Based on cuta-
tive cells), putatively giving birth to new cysts neous findings alone or in novel settings, it may
and (2) immunohistochemistry showing focal be difficult to differentiate chloracne from acne
expression of CYP1A1, the major dioxin-metab- vulgaris and other types of environmental acne –
olizing CYP enzyme, in the epithelial walls of oil folliculitis, pitch acne, and tropical acne – are
the cystic lesions. listed in Tables 5 and 6. Senile (solar) comedones
In summary, the histology of chloracne is of the Favre-Racouchot syndrome and Dowling-
characterized by the absence of sebaceous Degos’ disease also can be considered in the
glands (Panteleyev et al. 1997; Suskind 1985) clinical differential diagnosis (Kersevovich et
and the presence of epidermal cysts, either super- al. 1992). Histologically specific characteristics
ficial or deeper in the dermis (Suskind 1985; including the disappearance of the sebaceous
Saurat and Sorg 2010; Passarini et al. 2010). glands and the formation of epidermal cysts
In contrast to “acne,” there is no sebaceous may help confirm the diagnosis of chloracne/
gland hypertrophy in chloracne, but rather the MADISH.
disappearance of sebaceous glands. Therefore, In suspected cases, chloracnegens can be
Saurat and Sorg proposed the renaming of this assessed in serum and various tissues by direct
misnomer “chloracne” to be called “metaboliz- chemical analysis or a biological assay. How-
ing acquired dioxin-induced skin hamartomas” ever, titers of polyhalogenated aromatic hydro-
(MADISH) based on the observations made in carbons may not always correlate with the
Yushchenko’s case demonstrating involution of clinical cutaneous manifestations and discrepan-
sebaceous glands, epidermal cysts with high cies may occur (Passarini et al. 2010). AhR
activity can be assessed by chemical or biologi- 11.5.4 Treatment

cal assays which are both difficult and expensive Chloracne tends to resolve slowly upon cessa-
to perform. Activation of AhR may be assessed tion of chemical exposure. Its duration correlates
by measuring whole activation of the AhR with the severity of the disease which usually
signaling pathway expressed as TCDD reflects the degree and extent of exposure.
equivalent (TEQ) and EROD assay which deter- Dioxins are highly lipophilic and have a long
mines the enzymatic activity of the phase I half-life in fat tissue and low turnover rate in
enzyme CYP1A1 highly induced following the body. If exposure ceases, the lesions will
dioxin-like exposure (as described in detail by gradually improve over many years or decades.
Sorg 2014). The severely exposed victims of Yusho in
1968 had characteristic chloracne lesions that
continued to develop for as long as 14 years
Table 5 Clinical features of acne vulgaris compared with postexposure.
chloracne. (After Peter Pochi, MD with permission)
Treatment of chloracne is usually unsatisfac-
Acne tory as the modalities that are useful in acne
Clinical features vulgaris Chloracne
vulgaris are often ineffective in chloracne. Topical
Exposure to Absent Present
chloracnegen application of retinoic acid (0.005–0.3% concen-
Usual age Teenage Any age tration) or of tretinoin (Retin-A) gel or cream is of
Comedones Present Many (if absent, not some benefit in controlling comedones, but other
chloracne) topical agents are of little use (Caputo et al. 1988).
Straw-colored Rare Pathognomonic A combination of tetracycline and short courses
cysts of orally administered prednisone helped with
Temporal Rare Diagnostic severe inflammatory cases. A trial regimen of
comedones
methotrexate, 25 mg every 10 days for several
Inflammatory Common Uncommon
papules, cysts months was unsuccessful (Scerri et al. 1995;
Retroauricular Uncommon Common Taylor et al. 1977).
involvement There are anecdotal reports of both unsuc-
Nose Often Often spared cessful use (Sterling and Hanke 2005) and effi-
involvement spared cacious use of oral 13-cis-retinoic acid
Axillary, genital Rare Maybe (isotretinoin) which, if instituted early, may pre-
involvement
vent cyst formation. Isotretinoin 0.3–1 mg/kg/
Eye Absent Present
involvement day may be indicated in severe cases for a course
Sebaceous Active Atrophic/absent, of 20 weeks. The drug should be administered
glands with dry xerotic skin only by those experienced in its use and in strict
Associated Rare Common accordance with current prescribing instructions.
systemic The hepatotoxicity and lipid abnormalities
findings
sometimes associated with chloracne are
Table 6 Differential diagnosis of various forms of occupational and environmental acne

Etiology Location Lesions
Chloracne Halogenated Malar, retroauricular, mandibular Comedones, straw-colored cysts
aromatics (0.1–1.0 cm)
Oil Oil Arms, thighs, buttocks Comedones, inflammatory papules,
folliculitis pustules
Pitch acne Tar/pitch Exposed facial areas, malar, Open comedones
periorbital
Tropical Heat/humidity Buttocks, thighs Inflammatory nodules, cysts
acne Face spared
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Psoriasis and Work
32
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
3 Koebner Phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
4 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
5 Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
6 Occupational Contact Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
7 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Keywords • The frequency of occupationally triggered pso-

Psoriasis · Psoriasis palmaris · Occupational riasis in patients with occupational skin dis-
psoriasis · Koebner phenomenon · Isomorphic eases has been reported to be between 1.2%
response and 6.5%.
• In addition to adequate therapy, special skin
protection measures, such as anti-impaction
1 Core Messages gloves and the avoidance of irritant and
mechanical influences, are pivotal in terms of
• Psoriasis is a constitutional disease, but may be adequate prevention.
triggered by occupational factors.
C. Skudlik (*) · S. M. John

Department of Dermatology, Environmental Medicine and
Health Theory, University of Osnabrück, Osnabrück,
Germany
e-mail: cskudlik@uos.de; cskudlik@uni-osnabrueck.de;
johnderm@uni-osnabrueck.de

https://doi.org/10.1007/978-3-319-68617-2_32
462 C. Skudlik and S. M. John
2 Introduction phenomenon) also indicate this predisposition

(Boehncke and Sterry 2009; Nast et al. 2018).
Psoriasis is currently viewed as a systemic disor-
der with skin symptoms, potential joint involve-
ment, and various comorbidities (Mahler et al. 3 Koebner Phenomenon
2014; Michalek et al. 2016, 2017). The skin
symptoms are characterized by variable clinical In the case of an occupational cause of psoriasis,
features. Psoriasis vulgaris is the most common usually the so-called Koebner phenomenon plays an
type of psoriasis. Circular plaques are predomi- important role. Heinrich Koebner (1834–1904) was
nant on the elbows, knees, lower back, and the one of the leading dermatologists of the nineteenth
retroauricular areas of the scalp, whereas eruptive century. He was the Director of the Breslau Univer-
(guttate) lesions are often confined to the trunk sity, Head of the Breslau School of Dermatology,
and proximal extremities. Palmar psoriasis is also and the first President of the Berlin Dermatological
a frequent manifestation. Some authors have indi- Society. In 1872, he described a patient who, 5 years
cated that in a number of cases, there is an overlap after developing psoriasis, noted that various trau-
between psoriasis and eczema (Ancona et al. matic insults of his skin resulted in lesions of psori-
1986; Kolesnik et al. 2018, Maibach and Epstein asis (Rubin and Stiller 2002). Today the Koebner
1983). This form of psoriasis is sometimes diffi- phenomenon is defined as a nonspecific traumatic
cult to distinguish clinically and histologically skin stimulus eliciting a disease-specific skin reac-
from hyperkeratotic hand eczema. tion, especially in psoriasis. The Koebner phenom-
So palmar psoriasis is often confused with enon is also known as an “isomorphic response.”
chronic hyperkeratotic hand eczema, skin biopsies
often show nonspecific changes of eczema rather
than those of psoriasis, and the histological find- 4 Incidence
ings often do not help to confirm the diagnosis.
The incidence of psoriasis vulgaris in industri- Compared to the epidemiological data regarding
alized western countries is 1.5–2% (Nevitt and occupational hand eczema, there are only few data
Hutchinson 1996). Psoriasis vulgaris shows a mul- available on the incidence of occupationally
tifactorial, polygenetic pattern of inheritance. A induced psoriasis.
number of susceptibility genes predispose a person In a Swedish investigation of 246 patients with
to the disease. The psoriatic tissue reaction is an occupational hand dermatitis, psoriasis of the
extremely complex cutaneous immune reaction hands were diagnosed in 16 cases (n = 6.5%)
with a pronounced inflammatory component and (Agrup 1969).
epidermal hyperproliferation. By means of an anti- An Italian study reported that occupationally
gen or autoantigen through antigen-presenting induced psoriasis accounted for 1.2% of all occupa-
cells, specific T cells are activated and migrated tional dermatoses observed (n = 3000) (Moroni
into the skin. Homing factors include the cutaneous et al. 1988). Only 10% of the cases with occupa-
lymphocyte-associated antigen (CLA). Infiltration tionally derived psoriasis suffered from classical and
of the papillary dermis and epidermis leads to typically localized lesions. Most of the patients with
activation of the resident cells. Here, by means of occupationally induced psoriasis in this study had
central mediators (e.g., TNF-α), endothelial cells, mechanical effects on the skin during their work
fibroblasts, and keratinocytes are stimulated. activities (e.g., packaging workers, construction
Keratinocyte stimulation and proliferation lead to workers, mechanics, etc.) (Moroni et al. 1988).
increased epidermal turnover and parakeratosis. Angelovska and Mahler (2014) have evaluated
Keratinocytes in patients with psoriasis react 129 medicolegal evaluations on occupational skin
more strongly to the local release of mediators. diseases and found 6 cases (4,7%) of hand psoriasis.
Phenomena observed with psoriasis such as the In five cases of this, a professional context of psori-
isomorphous irritation effect (Koebner asis of the hands was observed. This was due to a
32 Psoriasis and Work 463
combination of mechanical effects and wet work or

irritation in three cases, as well as only mechanical
effects or irritation in each of the two remaining
cases.
Psoriasis of the hands was diagnosed in 100 of
1,788 patients (5,6%) who took part in an inter-
disciplinary inpatient rehabilitation measure for
recalcitrant occupational skin disease in Germany
(Skudlik et al. 2012, 2017). In 49 cases (2.7%) of
this, a professional context of psoriasis of the
hands was observed, and in other 36 cases
(2.0%) of this, a professional context of psoriasis
of the hands was considered possible.
Fig. 1 Occupational psoriasis of the hand of a masseur
(palmar) (Note: Clinical similarity to hyperkeratotic hand
eczema, but in contrast to this type of an eczema sharp
5 Diagnostics demarcation of the erythematous lesions)
Occupationally induced psoriasis of the hands is

rare in comparison to occupational hand eczema.
A family background of psoriasis and the pres-
ence of psoriasis lesions on typical predilection
areas can be helpful for the diagnosis.
Furthermore nail changes (pits in the nail plate,
yellowish macules beneath the nail plate or severe
onychodystrophy) may be indicative. In contrast to
hand eczema in most cases, psoriasis of the hands
showed raised, erythematous plaques with layers of
silvery scales (which are sharply demarcated).
Psoriasis palmaris can persist several weeks or
month after avoiding the occupational cause.
Clinically and histologically distinction between Fig. 2 Occupational psoriasis of the hand of a masseur
(back of the hand) (Note: Typically plaques at the
psoriasis of the hands and hand dermatitis can be
knuckles)
difficult (Figs. 1 and 2). Especially the differential
diagnosis to hyperkeratotic hand eczema may some-
times be difficult, but widespread lesions are not genes NOS 2 and CCL 27 in lesional skin has been
found in hyperkeratotic eczema (Agner 2011). developed, which allows to distinguish between
Although psoriasis of the hands is not an allergic psoriasis and dermatitis (Garzorz-Stark et al.
skin disease, patch testing with occupational and 2016). This method has recently been successfully
nonoccupational (e.g., domestic) allergens should implemented in medicolegal evaluations of occupa-
be performed in all patients with psoriasis of the tional dermatoses (Weisshaar et al. 2018).
hands because of the clinical similarity and a rele-
vant overlap with hand eczema in many cases. A
concomitant occurrence of psoriasis and dermatitis, 6 Occupational Contact Psoriasis
showing both clinical and histological features of
psoriasis and contact dermatitis, has been described. Occupational psoriasis palmaris is usually caused by
This constellation is termed “eczema in psoriatico” mechanical or physical trauma, friction, or contact
(Kolesnik et al. 2018). Recently, a molecular diag- with irritants (see ▶ Chap. 79, “Mechanical Causes
nostic method based on the expression of the marker of Occupational Skin Disease,” by R. Brans and
S.M. John). Such constellations are published for

various occupations, for example, baker, barkeeper,
bookbinder, bus driver (from the pressure of the
steering wheel), cashier, cleaner, construction
worker, dentist (caused by the pressure of various
instruments), draftsman, electrician, greenkeeper
(on the basis of skin irritation by the herbicide
glyphosate), joiner, laundry worker manufacturing/
packaging worker, masseur, mechanic (e.g., from
gripping tools), newspaper vendor, pharmacist
(from twirling finger movements while handling
bottle caps), seamstress and tailor, warehouse
worker, and worker at a viscose spinning mill
(Angelovska and Mahler 2014; Elsner et al. 2018; Fig. 3 Occupational psoriasis of the hand due to regular
Fisher 1979; Maibach and Epstein 1983; Menne and contact to a handle of packaging tool (Note: There is no
presence of psoriasis lesions on other areas except the right
Hjorth 1984; Ancona et al. 1986; Moroni et al. 1988; hand)
Kanerva et al. 1998; Kanerva and Estlander 2001)
(Figs. 3 and 4).
Koebner reactions may rarely also be triggered by
allergic processes. Such a constellation has recently
been reported in a metalworker who developed
severe allergic contact dermatitis against ingredients
of water-based cutting fluids (colophony). After the
replacement of the contact allergen, the dermatitis
healed, but for the first time, a psoriatic plaque
formed in this area (back of hands and palmar). He
had no psoriasis lesions before or later on other areas
of the body (Ebisch et al. 2009). Other publications
report psoriasis of the hands elicited by allergic
occupational contact dermatitis from thiuram in a
nurse and a farmer wearing rubber gloves (Hill and
Fig. 4 Occupational psoriasis of the hand due to regular
Ostlere 1998; Spiewak 2004). Mahler et al. (2014) contact to a handle of packaging tool: holding the tool
reported that by the German Social Accident Insur- (same patient as in Fig. 3). Lesions subsided after proper
ance (DGUV) on the basis of its BK-DOC registry therapy and use of anti-impaction gloves and anti-
from 1995 to 2010, 130 cases of psoriasis were impaction grip
classified as work related; however, only 25 of
these cases on occupational disease number 5101
training in a risk profession (e.g., mechanical
according to the German decree of occupational
trauma, wet work, etc.) (Wilke et al. 2018;
diseases were acknowledged, with consecutive
Wulfhorst et al. 2011). Trainees with severe psori-
compensation payments in 6 of these cases.
asis palmaris should not choose a risk profession.
On the level of secondary and tertiary preven-
tion, it is important for the physician to consider
7 Prevention the diagnosis of occupationally triggered psoriasis
of the hands and to distinguish this diagnosis from
On the level of primary prevention, it is important occupational hand eczema. In the same way, it is
to advise young people with psoriasis on adequate essential to ensure that the patient understands the
skin protection measures before starting job precise diagnosis and its consequences.
32 Psoriasis and Work 465
All necessary therapeutic options should be Ebisch MA, Skudlik C, John SM (2009) Berufsbedingte
taken according to the severity of the disease (Nast Psoriasis Palmaris: Köbner-Phänomen, induziert durch
allergisches Kontaktekzem bei Kontakt zu
et al. 2018). This comprises basic treatment (skin Kühlschmiermitteln. Dermatol Beruf Umwelt/Occup
care program and moisturizers), topical therapy Environ Dermatol 57:158–162
(e.g., salicylic acid, anthralin, vitamin-D3 analogues, Elsner P, Darr-Foit S, Schliemann S (2018) Occupational
tazarotene, tar, topical glucocorticoids), physical koebnerization of psoriasis caused by glyphosate. J
Dtsch Dermatol Ges 16(1):70–71. https://doi.org/10.1
therapy (e.g., photochemotherapy [topical PUVA 111/ddg.13393
of the hands], balneophototherapy, selective Fisher AA (1979) Occupational palmar psoriasis due to
UVB-therapy), and systemic therapy (e.g., retinoids, safety prescription container. Contact Dermatitis
methotrexate, fumaric acid esters, biologicals). 5:56
Frosch PJ, Aberer W, Agner T et al (2011) International
It is equally important to remove or reduce the comparison of legal aspects of worker’s compensation
potential triggers. Therefore, the working conditions for occupational contact dermatitis. In: Duus
should be altered as far as possible. Concerning this Johansen J, Frosch PJ, Lepoittevin JP (eds) Contact
from central importance are technical or work orga- dermatitis, 5th edn. Springer, Berlin/Heidelberg,
pp 1029–1051
nization measures to reduce mechanical or physical Garzorz-Stark N, Krause L, Lauffer F, Atenhan A,
trauma, friction, or contact with irritants (and aller- Thomas J, Stark SP, Franz R, Weidinger S, Balato A,
gens). In addition, the padding of contact materials, Mueller NS, Theis FJ, Ring J, Schmidt-Weber CB,
as, for example, handheld tools (soft grips, etc.), and Biedermann T, Eyerich S, Eyerich K (2016) A novel
molecular disease classifier for psoriasis and eczema.
the use of anti-impaction gloves, before return to Exp Dermatol 25(10):767–774. https://doi.org/10.11
work, are pivotal (Kwok et al. 2009; Wilke et al. 11/exd.13077
2018; Wulfhorst et al. 2011). To the social insurance Hill VA, Ostlere LS (1998) Psoriasis of the hands
system, the work relatedness of the disease needs köbnerizing in contact dermatitis. Contact Dermatitis
39:194
specific explanation; if possible tailored preventive Kanerva L, Estlander T (2001) Occupational post-
support for the patients should be made available by traumatic psoriasis. Contact Dermatitis 44:317–318
the occupational accident insurances, including skin Kanerva L, Talvi A, Estlander T (1998) Occupational
protection seminars (see ▶ Chap. 111, “Prevention contact psoriasis. Eur J Dermatol 8:217–218
Kolesnik M, Franke I, Lux A, Quist SR, Gollnick HP
and Rehabilitation,” by C. Skudlik and S.M. John). (2018) Eczema in psoriatico: an important differential
If preventive measures fail, job retraining and com- diagnosis between chronic allergic contact dermatitis
pensation will be required, if psoriasis was occupa- and psoriasis in palmoplantar localization. Acta
tionally triggered (Frosch et al. 2011). Derm Venereol 98(1):50–58. https://doi.org/10.2340/
00015555-2779
Kwok T, Arrandale V, Skotnicki-Grant S (2009) Repeated
mechanical trauma to the hands: the use of anti-
impaction gloves for treatment and return to work.
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00-0536.2011.01991.x Springer, Berlin/Heidelberg, pp 985–1028
Physical Causes: Heat, Cold, and Other
Atmospheric Factors 33
Wolfgang Uter and Lasse Kanerva
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
3 Heat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
3.1 Thermal Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
3.2 Electrical Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
3.3 Erythema ab igne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.4 Erythermalgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
3.5 Miliaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
3.6 Intertrigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
3.7 Miscellaneous Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
4 Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
4.1 Frostbite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
4.2 Immersion Foot/Nonfreezing Cold Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
4.3 Chilblains (Perniosis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
4.4 Pulling Boat Hands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
4.5 Other Reactions to Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
5 Other Atmospheric Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
5.1 Low Outdoor Humidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
5.2 Other Ambient Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
5.3 Low Indoor Humidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
5.4 Visual Display Units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Abstract
Several ambient conditions or physical work-
related exposures can induce skin changes.
W. Uter (*)
Department of Medical Informatics, Biometry and These may either represent normal reactions to
Epidemiology, University of Erlangen/Nürnberg, an “abnormal” level of an exogenous factor,
Erlangen, Germany e.g., high or low temperature, or abnormal reac-
e-mail: wolfgang.uter@fau.de tions to conditions which are normally compen-
L. Kanerva sated by skin homoeostasis and thus generally
Section of Dermatology, Finnish Institute of Occupational tolerated. Heat induces skin damage directly in

https://doi.org/10.1007/978-3-319-68617-2_33
468 W. Uter and L. Kanerva
terms of thermal or electrical burns of various • Sweat retention in different layers of the
degrees and extent, requiring adequate emer- eccrine sweat glands may cause miliaria.
gency treatment. However, heat may be applied • Cold has considerable systemic effects and can
to skin also via infra-red radiation or prolonged cause frostbite or, if only moderate, perniosis
direct exposure to moderate heat, causing Ery- (chilblains).
thema ab igne. Ambient heat may cause sweat • Prolonged wetness of the feet and lower legs,
retention in different layers of the eccrine sweat especially if combined with low temperature,
glands and thereby miliaria. Similar conditions can cause “immersion foot” as a nonfreezing
predispose to intertrigo, a macerated, Erythem- cold injury.
atous eruption in body folds, especially with • Both low outdoor and (subsequent) low indoor
excessive sweating and in obese persons. Cold air humidity may cause skin irritation and favor
has considerable, potentially life-threatening irritation by other agents, e.g., wet work.
systemic effects (exposure) and can cause frost-
bite. Moderate cold may cause an abnormal
reaction in the susceptible in terms of perniosis 2 Introduction
(chilblains) of exposed acral body regions,
mostly the fingers. Prolonged wetness, usually Injuries by some of the physical factors mentioned in
of the feet and lower legs, especially if com- this chapter are among the most ancient health risks
bined with low temperature, can cause “immer- of mankind and, indeed, of all living objects. Other
sion foot” as a nonfreezing cold injury. As factors have been introduced by man. Partly, these
another nonfreezing injury, and with mechanical produce the same morbidity, such as Erythema ab
effects of rowing contributing to etiology, igne not caused by open fires, from caves to castles,
“pulling boat hands” have been described. In but by holding lap top computers on the thighs for
addition to temperature, ambient humidity may prolonged periods. However, in a few instances,
have some adverse effect on skin, for instance, man-made physical factors may produce novel
in terms of low outdoor humidity (typically less skin changes, such as thermal effects of microwave
than 10 mg/l) contributing to skin irritation and radiation, or low-humidity dermatoses in “clean
eventually irritant contact dermatitis. Similarly, rooms.” The following chapter will present the
low indoor humidity, e.g., in clean-rooms, has most important types of injury in a systematic way.
been found to cause highly pruritic, if clinically
largely inconspicuous skin eruptions in a large
share of exposed workers. Symptoms may be 3 Heat
aggravated by, e.g., fine, irritating particles.
3.1 Thermal Burns
Keywords
Ambient humidity · Burn · Clean room · Cold · Burns result from exposure to extremes of heat.
Dermatitis · Electrical burn · Erythema ab The lowest temperature at which a burn can occur
igne · Heat · Immersion foot · Miliaria · has been estimated to be 44 C (111 F) (Moritz
Squamous cell carcinoma · Sweat retention · and Henriques 1947). Burns may be of industrial,
Temperature domestic, or environmental origin. Industrial
burns are common (Cason 1981) and may have
characteristic occupational patterns (Renz and
1 Core Message Sherman 1994; Woods et al. 1996). They may be
caused by direct contact with hot objects, radia-
• Heat induces skin damage not only directly in tion heat (infra-red, IR), or hot steam or air, e.g.,
terms of thermal or electrical burns, but also emitted by improperly handled heat torches.
via infra-red radiation or prolonged direct Moreover, accidental exposure to laser energy
exposure to moderate heat (Erythema ab igne). may cause thermal destruction through absorption
33 Physical Causes: Heat, Cold, and Other Atmospheric Factors 469
Table 1 Classification of burns based on the depth of the burns (From Burke and Bondoc 1993)
Classification Surface appearance Sensation Outcome/prognosis
First-degree Dry, erythematous, no Painful, hypersensitive Complete healing within 1 week; no scar
blisters
Second- Blisters, red oozing base, Painful, extremely Complete healing within 3 weeks; may be
degree good capillary refill, sensitive to pinprick erythematous early after healing
(superficial) blanching on pressure
Second- Blisters may be present; Some insensitive Firm, thick scar with loss of hair follicles,
degree (deep) pale, indurated areas; some areas; many areas sweat glands, and skin pigmentation;
areas red anesthetic to pinprick healing may take 1 month
Third-degree Pearly white or brown No sensation Total skin loss includes all appendages;
opaque gray; firm leathery, heals by scar formation if small
dry
by skin chromophores such as melanin and hemo- 18–24 months after the burn has completely
globin, well known from the therapeutic applica- healed.
tion of different lasers in dermatology.
Classification of burns is based on the depth of
the burn as first, second, or third degree (Table 1; 3.2 Electrical Burns
Burke and Bondoc 1993).
Although in many countries dermatologists are These occur from environmental, domestic, and
often not involved in the acute-phase treatment industrial sources. Out of 290 fatal factory acci-
(Jeschke 2016) of more severe burns, they fre- dents in Great Britain, 21 were due to electric
quently are requested to evaluate impairment of shock; a larger number died from burns after
patients with healed burns. Pigmentation, vascu- contact with domestic 240 V alternating (50 Hz)
larity, pliability, and scar height are the main current (Cason 1981). The lesions are due to heat
parameters (Sullivan et al. 1990) for dermatolog- and direct injury by electricity, the severity
ical evaluation. Sometimes scarring is extensive depending, e.g., on current voltage, thickness,
enough to limit joint mobility or muscle strength and wetness of the skin, and duration of contact
(Jonsson et al. 1997) in addition to producing (Kennedy 1992). High voltage burns are severe,
varying degrees of disfigurement. Squamous cell while low voltage (<1000 Volt) burns are milder,
carcinoma arising from burn scars was described but penetrate more deeply than is apparent follow-
by Marjolin in 1828; the frequency of this coming nerves and vessels, extending some distance
plication is unknown. The criteria established by away from the edge of the visible wound. Even
Ewing (1935) for associating a carcinoma with a 24 V may produce deep injury (Benmeir et al.
previous burn are still considered valid. 1993). Late rupture of blood vessels can occur
Burns may cause either hyperpigmentation or even as long as 2 weeks after the electrical burn
hypopigmentation. When total loss of pigment (Kennedy 1992). Electrothermal burns may be
occurs, it denotes deeper burns with destruction caused by touching a heated electrical element.
of melanocytes, and recovery of skin color is Burns from cardiac defibrillators have caused
doubtful. With more superficial burns, hyper- local skin ulcers. The depth of electric flash
pigmentation may result, depending on the depth burns depends on the temperature of the agent
of the burn and the genetic background of the and the duration of contact. Campbell and
patient. Blacks and other dark skinned persons coworkers (1996) reported high-voltage electrical
show the greatest hyperpigmentation, which on injury in two hang-glider pilots from 11,000 V
the face and other exposed areas may be very power lines. Magnetic resonance imaging (MRI)
disfiguring. Fading occurs slowly; a final evalua- is a valuable diagnostic aid in the care of high-
tion of permanency should not be made until voltage electrical burns (Nettelblad et al. 1996).
Burns from lightning cause a bizarre, superfi- stenographers who sit very close to radiators in
cial Erythema which is considered pathogno- cold weather has been described (Schwartz et al.
monic (Bartholome et al. 1975). The skin shows 1957). According to Bashir and Chew (2016), it
numerous erythematous macules arranged in a also occurs in the face of silversmiths and jewelers
streaked feather- or fern-like pattern. Blanching and on the arms of foundry men. A more recent
on diascopy does not occur, and in those persons source of Erythema ab igne mediated by contact,
who survive fading occurs in 24–48 h. The con- and not radiation, is laptop computers, if held for
dition is probably due to the transmission of static many hours and days (several case reports
electricity along the superficial vessels, similar to published, e.g., Bachmeyer et al. 2009). In men-
that occurring when an electrodessiccating current tally disturbed patients with thermophilia, bizarre
is used to destroy small angiomas. Lightning inju- areas of Erythema ab igne have been encountered
ries are an occupational risk of outdoor workers (Bashir and Chew 2016).
such as railroad and highway construction After an interval of up to over 30 years, thermal
workers, surveyors, geologists, foresters, and skin injury and Erythema ab igne may proceed to
agricultural workers. cancer (Kaplan 1987). Several variants, mostly
depending on a certain geographical influence or
habit, have been described (Kanerva 1999). Infra-
3.3 Erythema ab igne red radiation may significantly enhance aging and
carcinogenic effects of ultraviolet radiation
Infrared radiation, composed of wavelengths of (Kligman and Kligman 1984).
800–170,000 nm, results in thermal burns at
temperatures over 44 C (Zalar and Harber
1985). Chronic exposure to heat can result in 3.4 Erythermalgia
Erythema ab igne and skin cancer. It is charac-
terized by a mottled, reticulate hyperemia with Primary erythermalgia usually arises in childhood
melanoderma and telangiectasia and sometimes and is a rare autosomal dominant neuropathy
superficial epidermal atrophy and subepidermal characterized by the combination of recurrent
blistering. Erythema ab igne occurs after pro- burning pain, warmth, and redness of the extrem-
longed exposure to heat, i.e., infra-red radiation, ities (Tang et al. 2015). Secondary erythermalgia
which is usually insufficient to produce burn. At develops in adult age in association with or with-
one time the condition was common on the ante- out an apparent underlying disorder. It is charac-
rior legs and inner thighs of women who sat for terized by bilateral symmetric burning and
long periods before an open fire and on the abdo- redness of the lower, or sometimes upper, extrem-
mens of patients with chronic abdominal pain ities. Symptoms can be initiated by exercise or
who applied heating pads for hours at a time. exposure to heat, while rest and cold briefing relief
New cases are now being seen as heating with (Drenth and Michiels 1994; Gaur and Koroscil
wood fires has become more common again. 2009). Thus, occupational factors may aggravate
Heater cushions still cause Erythema ab igne symptoms (Table 2). Avoidance of triggering sit-
(Dvoretzky and Silverman 1991). Erythema ab uations by lifestyle modification (Gaur and
igne may be a sign leading one to suspect hypo- Koroscil 2009) has given the best results, but
thyroidism (Bashir and Chew 2016). It has also treatment may be difficult, and symptoms may
been reported as a marker of chronic pancreatitis persist throughout life. Secondary erythermalgia
(Mok and Blumgart 1984). can arise as a side effect of drugs but otherwise the
Workers who may develop Erythema ab igne etiology is yet unknown (Drenth and Michiels
include stokers, blacksmiths, glassblowers, 1994; Drenth et al. 1997). The past 20 years
bakers (especially those using old-fashioned have not produced literature on “secondary
brick-lined ovens), and cooks and others working erythermalgia,” but focused on the inherited, pri-
over a heat source. Historically, the condition in mary variant.
Table 2 Workers potentially exposed to excessive heat involvement may in rare cases interfere with
Type of work thermoregulation.
Animal rendering workers When closure occurs somewhat deeper in the
Asphalt workers epidermis, in the granular layer, firm vesicles are
Bakers formed accompanied by marked pruritus. Called
Bitumen workers miliaria rubra, or prickly heat, it is easily con-
Boiler heaters fused with contact dermatitis. This condition is
Cannery workers more troublesome than miliaria crystallina
Chemical plant operators working near hot containers because the eruption may be quite extensive
and furnaces
and accompanied by paroxysms of burning and
Cleaners
itching. The lesions are small erythematous mac-
Coke oven operators
ules and vesicles unassociated with follicular
Cooks and other kitchen workers
openings; a hand lens aids in visualization.
Firemen
Foundry workers
The lesions may appear a few days after
Glass manufacturing workers exposure to hot, humid environment, but most
Greenhouse workers commonly appear after one to several months
Kiln workers (Lillywhite 1992).
Miners in deep mines The trunk and intertriginous areas are particu-
Outdoor workers during hot weather larly involved, while the palms and soles are
Sailors passing hot climatic zones spared. When poral closure is severe, hyperpy-
Shipyard workers when cleaning cargo holds rexia and heat exhaustion occur, causing a
Smelter workers decrease in work efficiency. The lesions that
Steel and metal forges later develop may be pustular from infiltration of
Textile manufacturing workers (weaving, dyeing) inflammatory cells and may be complicated by
maintenance workers in nuclear plants
secondary bacterial infection.
Tight protective clothing (all occupations), e.g.,
maintenance worker in nuclear plants
If obstruction is even deeper, i.e., in the dermo-
Tire (rubber) manufacturing workers epidermal junction zone, miliaria profunda results
(Kirk et al. 1996), producing deep-seated asymp-
tomatic vesicles, that appear much like goose-
3.5 Miliaria flesh, but close examination shows that they
spare the follicles. The lesions consist of pale
Miliaria is caused by sweat retention. Heat causes white papules 1–3 mm in diameter, which are
swelling of the keratin within sweat ducts, most prominent on the trunk. Erythema and pru-
resulting in poral closure and rupture of the ritus are mild or absent. This serious condition is
ducts immediately beneath the obstruction. If the caused by widespread inactivation of sweat
obstruction occurs within the stratum corneum, glands from prolonged exposure to a hot environ-
miliaria crystallina (sudamina) results. This pro- ment. It usually follows an extended period of
duces small, clear vesicles that soon rupture and miliaria rubra. Heat exhaustion and collapse are
lead to desquamation. Cutaneous bacteria, partic- common sequelae. A condition called tropical
ularly Staphylococci, seem to play a role in the anhidrotic asthenia with acute fatigue, nausea,
pathogenesis of miliaria (Mowad et al. 1995). The dizziness, palpitations, tachycardia, and malaise
skin surface may or may not be faintly Erythem- has been observed among military personnel dur-
atous. It is most commonly seen after mild non- ing wartime in very hot, humid environments.
specific damage to the epidermis and/or profuse Tropical anhidrotic asthenia is secondary to wide-
sweating. While miliaria crystallina is usually spread miliaria profunda in particularly adverse
asymptomatic, patients may become concerned conditions (Cage et al. 1987).
when they suddenly notice the entire palm Treatment of miliaria consists of cooling the
is desquamating (Lobitz 1962). Widespread patient to reduce sweating. Mild, nonocclusive
lotions may be used. In miliaria crystallina, excessive heat also increases irritability, decreases
removal of the damaged area by mechanical workers’ ability to concentrate, and results in a
means or by natural sloughing stops the process. generally lower level of efficiency.
In miliaria rubra, a week of rest from the inciting
factors allows removal of the damaged portion of
the epidermis by natural desquamation while in 4 Cold
miliaria profunda rest in cool surroundings for
several weeks is needed for complete recovery. The effect of coldness is the result of a complex
Systemic and topical steroids are not helpful. interaction of climatic factors (air temperature, mean
Occupations where excessive heat exposure radiant temperature, humidity, and wind), protection
can occur are listed in Table 2; in addition, work (clothing), and metabolic heat production (activity).
in the tropics may be inadvisable for very suscep- The nature of cooling encompasses (i) whole-body
tible persons. cooling, (ii) extremity cooling, (iii) convective
cooling (wind chill), (iv) conductive cooling (con-
tact), and (v) airway cooling (Holmér 1993).
3.6 Intertrigo Cooling the brain leads to confusion and later to
impaired coordination, while cooling the limbs
A macerated, erythematous eruption in body folds – results in numbness and clumsiness, making the
intertrigo – can occur from excessive sweating, performance of intricate tasks difficult.
especially in obese persons. Friction between Local cooling in most cases produces discom-
opposing surfaces in addition to sweat retention fort and harmful effects, before more significant
are important etiologic factors. Secondary bacterial whole-body cooling develops. With strong wind
or Candida infection commonly accompanies or exposure to very low temperature, frostbite of
intertrigo. The groin, axillae, and interdigital areas unprotected skin may quickly develop (see
are favored sites. In particular, the interdigital space below). However, as digit cooling largely depends
between the third and fourth fingers is a common on whole-body heat balance, it is important to
site for intertrigo and secondary Candida infection control body cooling by selection and use of
among cannery workers, bartenders, medical and appropriate protective clothing (Holmér 1993).
dental personnel, and others performing wet work Everybody reacts to cold, but in addition to
for prolonged periods. Cooks, swimming instruc- physiologic responses to cold, abnormal reactions
tors, nurses, and others exposed to moisture are also may occur in some individuals. Chilblains may
disposed to this condition. An important differential result from chronic exposure to moderate cold.
diagnosis, if finger web spaces are affected, is Cold plays an important role in, e.g., Raynaud’s
interdigital dermatitis as a common, early type of phenomenon, cryoglobulinemia, and cold urti-
irritant contact dermatitis in wet work occupations caria. Cutaneous reactions to cold can be divided
(Schwanitz and Uter 2000). This will, however, into reactions to abnormal cold and abnormal
show scaling and probably fissuring without macer- reactions to “normal” cold. The diseases caused
ation and should respond well to emollient treatment or aggravated by cold are listed in Table 3.
and improved skin protection measures.
4.1 Frostbite
3.7 Miscellaneous Conditions
There are three stages of freezing cold injury:
Acne vulgaris and rosacea can be aggravated by (i) massive vasoconstriction causing a rapid fall
prolonged chronic exposure to heat, especially in skin temperature, (ii) the hunting phenomenon,
intense heat from ovens, steam, open furnaces, i.e., transient cyclic vasodilatation by the opening
or heat torches. Herpes simplex may be triggered of arteriovenous anastomoses causing a cyclic rise
by sudden blasts of heat. Prolonged exposure to and fall in skin temperature, and (iii) if cold
Table 3 Diseases caused or aggravated by cold Low air temperatures and high wind speeds
I. Reactions to abnormal cold (“wind chill”) are associated with an increased
1. Cold injury risk of freezing of the exposed skin. As the skin
2. Frostbite surface temperature falls from 4.8 C to 7.8 C,
3. Nonfreezing cold injury the risk of frostbite increases from 5% to 95%
(a) Immersion or trench foot (Danielsson 1996). Frostbite additionally causes
(b) Immersion foot impairment of circulation due to slowly pro-
(c) Tropical immersion foot gressing vasoconstriction.
II. Abnormal reactions to cold In its mildest form, only redness and pain are
1. Perniosis present. In more severe cases, tissue destruction
2. Pulling boat hands and blistering occur and this may be superficial,
3. Acrocyanosis
full thickness or involve deep tissues analogous to
4. Erythrocyanosis
the burns (Table 4). In its most extreme form,
5. Livedo reticularis
gangrene and loss of limb may result. Exposed
6. Cold urticaria
parts, i.e., toes, feet, fingers, ears, nose, and
7. Cold erythema
8. Cold panniculitis
cheeks, are most often affected.
9. Sclerema neonatorum As tissue temperature falls, the area becomes
10. Subcutaneous fat necrosis of the newborn numb, and the initial redness is gradually replaced
11. Cryoglobulinemia by a white, waxy appearance with blistering and
12. Raynaud’s phenomenon later necrosis; the affected part becomes decep-
tively anesthetic. In the early stages, it is difficult
to predict the extent of tissue loss becoming per-
exposure continues, freezing, as the skin temper- ceivable after rewarming, especially concerning
ature falls to approach ambient temperature deeper structures like muscle and bone. Accurate
(Kulka 1965). Risk increases with alcohol use estimation may clinically not be possible for several
and smoking (Bashir and Chew 2016). weeks (Knize et al. 1969); however, magnetic res-
The events that follow freezing and nonfreezing onance imaging (MRI) and angiography (MRA)
cold injury are similar and include: (i) arterial and provide for early recognition of damaged tissue
arteriolar vasoconstriction, (ii) excessive venular (Barker et al. 1997). The more superficial the
and capillary vasodilatation, (iii) increased endo- injury, the better the prognosis, especially if infec-
thelial leakage, (iv) erythrostasis, (v) arteriovenous tion is absent. However, even without loss of tissue,
shunting, (vi) segmental vascular necrosis, and long-term effects may include telangiectasia (Huh
(vii) massive thrombosis (Heller Page and Shear et al. 1996), vasomotor instability with Raynaud-
1993). like changes, paresthesia, and hyperhidrosis. This is
The degree of cellular injury depends on (i) the attributed to damage to the blood vessels and sym-
minimum temperature, (ii) the duration of time at pathetic nerves. Squamous cell carcinoma may
that temperature, (iii) the cooling rate, with rapid arise in the old scars (Rossis et al. 1982).
cooling causing more destructive intracellular ice In slow rewarming, intracellular ice crystals
crystal formation, and hence more destruction as is become larger and more lethal for the cells. There-
obvious from cryotherapy, and (iv) rewarming rate. fore, treatment entails rapidly rewarming the part
In slow rewarming, intracellular ice crystals become for which a whirlpool or water bath or warm air
larger and more lethal for the cell; (v) finally, for 20 min (until the most distal part is flushed) is
repeated freeze–thaw cycles lead to greater injury. useful. A temperature of 40–42 C (104–107.6 F)
Different cell types vary in their susceptibility to (Golant et al. 2008) has been recommended, e.g.,
cold. Melanocytes are very sensitive, and damage employing warm baths for 15–30 min.
occurs at 4 C to 7 C (25–19 F). Accordingly, Rewarming should not begin until definite medi-
cryotherapy causes hypopigmentation (Heller Page cal care can be provided, to avoid repeated
and Shear 1993). freeze–thaw cycles (Golant et al. 2008). After
Table 4 Four-degree classification of frostbite (Roberts Table 5 Workers potentially exposed to excessive cold
2008, after Heil et al. 2016)
Cooling room workers
Degree of Divers
frostbite Appearance after rewarming Dry ice workers
First degree Numb central white plaque surrounded Firefighters
by erythema but no blistering
Ice makers
Second Blister formation surrounded by
Liquefied gas workers
degree erythema and edema
Outdoor workers during cold weather
Blisters filled with clear or milky fluid in
first 24 h Packing house workers
Third degree Death of skin and subcutaneous tissues Refrigerated warehouse workers
forming hemorrhagic blisters resulting Refrigeration workers
in black eschar 2–3 weeks later Winter sports instructors
Fourth Tissue necrosis, gangrene and
degree eventually full thickness tissue loss;
initially body part is hard, cold, white,
and numb post rewarming 4.2 Immersion Foot/Nonfreezing
Cold Injury
rewarming, the affected part is rested at usual Formerly called trench foot, immersion foot
room temperature. Rewarming is painful and results from exposure to cold temperatures above
causes an increase in Erythema and blistering. freezing for several days. In the presence of mois-
The pain should be relieved with analgesics; non- ture and constrictive clothing, however, continu-
steroidal anti-inflammatory drugs (NSAIDs) also ous exposure for as little as 19 h may be sufficient
contribute to lessening levels of prostaglandins (Rietschel and Allen 1976). Immersion foot is less
and thromboxanes contributing to vasoconstric- severe than frostbite and develops in three stages:
tion (Bashir and Chew 2016). The damaged part initial Erythema, edema, and tenderness (stage I);
should be elevated and blisters left intact. Infec- followed within 24 h by paresthesia, marked
tion must be treated vigorously. As second-line edema, numbness, and sometimes bullae (stage
treatment, the intra-arterial infusion of tissue plas- II); and progressing to gangrene (stage III). Gan-
minogen activator (tPA) or administration of grene does not develop unless there is infection.
acetylsalicylic acid with iloprost have been Convalescence may be prolonged for several
shown to reduce the rate of amputations in third- weeks, months, or even years, during which time
degree frostbite (Bashir and Chew 2016). The there is cold sensitivity, vasomotor instability,
popular old idea of rubbing the affected part hyperemia, and hyperhidrosis (Bashir and Chew
with snow has an adverse, even disastrous effect. 2016). Rest, analgesics, and antibiotics are the
Historically, the persons at greatest risk of mainstays of treatment, which is the same as for
frostbite have been military personnel. Today, frostbite.
many cases are associated with alcohol consump- During the Korean and Vietnam Wars, thou-
tion, homelessness in urban centers, and car sands of cases occurred, and immersion foot
breakdown (Miller and Chasmar 1980). Frostbite became the major cause of disability. In industries
also occurs in winter sports, e.g., cross country in which workers are required to stand for long
skiers or backpackers. Occupations at risk include periods in cold wet mud or water, as when exca-
oil pipeline workers in northern regions, utility vating foundations for new construction,
maintenance personnel, sailors, especially those immersion-type injuries may be frequent
working on icebreakers, fishermen, firefighters, (Schwartz et al. 1957). Street and sewer workers
mail delivery persons, rescue personnel, as well as golf caddies walking for hours on wet
researchers in cold laboratories and polar areas, grass are also at risk (Chow et al. 1980). For the
and others who work outdoors in cold regions homeless, immersion foot can be a major health
(Table 5). problem (Wrenn 1991), aggravated by lack of
care. Interestingly, immersion foot can also 4.4 Pulling Boat Hands
develop in warm water (Humphrey and Ellyson
1997), including the tropics (tropical immersion This dermatosis has been described from coastal
foot, Table 3). New England (Toback et al. 1985). Erythematous
macules and plaques developed on the dorsa of the
hands and fingers of instructors and students after
4.3 Chilblains (Perniosis) 3–14 days aboard a pulling boat. Later, small vesi-
cles appeared, accompanied by itching, burning,
The mildest form of cold injury, chilblains or and tenderness. Subjects had been exposed to high
perniosis, occur as an abnormal reaction to cold humidity, cool air, and wind. This was considered an
in the temperate humid climate of Great Britain ideal setting for the development of this nonfreezing
and northwestern Europe, where there is a lack of type dermatosis. Hours of vigorous rowing provided
central heating (Heller Page and Shear 1993). additional repetitive trauma. Some of the patients
Chilblains are less often seen in continental cold also had a history of frostbite and Raynaud’s phe-
climates such as Finland, where well-heated nomenon. This syndrome may be caused by a com-
houses and warm clothing are essential. The bination of nonfreezing cold and the mechanical
lesions are reddish blue discolorations that effects of rowing (Toback et al. 1985).
become swollen and boggy, with tense bullae
and later ulcerations that may result in scarring.
Often, chilblains are superimposed on a back- 4.5 Other Reactions to Cold
ground of acrocyanosis or erythrocyanosis.
Lesions occur especially on the dorsa of the prox- Cold urticaria and Raynaud’s phenomenon are
imal phalanges of the fingers and toes, heels, dealt with later in this book. The reader interested
lower legs, thighs, nose, and ears. The shiny red in other types of abnormal reactions to cold
plaques itch and burn severely. Chilblains are (Table 3) is referred to major textbooks of derma-
particularly frequent in children, where they tend tology, e.g., the article of Bashir and Chew (2016),
to start at the beginning of winter. In adults who or a recent systematic review on freezing and non-
work outdoors, chilblains often seem to start in the freezing cold weather injuries (Heil et al. 2016).
spring months. Genetic factors are often apparent,
e.g., acrocyanosis as an underlying factor. Differ-
ential diagnoses of idiopathic pernionsis include 5 Other Atmospheric Factors
chilblain lupus erythematosus (Millard and
Rowell 1978), sarcoidosis, and several other enti- A low water content of ambient air may cause, or
ties which have to be considered clinically, histo- contribute to, occupational dermatoses, as empha-
logically, and serologically (Crowson and Magro sized by Rycroft and coworkers (Rycroft and
1997). Moreover, some patients with chilblains Smith 1980; White and Rycroft 1982; Rycroft
suffer from associated (nonlupus) connective tis- 1984, 1985), see below. In addition, low temper-
sue disease or hematologic malignancies (Cappel ature, wind, electromagnetic fields, or electro-
and Wetter 2014). static charge have been claimed to be ambient
The most important point in management is factors important to some skin conditions.
prophylaxis with warm housing, warm clothing,
and regular exercise. Once chilblain has appeared,
treatment is mainly symptomatic with local appli- 5.1 Low Outdoor Humidity
cation of an antipruritic. Nifedipine may be effec-
tive in the treatment of severe recurrent perniosis The following two measures are most commonly
(Dowd et al. 1986). In seven of ten patients, clear- used to quantify the humidity of air: absolute
ing ranged from 8 days for lesions of the hands to humidity (AH) is the mass of water vapor present
23 days for foot lesions (Dowd et al. 1986). in a unit volume of the atmosphere and is mostly
measured as mg/l. Relative humidity (RH) is the is always also low with low temperature,
ratio of the quantity of water vapor present in the according to the functional relationship men-
atmosphere to the quantity which would saturate it tioned above, and absolute humidity has not
at the existing temperature (expressed as %). been considered in most of these older studies.
Thus, with a given quantity of water per air vol- At present, the effect of temperature concerning
ume (AH), RH depends on the temperature: the irritant damage can most likely be regarded as
higher the temperature, the greater the water- indirect.
holding capacity of the atmosphere and the Wind speed had been found to be a significant
lower the RH, and vice versa. risk factor of the occurrence of “dry flaking” facial
Low humidity of the air is believed to cause skin (Cooper et al. 1992). Parish, who exposed the
dehydration of the horny layer and impairment of hands of volunteers to “a cold dry wind” 3 h daily,
the epidermal barrier function (Agner and Serup found visible alteration (roughness, desquama-
1989), i.e., increased irritability of the skin. Sub- tion) and impaired lipid and enzyme composition
clinical xerotic changes may occur within hours of of the epidermis after a few days (Parish 1992).
exposure and are more pronounced in atopics In addition to natural environmental condi-
(Eberlein-König et al. 1996). tions, anthropogenic factors may lead to occupa-
Persons working and living in (sub-) polar or tional (skin) disease:
even temperate climates with a strong continental
influence (prolonged periods of dry, frosty weather • During work on a television mast, exposure to
in winter) are regularly exposed to low atmospheric high levels of ultrahigh frequency radio-
humidity, such as 10 mg/l or less. Clinical experi- frequency radiation (UHF, 785 MHz mean fre-
ence from these countries gives a strong hint on the quency) caused an immediate sensation of
contributing role to irritant hand dermatitis of these intense heating and later transient Erythema,
meteorological condition (Kavli and Førde 1984), malaise, numbness, and pain (Schilling 1997).
which has recently been confirmed by an epidemi- • Similarly, microwave radiation (1–30 GHz)
ological study (Uter et al. 1998) and is in good has been reported as a cause of more or less
accordance with some experimental data (partially severe burns, lesser injury being followed by
reviewed by Uter et al. (1998)). paraesthesia (Kennedy 1992).
Interestingly, unexposed skin displays an
impaired epidermal barrier function also (Agner
and Serup 1989), which may indicate that even the 5.3 Low Indoor Humidity
wearing of protective (warm, wind-tight) gloves
may not completely be able to abolish the effect of Below a water content of 10%, the stratum
low humidity on the skin of the hands. The hands corneum loses its softness and pliability (Blank
may additionally be exposed to a variety of occu- 1952). The water content of the horny layer
pational irritants or to wet work. Thus, as (sub-) remains below 10% when the relative humidity
clinical irritation is known to often be a multifac- is less than 50% at room temperature (Rycroft
torial process (Malten 1981), this fairly inalterable 1985). High temperature and air flow accentuate
environmental condition puts extra emphasis on the drying of the horny layer. An open-plan office
the necessity of adequate skin protection, be it next to, or under, the ventilation system, where
domestic or occupational. warm, un-humidified air is introduced into the
room is a typical working site where the risk
of low humidity dermatosis is apparent. Low
5.2 Other Ambient Factors humidity dermatoses can be accentuated by
small irritant or hygroscopic airborne particles,
Several authors of experimental studies have such as textile particles, dust from ceramics,
attributed negative effects on epidermal properties small particles from paper cutting, and fine angu-
to low temperature. However, absolute humidity lar, hygroscopic particles, as in a soft lens factory
(Rycroft 1984, 1985). Domestic and general cli- inhalable and ingestible allergens, irritant or aller-
matic conditions can potentiate low humidity gic airborne contact dermatitis, psychological
occupational dermatoses: Air-conditioned build- causes, menopausal hot flashes, rosacea and seb-
ings have a low relative (and absolute) humidity, orrheic eczema, or scabies.
and in temperate areas such as Scandinavia, the Treatment should include routine use of emol-
low humidity/high temperature indoor environ- lients and increasing the relative humidity indoors
ment is accompanied by low humidity/low tem- to about 50% during the whole low humidity
perature outdoor climate during the winters, (winter) season.
which also has a drying effect on the stratum
corneum (see above). The empirical threshold
value of 40% relative humidity reported by 5.4 Visual Display Units
White and Rycroft (1982) corresponds at a tem-
perature of around 20 C well with a threshold In some countries, patients often complain of skin
value of 9–10 mg/l absolute humidity as signifi- symptoms from work with visual display units
cant outdoor risk factor (Uter et al. 1998). Some of (VDU; Lidén and Wahlberg 1985; Berg 1989;
the occupations where low humidity dermatoses Eriksson and Stenberg 2006). A study from Swe-
have been reported are listed in Table 6. den among 353 routine office workers showed an
These dermatoses are far more distressing than increased tendency for seborrheic eczema and
their comparative paucity of physical signs might nonspecific Erythema. Organizational conditions
suggest (Rycroft 1985). Pruritus and burning can during VDU work, such as high work load, and
be the only sign of low humidity. Puffiness of the inability to take rest breaks, were found to be
cheeks and eyelids has been observed. The skin associated with the reported skin symptoms. A
lesions evolve through dryness of the skin to low relative humidity was associated with a diag-
Erythema and round or oval patches of eczema. nosis of seborrheic eczema. However, no associ-
Erythema has been accompanied by urticarial ations were found between current field levels of
whealing possibly secondary to scratching pru- electric or magnetic field and skin diseases/signs
ritic skin. In some cases, areas covered by clothing or reported symptoms (Bergqvist and Wahlberg
have been predominantly involved, while facial 1994). Accordingly, a reduction of electric fields
itching with diffuse superficial scaling on the was only weakly associated with an improvement
cheeks, forehead, and neck have been the main of symptoms attributed to VDU-work (Oftedal
anatomical areas in other instances. Patchy Ery- et al. 1995). Possibly independent from the initial
thema on the shaved face of male employees has cause of skin problems, psychological condition-
been observed. Fair skinned individuals are at ing may lead to a perpetuation of symptoms even
higher risk. Both atopics and nonatopics have without exposure, as illustrated by experiments
been affected. with affected office workers (Swanbeck and
Differential diagnosis includes a wide variety Bleeker 1989). In some cases, perceived symp-
of possibilities that have to be considered such as toms, attributed to VDU-work or other indoor
factors, may be part of the ill-defined “sick build-
ing syndrome” (Stenberg et al. 1994; Norbäck
Table 6 Occupations reported to be related to low ambi- 2009).
ent humidity
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Chronic Venous Insufficiency and
Occupation 34
Edith M. de Boer
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
3 Chronic Venous Insufficiency: Epidemiology, Symptoms and Risk
Factors, Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
4 Risk Inventarisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
5 Studies on Occupation and Venous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
6 Preventive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
Keywords • Exact data on the influence of work on the

Chronic venous insufficiency · Occupation · development/progression of venous disease
Profession · Elastic stocking · Compression and vice versa lack.
• Ambulatory hypertension due to hampered
venous return occurs with inactivity of the
1 Core Messages calf muscle pump, such as in prolonged
standing.
• Chronic venous disease is an often-trivialized • Evening edema is physiological and can be
common multifactorial slowly progressive dis- prevented by low-pressure (10–20 mmHg)
ease, increasing with age and influenced by medical elastic stockings. The use of
obesity, parity, heredity, and lifestyle. low-pressure elastic below-knee stockings
• Comparison of studies on chronic venous dis- should be considered for each worker with a
ease and occupation is hampered by lack of predominantly standing or sitting position
uniformity of definition of venous disease, at work.
working position, sample size, etc. • With a short questionnaire and a simple phys-
ical examination (the risk for), venous disease
can be easily established.
E. M. de Boer (*) • Medical elastic stockings are the devices of
Department of Dermatology, VU Medisch Centrum,
Amsterdam, The Netherlands choice for the prevention of venous disease,
e-mail: em.dboer@vumc.nl for relief of complaints, and for slowing down

https://doi.org/10.1007/978-3-319-68617-2_34
482 E. M. de Boer
progression. They are an indispensable part of objective signs of venous incompetence. Subse-
the treatment of subjects with venous disease. quently, hyperpigmentation, lipodermatosclerosis,
The choice of stocking requires knowledge of white atrophy, eczema, phlebitis, thrombosis, or
the subscriber of both the properties of the ulcerations may develop. For a useful classifica-
individual worker and of stockings. tion for comparison between investigations, an
international system has been accepted and
modified, called CEAP (Eklöf et al. 2004),
2 Introduction based on Clinical signs, Etiology, Anatomy,
and Pathology. Apart from the clinical evalua-
Chronic venous disorders are one of the most tion, duplex ultrasound investigation is required
common ailments affecting mankind in the for this classification. In many studies, a (com-
world today. In the Netherlands, government plete) classification is not used.
authorities do not record the instance of venous From many large epidemiological studies among
disorders in a way that provides data for epidemi- the general population, it is evident that venous
ologic interpretation. In other countries, the situa- disorders are common, even more often present
tion is often similar, meaning that exact numerical than absent. In a large study among 2211 individuals
data are not available. in San Diego (40–79 years) using duplex investiga-
In contrast to other chronic conditions, patients tion, a modified CEAP classification was made.
and physicians alike often trivialize the presence and Only about 15% among the general white popula-
severity of venous disorders. This might be attrib- tion had no visible signs (Criqui et al. 2003, 2007).
uted to the fact that varicose veins are common and Among Hispanics, Afro-Americans, and Asians,
that progression takes place slowly. Many workers these data were about 20–30%. Subjective com-
with venous disorders, even with progressed forms, plaints were also not unusual, varying from painful
never consult a doctor (Krijnen et al. 1997a). Liter- legs in 18% and tired heavy legs in about 13%
ature shows indications that venous disorders lead to (Criqui et al. 2003, 2007). In the representative
incapacity to work in about 2% (Krijnen et al. randomized sample of 1566 individuals from the
1997a). In our study, we found that 7% of almost general population, 18–64 years in Edinburgh a
400 male workers with a standing profession had questionnaire, clinical investigation and duplex
been temporarily unfit for work due to phlebological examination were performed (Evans et al. 1999;
disorders (Krijnen et al. 1997a). Ruckley et al. 2002). C1 telangiectasias and reticular
veins occurred in over 80%, and the more severe
chronic venous insufficiency (CVI) occurs in some-
3 Chronic Venous Insufficiency: what less than 10%, increasing with age.
Epidemiology, Symptoms In the large epidemiological Bonn Vein Study,
and Risk Factors, Treatment 49% of males and 62% of females reported sub-
jective venous complaints, increasing with age
In the pathogenesis of venous disorders, the elevated (Rabe et al. 2003, 2009; Rabe and Pannier
venous pressure due to hampered venous return is 2009a, b; Pannier-Fischer and Rabe 2003).
crucial. The term “chronic venous insufficiency” Among more than 3000 participants, less than
(CVI) refers to an array of symptoms resulting 10% showed no sign of venous disease, 60%
from venous hypertension. Subjective complaints had telangiectasias or reticular veins, 14% vari-
of varicose veins and CVI often include a feeling cose veins, 13% edema, and 3% skin changes.
of heaviness and pain, a sensation of swelling of the Only 0.6% had healed venous ulceration
legs, nighttime calf cramps, and restless legs. Com- (C5) and 0.1% present ulceration of the leg
plaints increase during the course of the day, espe- (C6 in CEAP classification).
cially after prolonged standing and also after sitting. In a longitudinal study among schoolchildren, it
Edema, ankle flare, and corona paraplantaris appeared that varicose veins occur not often before
phlebectatica and varices in all sizes are the first puberty. From puberty on, varicose veins evolve to
34 Chronic Venous Insufficiency and Occupation 483
occur at the age of 20 years in 30%, increasing to performed, supplemented with ultrasound exami-
80% small caliber intracutaneous varices at nation. In the near past, this was usually a
30 years. At that age, 29% had already real larger continuous-wave Doppler, but nowadays duplex
varices (C2 in CEAP classification) and almost 4% scanning is widely available. This noninvasive
skin changes (C4) (Schultz-Ehrenburg et al. 1989, technique based on echo-Doppler enables visual-
2009). In the first years of this lasting study, children ization of both the superficial and the deep venous
were, in addition to a clinical investigation, exam- systems and blood flow measurements for the
ined by Doppler ultrasound, but in the more recent determination of refluxes.
follow-ups, duplex investigation was performed. There are several treatments available for venous
In the most recent epidemiological studies, the diseases. The main objective is to normalize venous
presence of rather severe CVI is declining to 2–4% physiology. In case of superficial varices, more
(Rabe et al. 2003; Evans et al. 1999) compared to invasive techniques like stripping of the superficial
about 10% in older studies (Fischer 1980; Widmer stem veins are more and more replaced by less
et al. 1981). The modern approach of earlier inter- invasive intravascular ablations using lasers, radio-
ventions seems to bear fruit and prevent the begin- frequency, or steam. Ambulatory phlebectomy by
ning stages of venous disease to develop to full- mini-incisions and sclerocompression therapy with
blown CVI and ulceration. There is evidence of sclerosing injections (fluids and foams) are widely
venous disease in the majority of leg ulcers. performed. In case of deep venous insufficiency,
The epidemiological studies have cited a num- compression therapy is the only option. This com-
ber of risk factors for venous disease. Age is a pression therapy remains the cornerstone of venous
major risk factor (Carpentier et al. 2004; Criqui therapy and is mostly realized by medical elastic
et al. 2007; Ruckley et al. 2002; Maurins et al. stockings, which support the function of the calf
2008; Rabe et al. 2003, 2009; Rabe and Pannier muscle pump, thus improving venous hemodynam-
2009a, b and many others). ics by lowering the ambulatory venous hyperten-
Gender is another factor which is often men- sion. Adequate compression intents to overcome the
tioned. However, though clinically less important effect of gravity. Medical elastic stockings exert
side branch and intracutaneous varices occur pressure on the leg. This so-called interface pressure
more often in females, more severe varices and changes with posture (van der Wegen-Franken
advanced CVI have about the same prevalence in 2009). The pressure exerted by a stocking changes
males and females (Criqui et al. 2007; Rabe et al. during movements, causing pressure pulsations.
2003). During pregnancy, hormonal changes The maximum pressure called working pressure
cause relaxation of smooth muscle and increased and the minimum pressure called resting pressure
venous distensibility. Higher prevalences of vari- are dependent on the characteristics elasticity, stiff-
cose veins are seen in women having had preg- ness, and hysteresis. The importance of this
nancies, related to the number of pregnancies, dynamic stiffness, next to the static stiffness for the
compared to women without pregnancies (Evans effectivity for medical elastic stockings, is demon-
et al. 1999; Carpentier et al. 2004). strated only recently (van der Wegen-Franken
Obesity is proven to be a clear risk factor, espe- 2009). For an optimal choice of compression stock-
cially for the development of more severe CVI ings, knowledge of the properties of both the patient
(Maurins et al. 2008; Criqui et al. 2007; Rabe et al. and the stocking is required.
2003; Schultz-Ehrenburg et al. 2009; van Rij et al.
2008). Also an urban life was mentioned to be a risk
factor (Rabe et al. 2003; Rabe and Pannier 2009a). 4 Risk Inventarisation
Heredity is an often-cited risk factor, but family
history is not always very reliable and family mem- Risk inventarisation may focus on general and
bers are seldom investigated for objectivation. individual aspects. The occupational physician
In the daily patient-related practice, a physical has access to the workplace of a given worker.
examination of the patient standing erect is By observing the physical activity, he is provided
484 E. M. de Boer
with information of the use of the calf muscle 5 Studies on Occupation

pump. Workers with static standing or sitting and Venous Disease
duties do not use their muscle pump, making
them prone to increased venous pressure. Further- Comparing data from different authors is often
more, individuals should be examined in terms of confusing, not equivocal. Some epidemiological
their own personal risk factors, focusing on CVI studies confirm to the CEAP criteria and others
and restrictions of the locomotor system, particu- use data from medical records. Definitions of var-
larly the lower extremities. ices, venous disease, edema, and subjective com-
As there are many factors of influence on the plaints vary in studies. Some studies are focused
development and progression of venous disease, on venous disease and others register venous dis-
both known factors and unknown influences and ease as an extra above the real goal of the study.
as venous disease progresses gradually and Some studies describe the general population,
slowly, it is difficult to determine the deteriorat- some special groups of patients, and some select
ing influence of work. In the years or decennia of on age or gender. Most of the larger studies just
life spent working, venous disease may also register professions and ask participants about
increase due to the natural process of aging and their main position at work, relying on the accu-
may decrease due to the nowadays more often racy of workers to describe their body posture at
applied interventions. In the Bonn Vein study, it work, often over long periods of time. There are
appeared that 13% of males and 31% of females only a few studies that mainly focus on the rela-
had been treated by surgery or sclerotherapy tion between occupation and venous disease.
and/or medical elastic stockings (Rabe et al. For effective venous return from the legs, inter-
2003). A history of interventions in the past action of the heart, a pressure gradient, venous
increased with age. Of the males, 7.5% had now muscle pumps in the leg, and competent valves
or in the past elastic stockings and 20% of in the veins are obligatory (Meissner et al. 2007).
females. Individuals appreciated these stockings During prolonged orthostasis, the calf muscle
as successful and the compliance was 50% (Rabe pump function, “the peripheral heart,” is dimin-
and Pannier 2009c). Other individual risk factors ished. In prolonged standing, the hydrostatic pres-
may change as well, such as body weight, parity, sure increases as the valves in the veins allow
and locomotor factors, especially in ankles, retrograde flow. The weight of the entire column
knees, and hips. Furthermore, working environ- of blood causes a huge pressure. During standing
ments may change in the course of a career. Not without skeletal-muscle activity, venous pressures
to neglect is the difficulty of ascertaining an in the legs are determined by the hydrostatic com-
individual’s posture at work by questionnaire, ponent and capillary flow, reaching up to
as has been done in most studies. A minority of 90 mmHg (Bergan et al. 2006). In the presence
studies describe the inspection of the investigator of competent valves, minor leg movements pro-
of the working environment of the individuals vide sufficient pumping, resulting in a decrease of
included in a study (Krijnen et al. 1997a, epide- intravenous pressure to about 20 mmHg. In case
miology). Not quantifiable is the interaction of of impairment of the venous system, e.g., due to
venous disease and ability to work. Data on incompetent valves in veins, high pressures in the
absence of work, disqualification, or change of superficial system and the microcirculation occur,
jobs due to venous disease are not known and known as ambulatory venous hypertension, as the
therefore not taken into account in studies. Pre- calf muscle contractions are not able to reduce
existent presence of varicose veins, early onset venous hypertension. Prolonged high pressure
beginning CVI, or subjective complaints may causes disturbed venous flow patterns (changes
influence the choice of profession. The influence in shear stress), inducing inflammation and the
of work/occupation on the development of production of free reactive radicals (Bergan et al.
venous disorders has been a challenge to many 2006). So prolonged standing results in venous
investigators. hypertension in the lower legs, activating
inflammatory mechanisms, and enhancing the In the Edinburgh Vein Study (Evans et al.
development of CVI. In a study among 200 female 1999), performed among a group of 1566 individ-
surgery room nurses and outpatient department uals below 54 years from a randomized sample of
nurses, the production of reactive oxygen species 12 general practices, the prevalence of varicose
(ROS) was measured before and after work. It veins tended to be clearly lower in those who
appeared that ROS increased during standing spent their working time sitting and higher in
work and did not return to prework levels as those who worked standing compared to the gen-
compared to actively walking nurses. Thus, eral population. A questionnaire, clinical investi-
enhanced oxidative stress was demonstrated in gation, and duplex investigation were used for
these standing workers, putting them at risk for CEAP classification.
the development of CVI due to damage of the In the longitudinal Framingham study, in
endothelium, but possibly also for other cardio- contrary, people leading a sedentary life were
vascular and systemic disease (Flore et al. 2004). more at risk for developing varicose veins
The same group demonstrated lower limb venous (Brand et al. 1988).
pressure increases in workers having a standing In a study especially focused on the relation-
position, but also in controls having more mobile ship between working posture and venous dis-
work. The standing operating theater nurses ease, 28 symptom-free male vascular surgeons
showed additionally higher levels of ROS (Flore without a history of venous treatment were com-
et al. 2007). While wearing class 1 elastic stock- pared to 25 male controls leading flexible lives.
ings (18–21 mmHg), venous pressures and ROS Duplex examination showed in 52% of surgeons
did not increase in both groups of workers. reflux in the superficial venous system compared
A representative random sample of 8664 to 32% in the volunteers (Labropoulos et al.
(being the 90% response rate) working individ- 1995). In over 75%, reflux was present in the
uals below 60 years in Denmark was interviewed long saphenous vein. The likelihood of venous
over the telephone (Tüchsen et al. 2005) about reflux was significantly higher in symptom-free
their work and lifestyle. During 12 years, data surgeons.
from the national hospital register were combined In a multicenter cross-sectional study in Poland,
with governmental information about occupation. over 40,000 individuals (16–97 years) were
It appeared that the relative risk for being hospi- assigned the clinical severity of venous disease
talized for varicose veins was 1.8 in employees (C classification according to CEAP) based on
with prolonged standing or walking at work, both medical records. No association of chronic venous
for men and women. Data were adjusted for other disease and spending a long time in the sitting
variables. It was calculated that this risk excess position was documented (Jawien et al. 2003 Phle-
accounted for more than 20% of all cases at the bology). There was a significantly higher propor-
working age. In this study, which was also not tion of men and women having a standing
primarily focused on occupation, individuals were occupation in the group with CVI compared to
not investigated and all outpatient treatments were the group without CVI ( p < 0.001). A lack of
left out of consideration. physical activity was strongly associated with
In a study among 204 hospital employees of all CVI in women (Jawien 2003, Angiology). Leg
varieties in Vienna, chronic venous disease was complaints were reported by 81% of people having
present in 34%, predominantly women (Ziegler varicose veins and by 35% without. No single
et al. 2003). The prevalence was highest among visible sign was reported present in 51%. This
those working in a standing position or in high extraordinary low figure might indicate that doctors
temperatures and humidity. Chronic venous dis- not especially trained in/focused on phlebology
ease was classified according to CEAP criteria. might diagnose less signs of venous disorder.
All kinds of risk factors were registered and taken In a study in Bulgarian general practitioners, in
into account. Regular evaluation and primary pre- rural and urban areas, each selected 50 consecutive
ventive measures were advocated. patients over 18 years and assigned them in the C
486 E. M. de Boer
classification of CEAP, based on a questionnaire and pathological venous refilling time, acquiring
and a clinical investigation. Over 2600 individ- a specificity of over 90% if symptoms were char-
uals were included and 400 subjects of these were acterized as marked or repeatedly.
seen by specialists for re-diagnosis. As a risk From the combination of both studies (Krijnen
factor in this subgroup, 34% of the individuals et al. 1997a, b; Stücker et al. 2010), it can be
indicated a prolonged standing position and 38% concluded that a simple questionnaire provides a
a prolonged sitting position (Zahariev et al. 2009). good tool for the screening for venous disease or
In our department, we performed a study in proneness to venous disease. A questionnaire
387 males having a strictly standing position at should contain questions about age and body
work. We inspected the work environment, took a weight, family history of varices, previous venous
questionnaire, and performed physical examina- interventions, thrombophlebitis, a tired feeling or
tion, Doppler investigation, light reflection heaviness in the legs, the presence of hyper-
rheography (LRR), and optical leg volume mea- pigmentation of the lower legs, and of visible
surements. CVI was present in 29% of the sub- varicose veins. A simple physical inspection of
jects and correlated with age, body weight, and the the standing subjects on signs of venous disease
duration of standing work. Complaints of the legs has additional value. In this way, an alert physi-
were reported by 81% of the individuals with cian can adequately screen for venous disease and
CVI, but also by 63% of the subjects without select individuals for preventive measures and
CVI (Krijnen et al. 1997a). Several screening referral to a specialist, using simple means and
methods were compared and evaluated. It without any equipment.
appeared that a short questionnaire in combina-
tion with physical examination (inspection and
palpation of the legs in a standing subject) had a 6 Preventive Measures
predictive value of 87% (sensitivity 85%, speci-
ficity 88%).The questionnaire consisted of only Early intervention in order to prevent venous
four items: age, body weight, history of treatment hypertension and venous reflux, and thus chronic
for phlebologic disorders, and a tired feeling in the inflammation, is the basis of prevention of or
legs. Age and weight appeared to be the most reducing the progression of chronic venous dis-
important risk factors, age being the dominant ease. Of course, the most ideal situation would be
factor. The value of LRR measurements as a pre- to ban working postures that require long-
dictive tool was low with a predictive value of standing inactivity of the calf muscle pump. By
73% (sensitivity 11%, specificity 95%) (Krijnen the way, what about hobbies? The most easy
et al. 1997a). device for intervention are medical elastic
Also others evaluated screening instruments stockings.
for the screening on venous disease. In a large Evening edema of the legs is a physiologic
car factory, a venous checkup was offered to phenomenon occurring after sitting and standing
9600 employees. In the response group of 1460 caused by extravasation of fluid from venules due
males and 370 females, a questionnaire was com- to increased venous pressure. In healthy individ-
pared with the outcomes of the determination of uals, subjective hinder may occur, but the swell-
venous refilling time by photoplethysmography ing is disappeared after a night’s rest. In case of
(Stücker et al. 2010). Subjects having a patholog- failing of the calf pump function, for instance, due
ical refilling time were considered to be venous to dysfunctioning of the ankle joint (orthopedic,
morbid. The prevalence was 32% of cases, neurologic, immobility) or incompetent venous
increasing with age. The self-administered survey valves, this edema may become irreversible, lead-
referring to venous disease in the parents, throm- ing to chronic inflammation. Using an opto-
bophlebitis, leg swelling, leg heaviness, hyper- electronic device (de Boer et al. 1999) or different
pigmentation, and visible varicosities was able to types of water displacement devices (Partsch et al.
distinguish between persons with physiological 2004) to determine the leg volume in the morning
and after a full working day showed this physio- benefit of higher pressure was not demonstrated.
logical diurnal volume increase. As edema in these studies was not differentiated,
In a study in our department on 387 healthy the overall conclusion must be restricted to sub-
male workers with a standing position at work, we jects with symptoms of mild venous insufficiency.
inspected the work environment, took a question- The cause of occasional pain in the legs and
naire, and performed physical examination, reported edema in apparently healthy individuals
Doppler investigation, and light reflection remains unknown. Medical elastic stockings of
rheography. With opto-electronical volume mea- 15 mmHg effectively relieve the symptoms resem-
surements, the diurnal changes in volume of the bling venous insufficiency, prevent edema, and are
lower legs were monitored several days. A mean well tolerated (Blättler et al. 2008). Stockings pro-
diurnal volume increase in the lower leg +1.6%, viding <10 mmHg were ineffective and those pro-
distributed as a Gaussian curve (Krijnen et al. viding >19 mmHg not well tolerated.
1998), not associated with subjective symptoms In our group of almost 400 male workers with a
or clinically evident edema in 197 healthy standing profession, only the individuals having
workers was confirmed. With the same opto- CVI (n = 114) were provided with class 2 stockings
electronic device, a mean higher diurnal volume (30–32 mmHg), randomly assigned in comparison
increase in individuals having CVI compared to with rubber floor mats and no intervention. These
healthy workers was demonstrated (Krijnen et al. semi-bouncy, uneven mats cause slight changes in
1997b). In male workers with “minor CVI,” this the position of the angle of the foot, resulting in
mean volume increase was +2.6% and in more lower leg muscle contractions, theoretically stimu-
severs CVI +3.6%. As a predictor of CVI, lating the calf muscle pump, especially in case of
isolated volume measurements appeared non- high resilient rubber mats. The group of individuals
discriminative because of overlap with the distri- treated with stockings experienced significant
bution of volume increase in healthy individuals. reduction of subjective complaints and of the devel-
These volume increases in case of CVI were asso- opment of edema, while both other groups
ciated with complaints. remained unchanged (Krijnen et al. 1997a, b, c).
In healthy individuals also other studies could Patients suffering from more severe CVI, with
not demonstrate a correlation with subjective more prominent edema, need adaptation of therapy
complaints and volume increase (de Boer et al. with stronger compression.
1999; Partsch et al. 2004). Both authors showed
an increase in volume of the lower legs in the
course of a working day in healthy individuals.
Intervention with compression stockings is able to
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Part III
Causative Factors
Antiseptics and Disinfectants
35
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
3 Definitions and General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
3.1 Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
3.2 Disinfectants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
4 Skin Side Effects of Antiseptics and Disinfectants . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
4.1 Irritant Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
4.2 Allergic Contact Dermatitis Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
4.3 Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
5 The Repertoire of Skin Side Effects of Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . 496
5.1 Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
5.2 Iodine Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
5.3 Hydrogen Peroxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
5.4 Chlorines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
5.5 Synthetic Biguanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
5.6 Quaternary Ammonium Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
5.7 Hexamidine Diisethionate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
5.8 Hexetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
5.9 Triclosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
5.10 Potassium Permanganate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
5.11 Nitrofurazone (or Nitrofural) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
5.12 Chloroxylenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
5.13 Silver Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
5.14 Octenidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
5.15 Mercuric Compounds (Mercurials) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
5.16 Triphenylmethane Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
6 The Repertoire of Skin Side Effects of Disinfectants . . . . . . . . . . . . . . . . . . . . . . . . 502
6.1 Preliminary Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
6.2 Eau De Javel (Bleach) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
J.-M. Lachapelle (*)

e-mail: Jean-marie.Lachapelle@uclouvain.be

https://doi.org/10.1007/978-3-319-68617-2_36
6.3 Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502

6.4 Quaternary Ammonium Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
Alcohols · Allergic contact dermatitis ·
Antiseptics · Benzalkonium chloride · Antiseptics and disinfectants are largely present in
Chlorhexidine · Disinfectants · our modern environment. Antiseptics are mainly,
Formaldehyde · Glutaraldehyde · Glyoxal · but not exclusively, used in relation with medical
Immunological contact urticaria · Irritation · and nursing activities.
Povidone-iodine · Silver-based dressings Disinfectants have a very broad field of indi-
cations in daily life.
Both antiseptics and disinfectants are not
1 Core Messages
devoid of some side effects which are of great
concern in occupational dermatology.
• Antiseptics and disinfectants (see definitions)
share common skin side effects, i.e., irritation,
allergic contact dermatitis, and eventually
3 Definitions and General
immunological contact urticaria.
Considerations
• Some antiseptics fall into disuse, due to
their lack of efficacy (dyes) or their strong
3.1 Antiseptics
allergic properties (mercurials), except
thiomersal, the indications of which remain
3.1.1 Preliminary Remarks
important.
Antiseptics are – by definition – substances that
• Current antiseptics (i.e., povidone-iodine or
inhibit the growth and development of microor-
chlorhexidine) are of great importance, due
ganisms (without necessarily killing them) in liv-
to the emergence of MRSA and CA-MRSA,
ing tissue. Their indications are varied, such as
leading to a decrease in the use of topical
cleansing of preoperative skin, cleansing of acute
antibiotics to which Gram-positive and
and chronic wounds, and also, on some occasions,
Gram-negative bacteria are more and more
treatment of skin infections.
resistant.
Some qualities are required for a suitable use of
• Silver-based wound and burn dressings may
antiseptics (Table 1).
lead to new cases of allergic contact dermatitis,
The emergence of methicillin-resistant
mainly related to the incorporation of new anti-
Staphylococcus aureus (MRSA) infections
septics, such as octenidine or PHMB.
has been confirmed in health-care centers for
• Disinfectants are a common source of occupa-
tional irritant and/or allergic contact dermatitis.
• Aldehydes are widely used as disinfectants.
Formaldehyde, glutaraldehyde, and glyoxal Table 1 Qualities of antiseptics required for a suitable use
are responsible for many cases of allergic con- Broad spectrum of activity
tact dermatitis. Low irritancy
• Quaternary ammonium compounds, and par- Low allergenicity
ticularly benzalkonium chloride, are disin- Good tolerance
fectants provoking irritant and/or allergic No (or very low) cytotoxicity
contact dermatitis. The interpretation of Fast and long-lasting efficacy
No (or very limited) inhibition by organic matter
patch tests is difficult, and the use of
No propensity to select bacterial resistance
ROATs is advised.
35 Antiseptics and Disinfectants 495
decades. More recently, MRSA infections Table 2 Antiseptics of common use and their in vitro
have been increasingly observed in healthy spectrum of activity against Gram-positive and Gram-
negative bacteria
individuals with no exposure to health-care
centers (community-acquired MRSA or Bacteria
CA-MRSA). Gram- Gram-
Antiseptics positive negative
The management of such infections is the
Ethanol xx xx
responsibility of the medical and paramedical
Povidone-iodine (PVP-I) xxx xxx
staff: nurses, kinesiotherapists, etc. Hydrogen peroxide x x
In order to reduce the prevalence of such infec- Chlorines (ex. Dakin) xxx xx
tions, a very important (sometimes neglected) Chlorhexidine xxx xx
measure is to reduce the use of topical antibiotics Quaternary ammonium xx x
such as bacitracin, mupirocin, fusidic acid, and compounds (ex. cetrimide)
retapamulin. They can be replaced advanta- Hexamidine x x/0
geously by antiseptics that do not induce resis- Hexetidine x x/0
tance. The inevitable corollary is an increased use Silver salts x x
of antiseptics, not only at the hospital but also in Phenols (ex. triclosan) xx xx
different communities and even now at home After Teot et al. 2004
(Upton et al. 2003; Gosbell 2004; Osterlund xxx, very strong; xx, strong; x, weak; 0, no activity
et al. 2006).
The general rules of personal hygiene are
of course of prime importance (Lorette et al. 4 Skin Side Effects of Antiseptics
2009). and Disinfectants
3.1.2 An Overview of Antiseptics Antiseptics and disinfectants share common skin

of Common Use Nowadays side effects. These are of course particularly
Many different antiseptics have been used in important for antiseptics, which are designed to
the past; some of them have been almost aban- be in direct contact with the skin.
doned in most countries, due to either their
high allergenic properties (e.g., mercury com-
pounds) or their limited antiseptic activity 4.1 Irritant Reactions
(e.g., dyes).
A list of antiseptics of common use nowadays, The most common side effect of antiseptics
including their in vitro spectrum of activity and disinfectants is irritation (Lachapelle 2014).
against Gram-positive and Gram-negative bacte- There is a common sentence in the literature
ria, is presented in Table 2. that “an antiseptic or a disinfectant devoid
This list provides indicative information and of any irritant properties does not exist.” It
has to be modulated in vivo, taking into account is roughly true, but irritant reactions
the concentration of each antiseptic and the vehi- depend upon several factors, which are listed in
cle in which it is incorporated. Table 3.
Health workers can be affected when they
do not apply protective measures for the
3.2 Disinfectants hands, when using antiseptics. In those
conditions, irritant hand dermatitis is not a rare
Disinfectants refer, by definition, to substances event.
designed to destroy pathogens in the environment On the other hand, irritant reactions to disin-
(e.g., on working surfaces or operating materials). fectants are a major problem in occupational der-
They are very diversified, with different chemical matology. Preventive measures are of prime
structures. importance in this respect.
Table 3 Factors influencing the irritancy of antiseptics 5.1 Alcohols

Concentration of antiseptic
Vehicle Probably the most widely used antiseptics are the
Application under occlusion or nonocclusion lower aliphatic alcohols, ethanol and isopropanol.
Repeated applications (cumulative effect) The bactericidal activity of the aliphatic alcohols
Site of application on the skin (e.g., folds, scrotum, increases with their molecular weight. Alcohols
vulva, eyelids, mucosae are more susceptible to irritant are considered less irritating than aldehydes.
effects)
The irritancy of an alcohol compound decreases
Excited skin syndrome (in case of active eczematous
reaction) as the molecular size of the compound increases.
Atopic background (mainly, but not exclusively, on Alcohols are known to delipidize and dehydrate
clinically affected areas of the skin) the upper part of the stratum corneum, thereby
impairing the barrier function of the epidermis.
5.1.1 Ethyl Alcohol (Ethanol)

4.2 Allergic Contact Dermatitis Irritant contact dermatitis is the most common skin
Reactions side effect due to ethanol. It results most often in the
cumulative irritant contact type, and, in rare cases,
The allergenic properties of antiseptics and disin- in the acute irritant type (Tupker et al. 1997).
fectants can differ considerably from a substance The current advices (in terms of antisepsis)
to another (Lachapelle 2014). given to the members of the hospital staff, i.e.,
It is generally accepted that they are not very frequent washing of the hands with a 70% ethanol
frequent nowadays with the products on the mar- solution (Mc Donnell and Russell 1999) may lead
ket, contrary to the situation observed in the past to an increase in the number of cumulative irritant
decades. contact dermatitis. It is therefore a problem of
They are reviewed in the following sections occupational dermatology of great actuality.
and discussed individually for each antiseptic Ethanol dermatitis may take the form of an
and/or disinfectant. eczematous eruption.
More rarely, an urticarial reaction has been
noticed at the exposed site (Fregert et al. 1963).
4.3 Other Reactions Undiluted ethanol (95%) causes a short-lasting
sharp stinging sensation in most individuals in
Other types of reactions can occur, such as immu- sensitive skin regions (face and neck, genital
nological contact urticaria and, very rarely, ana- areas). If the skin has slight abrasions, e.g., due
phylactic reactions. to shaving, this phenomenon is experienced by
everybody (Frosch and John (2011).
Allergic contact dermatitis to ethanol has been
5 The Repertoire of Skin Side very rarely reported (Patruno et al. 1994;
Effects of Antiseptics Ophaswongse and Maibach 1994).
Patch testing: 10% aq.
The repertoire of skin side effects of antisep-
tics is broad. In this section, the common (or 5.1.2 Isopropyl Alcohol (Isopropanol)
uncommon) use of antiseptics is not taken into Skin side effects due to isopropanol are less
account. documented but, by extrapolation, are comparable
Referring to patch test procedures, if to reactions to ethanol with a lesser irritant effect.
not specifically mentioned, concentrations For instance, cases of contact urticaria have been
and vehicles are derived from de Groot’s reported (de Groot 2008).
textbook (2008). Patch testing: 10% aq.
5.2 Iodine Compounds eczematous lesions of atopic dermatitis, peri-

lesional irritated skin, encountered in various
5.2.1 Iodoform types of wounds or stomas). Povidone-iodine
Iodoform (triiodomethane) released iodine under is intended to be used on intact skin. It has
the influence of light and temperature. It was been shown that povidone-iodine could be
considered an irritant and a strong contact aller- used for the treatment of a large variety of skin
gen. The first cases were described by Bruno superficial infections (Lachapelle and de Prost
Bloch (1911) under the term “idiosyncrasies,” 2007).
very popular in the first years of the twentieth Cases of allergic contact dermatitis to
century. It is almost beyond doubt that it is not in povidone-iodine have been reported in the liter-
use nowadays. ature. An epidemic of occupational allergic
Patch testing: 5% pet. contact dermatitis of the hands has been reported
in a pig slaughterhouse (Lachapelle 1984).
Slaughterers worked barehanded and suffered
5.2.2 Iodine Tincture from frequent cuttings. They washed their
Iodine tincture (alcoholic solution) has been used hands many times daily with a povidone-iodine
extensively in the past, either at a 5% concentra- solution.
tion for human use (against bacteria and ring- Other cases have been reported (Tosti et al.
worm) and a 10% concentration for veterinary 1990; Erdmann et al. 1999; Pecquet 2003).
use (e.g., ringworm of cattle). In past years, it The results of patch tests to PVP-I (10% pet,
was considered a gold standard for many infec- i.e., 1% free iodine), considered positive in the
tions. It was a strong irritant, and cases of allergic literature, can be in some cases false positives,
contact dermatitis were not infrequent among due to an irritation to PVP-I (under occlusion).
medical personnel, nurses, veterinarians, and In a recent study (Lachapelle 2005), 500 consec-
farmers, mainly due to a total lack of protection utive patients were patch tested with PVP-I.
of the hands. Fourteen had a positive patch test (2.8%).
As iodine tincture is a strong irritant, it is In a second step, the 14 patients were tested
advised to test it by the “open method” as is again, in a different way: The PVP-I aqueous
(Mathelier-Fusade 1994; Lee et al. 2005). solution was applied twice daily (without
occlusion) at the flexor aspect of the forearm
(5 5 cm) during 7 days, i.e., 14 open applica-
5.2.3 Povidone-Iodine tions (ROAT test, after Hannuksela and
(Polyvinylpyrrolidone-Iodine; Salo 1986). At day 7, 2 patients only had a
PVP-Iodine) positive ROAT test, and 12 had a negative
Povidone-iodine has replaced since many years ROAT test. Therefore, it means that only 2 out
other iodine compounds, such as iodoform or of 500 patients were allergic to PVP-I (preva-
iodine tincture. lence: 0.4%).
Povidone-iodine is an iodophor used as a top- Patch testing (de Groot 2008) reflects anyway
ical antiseptic, on a very large scale, throughout the difficulties encountered in practice. Several
the world, under several trade names (the most options had been proposed: 5–10% water;
common is Betadine ®). A 10% povidone-iodine 5–10% pet; 0.5% alcohol. In the abovementioned
solution contains 1% available iodine, but free study (Lachapelle 2005), the problem has been
iodine is at 0.1% concentration. partially solved.
It is well demonstrated nowadays that skin In recent years, some anaphylactic reactions
exposure causes irritant rather than allergic to povidone-iodine have been reported and
contact dermatitis. It is therefore advised not to attributed to polyvinylpyrrolidone, not to iodine.
use povidone-iodine on damaged skin (e.g., They can be considered exceptional, due to the
large use of povidone-iodine in clinical practice the eyelids, rhinitis, dyspnea, and asthma
(Pedrosa et al. 2005; Yoshida et al. 2008; (Dooms-Goossens et al. 1983), in particular, in
Palobart et al. 2009). industrial settings.
Cases of allergic occupational contact derma-
titis are very rare (Lombardi et al. 1989).
5.3 Hydrogen Peroxide Patch testing: 2% aq.
Chloramine-specific IgE serological testing
Hydrogen peroxide has been and is still used as a is highly recommended in immediate-type
topical antiseptic (i.e., for the cleansing of reactions.
wounds) due to its oxidizing properties. The
concentration of the hydrogen peroxide solution
is expressed in volume or percentage: 10 vol- 5.5 Synthetic Biguanides
umes correspond to 3%. Depending upon its
concentration, it is a well-known irritant. Aller- 5.5.1 Chlorhexidine
gic reactions, if any, are exceptional, and, there- Chlorhexidine is a broad-spectrum antimicrobial
fore, its implication in occupational dermatology agent, a synthetic biguanide used as antiseptic
is very limited. and disinfectant, available under different forms
Patch testing: 3% aq. (diacetate, dihydrochloride, and digluconate).
The use of chlorhexidine as an antiseptic has
increased in recent years at the expense of qua-
5.4 Chlorines ternary ammonium compounds. Chlorhexidine
is used clinically for disinfection of the hands
5.4.1 Sodium Hypochlorite (Dakin’s and operation sites, in the treatment of burns
Solution) and scalds, in urology and gynecology, and by
Sodium hypochlorite is an antiseptic which has dentists in the treatment of caries and periodon-
largely been used in the past. It was introduced by titis. It can be considered irritant, when concen-
Dakin, and some papers refer to the historical trations are high, depending on each
aspects of this discovery (Mc Donnell and Sculco individual use.
1997; King 2008). Its current popular name is Although chlorhexidine is used widely, cases
“bleach.” It has a large spectrum activity, and it of allergic contact dermatitis are rare, some of
is used as an antiseptic or disinfectant. Hypochlo- them being occupationally related (Muston et al.
rites are essentially irritants and, in occupational 1977; Rudzki et al. 1989). Differential diagnosis
life, have caused hand, diffuse, or periulcerous with irritant reactions is important, in particular,
dermatitis. Cases of allergic contact dermatitis to when chlorhexidine is used under occlusion.
sodium hypochlorite have been rarely reported In recent years, much attention has been paid to
(Osmundsen 1978). Eau de Javel is exclusively immediate IgE-mediated skin reactions, such as
used as a disinfectant (see Sect. 6.2). urticaria, angioedema, and anaphylaxis. Asthma
Patch testing: 0.5% aq. is another side effect. Many cases have been
reported in the literature (Beaudouin et al. 2004;
5.4.2 Chloramine T (Chloramine, Krautheim et al. 2004; Sharma and Chopra 2009).
Tosylchloramide Sodium) Furthermore, chlorhexidine is considered now-
Chloramine T (paratoluene-sulfonyl-sodium adays a new occupational hazard. Urticaria,
chloramide) is a potent antiseptic. angioedema, and anaphylaxis have been reported
It has been described as an occupational hazard in health-care workers (Nagendran et al. 2009).
for pharmaceutical workers, nurses, butchers, Increased awareness and easier access to
cleaners, and brewers (Key 1961). Immediate chlorhexidine-specific IgE serological testing
reactions are the most frequent side effects: con- should facilitate early diagnosis of affected
tact urticaria, recurrent attacks of edema around health-care workers, avoiding appropriate
measures to be investigated, thus reducing the risk 5.6 Quaternary Ammonium

of potentially severe allergic reactions in the Compounds
future.
Patch testing: 0.5% aq. Quaternary ammonium compounds are a vast
Chlorhexidine-specific IgE serological testing family of cationic detergents and are mainly
is highly recommended. used as disinfectants (and therefore described in
Sect. 6.4).
5.5.2 Polyhexanide Their use as antiseptics is rather limited, e.g.,
(Polyhexamethylene Biguanide; topical antiseptics for burns, ointments, and
PHMB) mouth- and handwashes.
Polyhexanide (polyhexamethylene biguanide or
PHMB) is available as a solution, a gel, and in
certain dressings. It belongs to the family of cat- 5.7 Hexamidine Diisethionate
ionic biguanides. The range of antimicrobial
dressings offers dressings containing PHMB This antiseptic has been (and it is still) used in
with a low concentration of 0.2%. For instance, some countries, such as France or Belgium. It is
Suprasorb ® + PHMB is a swab of large cellulose well tolerated in most cases, but its antiseptic
fibers arranged in a broad woven matrix impreg- spectrum (Table 2) is considered nowadays lim-
nated with 0.3% PHMB. A chemical composition ited, as compared to other antiseptics, such as
close to that of PHMB is found in Protosan ® povidone-iodine. It is not irritant, but well-
which is available as a gel or a solution. It contains documented cases of allergic contact dermatitis
polyhexanide at a concentration of 0.1%, used as a have been reported, usually severe in their clin-
preservative. It is used particularly in the treat- ical expression (Revuz et al. 1984; Dooms-
ment of venous leg ulcers and/or pressure Goossens et al. 1989). Some characteristics
wounds. It is claimed that, in orthopedic surgery, deserve attention: the long duration of the
polyhexanide promotes apoptosis of human lesions, after disuse of the allergen; the histo-
chondrocytes in vitro, which may indicate the pathological features, spongiosis is rare, and
use of polyhexanide in septic joint surgery. leukocytoclastic vasculitis is not uncommon
As far as skin side effects are concerned, poly- (Arthus’ phenomenon).
hexanide is considered an uncommon contact Patch testing: 0.15% aq.
allergen in terms of irritant and/or allergic contact
dermatitis (Schnuch et al. 2007). Nevertheless, in
the future, health-care personnel should be aware 5.8 Hexetidine
of the potential risk of occupational disease. In
other terms, when a new chemical to be applied on Its use is very limited nowadays (mainly as a
the skin is introduced, it usually takes some time collutory). Exceptional cases of allergic contact
to evaluate its implication in events of irritation dermatitis have been reported (Merk et al. 1982).
and allergenicity. Cases of severe anaphylaxis Many years ago (but not now), it has also been
have been reported (Olivieri et al. 1998; Kautz used as a fungicide.
et al. 2010). This is not surprising, since poly- Patch testing: 0.1 aq.
hexanide is a polymer of chlorhexidine. When
this particular event occurs, the tool of investiga-
tion for confirming the diagnosis is prick testing, 5.9 Triclosan
monitored with great caution to avoid systemic
symptoms (see Sect. 76). But, on the whole, poly- Triclosan (Irgasan DP300 ®) is a lipophilic
hexanide may be considered a safe and effective chlorophenol antiseptic agent, used mainly in
biocide. soap bars, deodorants, and antiperspirants. It has
Patch testing: 2.5 and/or 5% aq. been shown (Lachapelle and Tennstedt 1979) that
the allergenic properties of triclosan were very 5.13 Silver Compounds

low, using the maximization test in guinea pigs
and in humans, but this test is considered nowa- 5.13.1 Silver Nitrate
days of questionable value in predicting the real Silver nitrate has been used extensively in der-
allergenicity of chemicals in clinical settings. matology in the past but very much less
Indeed, the prevalence of positive patch tests to nowadays.
triclosan was 0.7% (Schena et al. 2008). Allergic It was kept in an amber bottle because on
contact dermatitis from triclosan used in anti- exposure to air and light, it decomposes, forming
bacterial handwashes has been reported (Wong small amounts of nitric acid, silver nitrite, and
and Beck 2001) and is a potential occupational colloidal silver, which liberate silver ions. The
problem in nursing staff. ionized silver is considered allergenic. Some
Patch testing: 2% pet. cases of allergic contact dermatitis have been
reported (Gaul and Underwood 1948), some of
them being of occupational origin. It has also been
5.10 Potassium Permanganate mentioned that the prolonged use of topical silver
nitrate can lead to systemic argyria.
Diluted solutions (1/10,000) have been used as Recently, a new formulation of silver nitrate
wet dressings on weeping dermatitis or leg ulcers. has been proposed, based upon the “nanoparticles
This use has declined considerably nowadays. technology.” It is developed as a gel, without
A skin side effect was irritation (van der Valk and preliminary side effects (Jain et al. 2009).
Maibach 1996), but no case of occupational der- Patch testing: 2% aq.
matitis has been described.
5.13.2 Silver Sulfadiazine
Silver sulfadiazine (often under the trade name
5.11 Nitrofurazone (or Nitrofural) Flammazine ®) has been (and is still) extensively
used in the treatment of burns and, more recently,
Nitrofurazone was once a popular antiseptic of epidermolysis bullosa. A complete review of
remedy for the treatment of burns and stasis the literature indicates that allergic contact derma-
ulcers. titis to silver sulfadiazine is quite uncommon, but
So many instances of allergic contact dermati- this has been potentially underestimated (Degreef
tis to this remedy occurred that its use has largely and Dooms-Goossens 1985; Fuller 2009).
been abandoned. In particular, as nitrofurazone Argyria may – exceptionally – be consecutive to
was also used as an antibacterial agent in animal its application on large areas of ulcerated skin, as
feeds, occupational dermatitis was reported in observed in burns or epidermolysis bullosa
cattle breeders or farmers (Vilaplana et al. 1990; (Browning and Levy 2008).
Condé-Salazar et al. 1995). Patch testing: 5% pet.
Patch testing: 1% pet.
5.13.3 Silver-Based Wound and Burn
Dressings
5.12 Chloroxylenol Silver dressings, introduced a few years ago, vary
widely according to their matrix, since almost all
Chloroxylenol is widely used as a topical antisep- existing modern dressings (alginates, foams,
tic and/or disinfectant with low irritant potential. It hydrofibers, interfaces, etc.) are now combined
has been a substitute for hexachlorophene in a with silver. The shapes and ions (salt, ions
large number of products. Sensitization has been exchanger), metallic or organic, as well as the con-
reported, but it is very rare (Myatt and Beck 1985; centrations of silver vary greatly from one dressing
Ranchoff et al. 1986). to another. No standard has been applied in this
Patch testing: 1% pet. field, and it is not only the quantity present in the
dressing that is important but, above all, the quan- dermatitis among members of the medical staff.
tity of silver that is left behind by the dressing in the Cases of “baboon syndrome” have been described
wound. Silver sulfadiazine has been more recently in this occurrence (Lerch and Bircher 2004; Wen
introduced on the market in some dressings. et al. 2007).
The efficacy of silver dressings, compared to Patch testing: 0.5% pet.
non-silver dressings, has not been assessed con-
vincingly (Chaby et al. 2007; Trial et al. 2010). 5.15.2 Inorganic Mercuric Compounds
No occupational allergic and/or irritant contact Mercuric salts have been broadly used in the past
dermatitis to silver dressings has been described as antiseptics. Ammoniated mercury, yellow mer-
so far. curic oxide, and cinnabar were considered rightly
efficacious antiseptics, before the advent of new
molecules. But they were also potent and frequent
5.14 Octenidine allergens, occupational and nonoccupational.
Therefore, their disuse was programmed inexora-
Octenidine is a cationic antibacterial of the bly. A page of dermato-allergology has been
bis-pyramidine class, present in Octenilin ® Solu- turned, for the sake of everyone. Nevertheless, it
tion and Octenilin ® Gel, at a concentration of is always possible that isolated cases of allergic
0.05%. It is also available at a higher concentra- contact dermatitis occur and vigilance is needed.
tion (0.10%) as Octenisept ®. The areas of appli- Patch testing: Refer to de Groot’s recommen-
cation are the moistening of chronic wounds and dations (2008). Note that when patch testing with
burns, the facilitation of the mechanical debride- mercuric compounds’ solutions (aq.), there is an
ment of wounds and burns, and the prevention of incompatibility between aluminum Finn Cham-
bacterial infections. bers ®, which are corroded by the mercurials.
The efficacy of octenidine in methicillin- The use of plastic chambers is therefore compul-
resistant Staphylococcus aureus decolonization sory (Lachapelle and Douka 1985).
seems evident (Krishna and Gibb 2010).
Skin side effects include irritation and allergic 5.15.3 Mercuric Organic Compounds
contact dermatitis (Calow et al. 2009). Health- Here again, organic mercuric compounds were once
care personnel have to be aware nowadays of popular as skin antiseptics (Rietschel and Fowler
this potential hazard, if preventive measures are 2008), but they also carried the risk of sensitization,
not taken when treating wounds and burns. and they have fallen into disuse (except thiomersal,
Patch testing: 0.1% aq. see later). These compounds likely still appear in
many over-the-counter products.
Merbromin (or mercurochrome) is of course
5.15 Mercuric Compounds (Mercurials) the oldest known organic mercurial antiseptic.
Patch testing: 2% aq. or pet.
Mercuric compounds have been implicated in the Thiomersal (thimerosal, Merthiolate) is a very
occurrence of innumerable cases of allergic con- particular mercuric organic compound. Its use is
tact dermatitis, already confirmed by patch testing still important, when compared to other mercu-
in the last years of the nineteenth century. Cross- rials. It is used as a disinfectant and a preservative
reactions between mercury and inorganic and but less commonly than previously, especially in
organic mercurials have always been advocated, contact lens fluids, eye drops, and vaccines. It is
optional or not. prepared by reacting ethylmercuric chloride with
thiosalicylic acid. The ethylmercuric moiety is the
5.15.1 Mercury major allergenic determinant, sometimes associ-
Sensitization to mercury itself is mainly reported ated with mercury sensitivity. Thiomersal is an
when breaking a thermometer and is therefore indicator of photosensitivity to piroxicam,
responsible for occupational allergic contact through its thiosalicylic moiety.
Many publications have been dedicated to 6.2 Eau De Javel (Bleach)

thiomersal and have been broadly reported in
most textbooks of environmental dermatology. “Eau de Javel” (liquid bleach) is a disinfectant
Patch testing: thiomersal 0.1% pet; thiosalicylic largely used in some countries (France, Belgium,
acid 0.1% alcohol. Spain, Italy, Maghreb countries). It has a yellow-
ish color, due to the addition of sodium dichro-
mate used not as a preservative but as a dye. Many
5.16 Triphenylmethane Dyes cases of allergic contact dermatitis to chromates
have been reported in the past (Lachapelle et al.
The triphenylmethane dyes, such as gentian vio- 1980). Chromates have been removed from the
let, methyl violet, rosaniline, malachite green, formulation in France in 1978, and this was a
brilliant green, chrysoidine, and eosine, have good example of prevention in the field of contact
been used extensively in dermatological practice; dermato-allergology.
their use has declined due to three factors: Occupational allergic contact dermatitis to
“Eau de Javel” still occurs in other countries.
A rather limited spectrum activity as antimicrobial Irritant contact dermatitis of the hands is
and/or antifungal agents another skin side effect, depending upon the con-
The limitations of the “coloring effect” in terms of centration used and the lack of preventive
antiseptic effectiveness measures.
The launching of new antiseptics, more effica- Patch testing: Sodium hypochlorite 0.5% aq.;
cious for the treatment of wounds and burns potassium dichromate 0.5% pet.
In retrospect, the dyes were considered mild

irritants and weak allergens (Rietschel and Fowler 6.3 Aldehydes
2008).
Eosine deserves special attention: it has been Aldehydes represent an important class of disin-
used extensively in the past and created some fectants, broadly used throughout the world for
allergic reactions. Dermato-allergologists were various purposes. They are well known for their
confronted with patch testing problems. As eosine irritant and/or allergenic properties and are of
did not penetrate the skin easily; late reactions did daily concern in occupational and/or environmen-
occur and had to be taken into account. tal dermatology.
Patch testing: For most dyes, 2% aq.; eosine,
50% pet. 6.3.1 Formaldehyde
Innumerable publications have been dedicated to
formaldehyde, the undisputed “leader” of alde-
6 The Repertoire of Skin Side hydes. Its use is so ubiquitous (as well as its skin
Effects of Disinfectants side effects) that it has always been present in the
baseline series of patch tests (Lachapelle and
6.1 Preliminary Remarks Maibach 2012).
Formaldehyde is an excellent disinfectant.
Many chemicals that have disinfectant properties Members of the medical and allied professions
have been quoted in the former sections, due to the may be exposed to formaldehyde when it is used
fact that they have also been used as antiseptics, for sterilizing purposes, as a disinfectant, or a
either in the past or at present. fixing solution for tissues. Cleaners, painters, met-
Such examples include alcohols, chlorines alworkers, and to a less extent photographers
such as sodium hypochlorite and chloramine T, (color developers) and carbonless copy paper
hexamidine, hexetidine, etc. users are also at risk.
Depending upon individual situations, many 6.3.3 Glyoxal

skin side effects have been reported. Glyoxal (ethanedial) is a dialdehyde used in med-
ical and dental offices as a disinfectant for surfaces
First of all, formaldehyde is a potent primary and instruments. It is considered a contact allergen,
irritant. Irritant contact dermatitis is therefore and cross-reactions to formaldehyde and glutaral-
common. In fact, a strong solution of formaldehyde have been reported. Occupational hand
dehyde (formalin) can coagulate the proteins of dermatitis among hospital workers is not uncom-
the skin and produce necrosis and scarring. mon (Uter et al. 2001; Aalto-Korte et al. 2005).
Prolonged contact may cause extreme dryness Patch testing: 2% aq.
of the skin with fissuring. The nails can
become discolored, soft, or brittle. Paronychia
and even suppuration of the matrix may follow 6.4 Quaternary Ammonium
exposure to the chemical (Rietschel and Fow- Compounds
ler 2008).
Allergic contact dermatitis to formaldehyde is very These compounds are the active ingredient in dis-
common. When an allergic sensitization solu- infectants and sanitizers for homes, farms, offices,
tion does occur, the dermatitis may become and public transportation vehicles. They are also
widespread. In sensitive individuals, a minute used as algaecides and slimicides for swimming
amount of formaldehyde on thermometers, pools, industrial water reservoirs, and farm ponds.
instruments, slides, and biopsy containers is They are included in the last rinse in laundering by
also sufficient to produce allergic contact der- some hospitals, diaper services, and various insti-
matitis (Flyvholm and Menné 1992). tutions (Rietschel and Fowler 2008).
Formaldehyde can induce, in rare cases, immuno- Quaternary ammonium compounds are irritant,
logical contact urticaria (Tupasela and for instance, even as dilute as 0.1% under
Kanerva 1997). occlusion, and their allergenic properties do
exist, are not so frequent, and are masqueraded
Patch testing: 1% aq., but it is suggested in by their strong irritancy. All of them have
recent publications that a 2% concentration is been incriminated in the occurrence of occupa-
more appropriate (Hauksson et al. 2010). tional dermatitis (irritant and/or allergic) in people
at risk.
6.3.2 Glutaraldehyde
Glutaraldehyde (1,5 pentanedial) is available 6.4.1 Benzalkonium Chloride
most frequently as a 50% aqueous solution. It is Benzalkonium chloride is the most widely used qua-
used in a 2% water solution as a cold disinfectant, ternary ammonium compound. Its irritation potential
especially in hospital–medical work for sterilizing is mentioned extensively in all textbooks of environ-
instruments, bronchoscopes, cystoscopes, anes- mental dermatology. Allergic contact dermatitis of
thetic equipment, and in renal dialysis units for the hands has been reported in many occupations,
sterilizing forceps. Health-care workers are eight particularly in medical personnel from exposure to
times more likely to be allergic to glutaraldehyde instruments soaked in it. It has also provoked air-
than non-health-care workers (Rietschel and Fow- borne reactions (Corazza and Virgili 1993).
ler 2008). Patch testing with benzalkonium chloride is a
Allergic contact dermatitis to glutaraldehyde is difficult issue (0.1% aq.) (Basketter et al. 2004).
considered a common occupational skin disease, When positive, skin reactions are often weak or
as emphasized by recent publications (Takigawa questionable. As emphasized by the North Amer-
and Endo 2006; Nayebzadeh 2007; Maier et al. ican Contact Dermatitis Group, caution should be
2009). used when interpreting results, and a ROAT test is
Patch testing: 0.2–0.3% pet. very often advisable (Warshaw et al. 2010).
Patch testing: 0.1% aq. ROAT test is advised. Erdmann S, Herti M, Merk HF (1999) Allergic contact
dermatitis from povidone iodine. Contact Dermatitis
40:331–332
6.4.2 Others Flyvholm MA, Menné T (1992) Allergic contact dermatitis
Other quaternary ammonium compounds have from formaldehyde. A case study focussing on sources
been incriminated in the occurrence of occupa- of formaldehyde exposure. Contact Dermatitis
tional or nonoccupational contact dermatitis, 27:27–36
Fregert S, Groth O, Hjorth N et al (1963) Dermatitis from
either irritant or allergenic. Their profile of skin alcohol. J Allergy 34:904
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Isothiazolinones
36
Jakob Ferløv Schwensen and Jeanne Duus Johansen
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
3 Contact Allergy to Isothiazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
3.1 Contact Allergy to Methylchloroisothiazolinone/Methylisothiazolinone . . . . . . . . 509
3.2 Contact Allergy to Methylisothiazolinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
3.3 Contact Allergy to Benzisothiazolinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
3.4 Contact Allergy to Octylisothiazolinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
4 Isothiazolinones in Cosmetic Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
4.1 Methylisothiazolinone and Methylchloroisothiazolinone/
Methylisothiazolinone in Cosmetic Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
5 Isothiazolinones in Products for Occupational Use . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
5.1 Methylchloroisothiazolinone/Methylisothiazolinone and
Methylisothiazolinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
5.2 Benzisothiazolinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
5.3 Octylisothiazolinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
6 Cross-Reactivity Between Isothiazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
Abstract The use of the isothiazolinone methylchloroi-

Isothiazolinones are used in cosmetic and sothiazolinone (MCI) in 3:1 combination with
chemical substances for occupational use and methylisothiazolinone (MI) (MCI/MI) resulted
possess bacteriostatic and fungiostatic activity. in the 1980s in high prevalence rates of contact
Isothiazolinones are potent contact allergens. allergy to MCI/MI across the EU. This rapid
increase in new cases of MCI/MI contact
allergy instigated a restriction of MCI/MI to
J. F. Schwensen (*) · J. D. Johansen
15 ppm that subsequently resulted in decreas-
National Allergy Research Centre, Department of
Dermatology and Allergy, Herlev-Gentofte University ing prevalence rates of contact allergy to
Hospital, Hellerup, Denmark MCI/MI in the EU. Later, around the millen-
e-mail: jakobschwensen@gmail.com; nium, MI was introduced as a single
jeanne.duus.johansen@regionh.dk

https://doi.org/10.1007/978-3-319-68617-2_216
508 J. F. Schwensen and J. D. Johansen
preservative in chemical substances for occu- in new cases of contact allergy to MI that has
pational use, and in 2005 and onward, MI was manifested as allergic contact dermatitis, pri-
introduced in cosmetic products as a single marily affecting the face and hands.
preservative. The use of MI has resulted in an • The European Commission (EC) has restricted
unprecedented steep increase in new cases of the use of MI to 15 ppm in rinse-off cosmetic
contact allergy to MI on the European conti- products as of 2018, and as of February 2017
nent, the US, Asia, and Australia. In many MI has been totally banned in leave-on cos-
countries, the prevalence rates of MI exceed metic products.
7–10%. These two epidemics have mainly • MI and MCI/MI are important allergens in the
been driven by use of MCI/MI and MI in work environment. Occupations at special risk
cosmetic products, but both are as well impor- are painters, blacksmiths, machine operators,
tant allergens in the work environment. Occu- cosmetologists, and tile setters.
pations at special risk for MCI/MI or MI • Occupational exposures associated with MI
sensitization are painters, blacksmiths, machine contact allergy are mostly cosmetic products
operators, cosmetologists, and tile setters. such as moisturizers, liquid soaps, and wet
Other isothiazolinones, e.g., benzisothia- wipes used at the workplace followed by
zolinone (BIT) and octylisothiazolione (OIT), cleansing agents, water-based paints, cutting
are only used in industrial products and oils, and glues and lacquers.
non-cosmetic consumer products such as • Other isothiazolinones (e.g., BIT and OIT) are
paints and leather products and also pose a not permitted in cosmetic products but may be
problem in special occupations. used in industrial products. The most frequent
products are paints, cutting oils, and leather
Keywords products.
Methylisothiazolinone · Benzisothiazolinone · • MI, along with other isothiazolinones, is added
Octylisothiazolinone · Risk occupations to water-based paint in relatively high concen-
trations, and MI may evaporate from newly
painted rooms that may result in flare-ups of
1 Core Message airborne allergic contact dermatitis.
• Isothiazolinones have been used since the

1970s and are preservatives that possess bac- 2 Introduction
teriostatic and fungiostatic activity.
• The extensive use of a mixture of iso- Isothiazolinones are a group of chemicals with
thiazolinones (methylchloroisothiazolinone in antimicrobial effect, which since the 1970s has
fixed 3:1 combination with methylisothia- been used as preservatives in cosmetics, in other
zolinone; MCI/MI; Kathon™ CG) in cosmetic consumer products, and in chemical products for
products resulted in the 1980s in a rapid occupational use (de Groot and Herxheimer 1989;
increase of new cases of contact allergy to Flyvholm 2005).
this mixture. Later the use and maximum con- Although isothiazolinones are effective antimi-
centration of MCI/MI was restricted due to its crobial agents, they also have an inherent risk to
tendency to cause contact allergy. cause sensitization (Bruze et al. 1987). Thus, each
• The use of MI as a stand-alone preservative time an isothiazolinone has been permitted in cos-
was introduced in industrial products around metic products, the risk of becoming sensitized to
the millennium and soon thereafter in cosmetic isothiazolinones has increased manifold (de Groot
products. and Herxheimer 1989; Gonçalo and Goossens
• The use of MI, primarily in cosmetic products, 2013; Bruze et al. 2015). In spite of this insight,
has resulted in an unprecedented rapid increase the use of isothiazolinones has increased in the
36 Isothiazolinones 509
domestic and occupational environment (Slovak Denmark (0.9% and 1.3%) and the UK (0.9%)
1980; Roberts et al. 1981; de Groot and (Hjorth and Roed-Petersen 1986; Menné and
Herxheimer 1989; Gonçalo and Goossens 2013; Hjorth 1988; Shuster and Spiro 1987). The use
Bruze et al. 2015; Friis et al. 2014), and major of MCI/MI in cosmetic products accounted for the
problems of contact allergy have been seen majority of the cases (de Groot and Herxheimer
(Schwensen et al. 2014, 2017a). 1989). Accordingly the EC acted upon request
and managed to restrict and lower the maximum
permitted concentration of MCI/MI in cosmetic
3 Contact Allergy products. This subsequently lowered the preva-
to Isothiazolinones lence rates of contact allergy to MCI/MI in
European countries, however still remaining as
A number of isothiazolinones exist which all may significant and frequent allergens (Schnuch et al.
be used in products for occupational use, while 2011; Wilkinson et al. 2002).
only two have been permitted in cosmetic prod-
ucts: the mixture of methylchloroisothiazolinone
with methylisothiazolinone (MCI/MI) in 3:1, also 3.2 Contact Allergy
often named by its most common tradename to Methylisothiazolinone
Kathon™.
3.2.1 Introduction
of Methylisothiazolinone
3.1 Contact Allergy to The patent of Kathon™ preservative (MCI/MI)
Methylchloroisothiazolinone/ expired around the millennium and shortly after
Methylisothiazolinone MI was introduced as a stand-alone preservative
for use in chemical products for occupational
Since the 1980s, the use of isothiazolinones has use. Subsequently, the cosmetic industry sub-
been recognized as contact allergens of special mitted experimental data to support the use of
interests (de Groot and Herxheimer 1989). MI in cosmetic products, as MI was believed to
MCI/MI (CAS no. 55965-84-9) was in the be an efficient and safe preservative. In 2003,
1980s introduced by Rohm and Haas for use in the Scientific Committee on Cosmetic Products
cosmetics to avoid microbial contamination. The and Non-Food Products (a predecessor of the
initial recommended use concentration of Scientific Committee on Consumer Safety;
Kathon™ CG (“cosmetic grade”) was 3–15 ppm SCCS) concluded that the submitted risk assess-
(Cronin et al. 1988). MCI/MI was additionally ment data of MI was inadequate regarding
used in a wide range of chemical substances for genotoxicity/mutagenicity and should be
occupational use in recommended concentrations reworked and resubmitted, while the risk
up to 25 ppm (Cronin et al. 1988) but with no assessment of the sensitizing potential was
upper concentration limit. deemed adequate (SCCNFP/0625/02 opinion)
During the 1980s, several retrospective obser- (SCCNFP 2003). A British study from 2003
vational studies of consecutive patch-tested did however at that point show that MI pos-
patients showed that the prevalence of contact sessed strong sensitizing properties in the local
allergy to Kathon™ increased alarmingly to lymph node assay – the data was however not
8.4% in Italy, 5.7% and 3.4% in Germany, 4.2% included in the second opinion, SCCNFP/0805/
in Sweden, 3.6% in the USA, and 2.9% in Finland 04 (SCNNFP 2004; Basketter et al. 2003). Later
(Hannuksela 1987; Frosch and Schulze-Dirks the EC included MI in Annex V (list of permit-
1987; Fuchs 1986; Tosti 1988; Bjorkner et al. ted preservatives), and MI was thereafter to be
1986; Fransway 1988). Lower prevalence ratios used at a maximum concentration of 100 ppm in
were throughout the 1980s, however, observed in cosmetic products.
3.2.2 Contact Allergy British Society for Cutaneous Allergy (BSCA)

to Methylisothiazolinone: The 2014). In some centers the patch test concentra-
Epidemic tion of MI was raised from 0.05% aq. to the
Already in 2004 and 2006, studies showed occu- recommended 0.2% aq. during the test period
pational cases of contact allergy to MI following (Johnston and Contributing Members of the Brit-
contact with water-based paint, wall-covering ish Society for Cutaneous Allergy (BSCA) 2014;
glue, and a biocide (Isaksson et al. 2004; Thyssen Johansen et al. 2015). Recent British studies have
et al. 2006), while it was not until 2010 that the shown that the incidence rate of MI contact
first cases of MI contact allergy ascribed exposure allergy has decreased from 11.7% at its peak in
to MI in cosmetic products, primarily wet wipes, 2013 to 6.7% in the second half of 2015 (Venables
were published (García-Gavín et al. 2010). et al. 2016;Urwin et al. 2017), following regula-
Shortly thereafter, a Danish study showed an tory intervention.
increasing prevalence rate of MI contact allergy Two large epidemiological studies showed that
(1.5%), which partly was ascribed exposure to MI contact allergy was associated with hand der-
cosmetic products but also occupational cases in matitis, facial dermatitis, and occupational contact
painters (Lundov et al. 2010). The same trend was dermatitis (Uter et al. 2013; Schwensen et al.
later observed in Germany, where high prevalence 2014). Painters, machine operators, and beauti-
rates of MI contact allergy were linked to an cians were shown to be at special risk of develop-
increasing rate of MCI/MI contact allergy (Geier ing MI contact allergy (Uter et al. 2013;
et al. 2012). Schwensen et al. 2014). The first European mul-
Since then, the prevalence rates of MI contact ticenter prospective observational study of MI
allergy in the EU has unprecedentedly gained contact allergy showed a relatively high preva-
additional pace with prevalence rates increasing lence rate of MI contact allergy of 6.0% in 3434
to >7% in many countries (Aerts et al. 2014; patch-tested patients in 11 departments
Lammintausta et al. 2014; Hosteing et al. 2014; (Schwensen et al. 2017a). Here a relevant contact
Johnston and Contributing Members of the British allergy was found in 72.7% (149/205) of the cases
Society for Cutaneous Allergy (BSCA) 2014; as in accordance with other (retrospective) studies
Madsen et al. 2014; Gameiro et al. 2014; Uter (Schwensen et al. 2015c, 2017a; Uter et al. 2013;
et al. 2013; Schwensen et al. 2015c). Aerts et al. 2014; Johnston and Contributing
In 2014, a Finnish retrospective observational Members of the British Society for Cutaneous
study of data from a center with special interests in Allergy (BSCA) 2014), among these several
occupational cases observed an alarmingly high occupational cases.
prevalence rate >10% (Lammintausta et al. A large retrospective observational study of
2014). A Belgian retrospective observational 31,689 European patients, patch tested in 46 -
study of patch-tested patients showed that the European departments, showed in 2017 that the
prevalence rate of MI contact allergy had prevalence rate of MI in 2013/2014 was >7% for
increased from 3.1% in 2010 to 7.2% in 2013 3 different patch test doses, 200 ppm, 500 ppm,
(Aerts et al. 2014). A few Scandinavian studies and the recommended 2000 ppm (0.2%), all in
did also show prevalence rates of MI contact aq. (Uter et al. 2017).
allergy that has increased with an alarmingly In the USA, the same trend is observed – a
pace to >5% in 2013/2014 (Schwensen et al. recent multicenter study found that the prevalence
2015c; Lundov et al. 2013; Isaksson et al. 2017). of MI contact allergy in 2013/2014 was an alarm-
The same had been observed in the British Isles, ingly 10.7% (Zirwas et al. 2017). Also in Canada,
where a study collecting data from 11 centers a single center retrospectively found increasing
showed an increasing trend of MI contact allergy prevalence rates of MI contact allergy from 6.6%
in consecutive patch-tested patients from 1.7% in in 2013 to 12.9% in 2015 and of MCI/MI contact
2010, 2.9% in 2011, 7.1% in 2012 to 11.1% in allergy from 0.0% in 2008 to 9.4% in 2015
2013 (Johnston and Contributing Members of the (Wilford and de Gannes 2017).
3.3 Contact Allergy an exposure to OIT was found (Aalto-Korte and

to Benzisothiazolinone Suuronen 2017). In an aimed patch-tested group
of patients with MI contact allergy (n = 44) due to
Contact allergy to BIT was recognized as early as airborne exposure to water-based paint, a total of
in the late 1970s (Slovak 1980; Roberts et al. 42.8% (9/21) also reacted to a patch test dose of
1981). 0.1% OIT (Amsler et al. 2017).
A Dutch study found in 1992 that 1.8% of
556 patients who were consecutively patch tested
with BIT had contact allergy to BIT (Damstra 4 Isothiazolinones in Cosmetic
et al. 1992). Later in 2015, a German study Products
found that 1.6% (141/8728) of patients who
were consecutively patch tested with the metal 4.1 Methylisothiazolinone and
working fluid series had contact allergy to BIT Methylchloroisothiazolinone/
(Geier et al. 2015). A Danish observational study Methylisothiazolinone
found that contact allergy to BIT was seen in 0.4% in Cosmetic Products
of 3636 patients consecutively patch tested with
BIT (Schwensen et al. 2014). However, it is In 2005 MI, as a stand-alone preservative, was
important to emphasize that since BIT is not permitted for use in cosmetic products in a max-
included in the European baseline series and imum concentration of 100 ppm. However, it was
other standardized (baseline) series across the not until 2010 that initial cases of contact allergy
world, the aforementioned studies may be based to MI were identified due to exposure to wet wipes
on targeted patch testing (Johansen et al. 2015). (García-Gavín et al. 2010). Later that year,
A few occupational groups may be at special another study found that 32% of the patients
risk for developing contact allergy to BIT: pain- with contact allergy to MI had been exposed to
ters and woodworkers (Mose et al. 2012; cosmetic products containing MI (Lundov et al.
Schwensen et al. 2014; Meding et al. 1996; 2010). A German study concluded in 2013 that
Fischer et al. 1995; Sanz-Gallén et al. 1992). the increasing prevalence rate of contact allergy to
MI (from 1.9% in 2009, 3.4% in 2010, to 4.4% in
2011) allegedly was due to the introduction of MI
3.4 Contact Allergy in cosmetic products (Geier et al. 2012). Other
to Octylisothiazolinone studies showed additionally increasing prevalence
rates of MI contact allergy, primarily due to expo-
Octylisothiazolinone (OIT) is only included in sure to cosmetic products including wet wipes
specialized patch test series, for example, patch accounting for 60–80% of all cases (Aerts et al.
test series with preservatives (Johansen et al. 2014; Uter et al. 2013; Lundov et al. 2013;
2015). Thus published studies are mainly case Hosteing et al. 2014; Schwensen et al. 2017a).
studies. However, a Danish study of 648 patients Leave-on cosmetic products seem to pose a spe-
that was aimed patch tested with OIT showed that cial risk in the MI sensitization (Aerts et al. 2014;
3.1% had a positive patch test reaction to OIT Uter et al. 2013; García-Gavín et al. 2010; Lundov
(Mose et al. 2013). Further a German study et al. 2013; Schnuch et al. 2011; Schwensen
which investigated potential cross-reactivity 2017). However, a repeated open-application test
between different isothiazolinones found that (ROAT study) showed that patients with MI con-
1.0% of patients had a positive patch test reaction tact allergy experienced flare-up episodes of aller-
to OIT in German patients under suspicion of gic contact dermatitis when they were exposed to
preservative contact allergy (Geier et al. 2015). 50–100 ppm MI under standardized conditions
A Finnish study found recently that 2.9% of (Yazar et al. 2015). This is in accordance with a
patients patch tested with OIT had a positive recent Italian study that further suggests that
patch test reaction, but only in 26% of the cases patients with MI contact allergy had flare-up
episodes of allergic contact dermatitis when they glues and paints had contact allergy to MCI/MI
were in skin contact with rinse-off cosmetic prod- (Gruvberger et al. 1998). A similar study from
ucts containing MI (Gallo et al. 2016). In 2017, a Great Britain of workers at a paint manufacturer
large prospective European multicenter study showed that MCI/MI and BIT contact allergy
showed that in 149 patients with relevant MI were frequent (Hardcastle and Gawkrodger
contact allergy, 83.2% of them were exposed to 2005). This is in line with a Swiss study from
MI or MCI/MI in cosmetic products: (i) 19.5% 2001 that showed that MCI/MI in paint may evap-
were exposed to leave-on and rinse-off cosmetic orate after application and MCI/MI was fre-
products, (ii) 24.8% were exposed only to leave- quently registered in the product category of
on cosmetic products, (iii) and 38.9% were ‘paints, varnishes, and coatings (Reinhard et al.
exposed only to rinse-off cosmetic products 2001)’.
(Schwensen et al. 2017a). Although two occupational relevant cases of
Several market surveys have investigated the MI contact allergy were registered in Sweden in
mandatory labeling of MI if present as an ingre- 2004 (wall-covering glue and biocide), it was not
dient in cosmetic products and household prod- until 2006 that a substantial outbreak of MI con-
ucts in European purchased products; MI was tact allergy in workers at a paint factory was
present between 0.5% and 7.7 and 10.0% and observed (Isaksson et al. 2004; Thyssen et al.
16% in cosmetic and household products, respec- 2006). A study showed in 2010 that approxi-
tively (Lundov et al. 2013; Yazar et al. 2011; Uter mately 30% of patients with MI contact allergy
et al. 2014; Magnano et al. 2009; Schnuch et al. were occupationally exposed to, for example,
2011; Garcia-Hidalgo et al. 2017; Gallo et al. paint at their workplace, for example, as a painter
2016). Further, according to a Swiss study, 6.4% or decorator (Lundov et al. 2010).
of cosmetic products intended for babies includ- In 2013 and 2014, retrospective data of
ing baby wipes contained MI (Garcia-Hidalgo patients with MI contact allergy showed that pain-
et al. 2017). ters, machine operators, tile setters, and beauti-
Previous reports have shown that exposure to cians were at special risk of developing MI
MI may be hidden, as it is not always labeled even contact allergy (Uter et al. 2013; Schwensen
though present, e.g., in wet wipes and in a sponge et al. 2014; Mose et al. 2013). MI is accordingly
for grooming (Isaksson and Persson 2015; found in a various number of product categories,
Vanneste et al. 2013; Madsen et al. 2016). for example, “paint and varnishes,” “cleaning and
Other isothiazolinones are not allowed for use washing agents,” “polishing agents,” “biocides,”
in cosmetic products (Table 1). “softeners,” and “binding agents” (Friis et al.
2014). Directly in line with this is MI found in
European-purchased water-based paints, and MI
5 Isothiazolinones in Products may further evaporate from newly painted sur-
for Occupational Use faces for at least up to 42 days after its application
(Schwensen et al. 2015a; Lundov et al. 2014). A
Isothiazolinones have presumably been added to Danish study of water-based paints from 2012
chemical substances for occupational use for more employing chemical analysis found that MI was
than four decades. in all the analyzed paints up to a concentration of
300 ppm (Lundov et al. 2014). The aforemen-
tioned European study of purchased water-based
5.1 Methylchloroisothiazolinone/ paints showed no difference in MI concentration
Methylisothiazolinone and in between five European countries (Denmark,
Methylisothiazolinone France, Germany, the UK, and Sweden), but the
maximum MI concentration was relatively high
In 1998, a Swedish study found that 11.8% (9/76) with 180 ppm MI and a median of approximately
of workers at a factory plant producing binders for 50 ppm (Schwensen et al. 2015a). Only a few
36
Isothiazolinones
Table 1 Main isothiazolinones, patch test concentrations, and regulations (Based on Friis et al. (2014) and Thomsen et al. (2017))
Harmonized Concentration
classification as skin limits for warning/ Patch test
Name Abbreviation Cas. no. Regulations in cosmetics sensitizer H317 labelinga concentrations
Benzisothiazolinone BIT 2634-33-5 Not permitted Yes 0.05%/0.005% Not standardized
0.05% pet (C)
0.1% pet (A)
Dichlorooctylisothiazolinone DCOIT 64359-81-5 Not permitted No Not available
Methylisothiazolinone MI 2682-20-4 Not permitted in stay-on Yes (agreed 2017) 0.0015% 0.2% in aq.
cosmetics. Restricted to 15 ppm (15 ppm)/ (Bruze et al. 2013:
in rinse-off cosmetics 0.00015% ESCD
(1.5 ppm) recommendation)
Methylchloroisothiazolinone MCI 26172-55-4 Not permitted No Not available
Methylchloroisothiazolinone/ MCI/MI 55965-84-9 Not permitted in stay-on Yes 0.0015% 0.02% in aq.
methylisothiazolinone (3:1) cosmetics. Restricted to 15 ppm (15 ppm)/ (Bruze et al. 2014:
in rinse-off cosmetics 0.00015% ESCD
(1.5 ppm) recommendation)
Octylisothiazolinone OIT 26530-20-1 Not permitted Yes 0.05%/0.005% Not standardized
0.025% in pet. (A)
(C)Test substance as available from Chemotechnique or Allergeaze (A)
a
Labeling to protect already sensitized individuals (EUH208): ‘contains (name of substance). May produce an allergic reaction’
513
water-based paints were preserved without the use (ECHA 2011, 2016). However, in March 2016,
of isothiazolinones (Schwensen et al. 2015a). the Committee for Risk Assessment (CRA)
Currently, it is unknown to which extent con- recommended that MI should be officially classi-
sumers are primarily sensitized due to exposure to fied as a skin sensitizer (“Skin Sens 1A, H317”)
paint preserved with MI. A Belgium case however with a specific concentration limit of 0.0015%
showed in 2013 that 53 ppm MI in a paint was (ECHA RAC 2016).
enough to elicit airborne allergic contact dermati-
tis in a girl, which is in accordance with several
other published cases of airborne allergic contact 5.2 Benzisothiazolinone
dermatitis (Aerts et al. 2013; Schwensen et al.
2015a; Amsler et al. 2017). Different products have been shown to contain
Airborne allergic contact dermatitis is associ- BIT ranging from gum arabic to cutting oils to
ated with contact allergy to MCI/MI that since medical gloves (Roberts et al. 1981; Aalto-Korte
2012 has been “linked” to MI contact allergy et al. 2007; Taran and Delaney 1997; Dias et al.
(Geier et al. 2012; Breuer et al. 2015). In the 1992; Freeman 1984; Alomar 1981; Friis et al.
aforementioned prospective European multicen- 2014). These exposures has, for example, resulted
ter study, it was shown that approximately 7% of in occupational allergic contact dermatitis due to
all patients with MI contact allergy previously had exposure to BIT in the aforementioned products
experienced allergic symptoms (dermatitis, rhini- and in working environment such as in a pottery
tis, and conjunctivitis) when being in newly and during the production of carpets and air fresh-
painted rooms (Schwensen et al. 2017a). A Bel- eners (Roberts et al. 1981; Aalto-Korte et al. 2007;
gium study recently found that in 44 cases with Taran and Delaney 1997; Dias et al. 1992;
airborne allergic contact dermatitis due to expo- Freeman 1984; Alomar 1981).
sure to paint preserved with MI, approximately A Swiss market survey from 2017 of house-
80% of the cases were nonoccupational exposure, hold products (detergents) showed that BIT was
and a quarter of all had mucosal symptoms contained in 31.2% of all liquid detergents but
(Amsler et al. 2017). was not found in cosmetic products (Garcia-
Furthermore, MI has in the northern parts of Hidalgo et al. 2017). BIT has also previously
the EU been seen to be undisclosed in several been illegally found in a liquid soap where it
product categories: wet wipes for hospital set- resulted in sensitization to BIT in a worker
tings, ultrasound gel for hospital settings, and (Meysman and Goossens 2017).
water-based paint (Madsen et al. 2014;
Schwensen et al. 2015b).
5.3 Octylisothiazolinone
5.1.1 Methylisothiazolinone Is
Classified as a Skin Sensitizer OIT is only permitted for use in chemical sub-
Hitherto, MI is only to be labeled on the stances for occupational use, as it is not listed in
(non-cosmetic) chemical products if the concen- Annex V of the Cosmetic Directive (Table 1). Its
tration of MI exceeds 1000 ppm according to the use has been investigated in a previous compre-
rules self-classification (ECHA 2011, 2016). The hensive study from 2014 of extracted data from
rules of self-classification states that a substance, the Danish Product Register, which is a register of
which is a known sensitizer, but not officially hazardous chemical substances for occupational
classified as skin sensitizer in the EU, must be use in Denmark (Friis et al. 2014). OIT (n = 111)
labeled on the product and/or the safety data was less frequently used in Danish hazardous
sheet only if the concentration exceeds one-tenth chemical substances than MI (n = 884), MCI
of the standardized “generic concentration for (n = 474), MCI/MI (n = 611), and BIT
classification and labelling” of 10,000 ppm (1%) (n = 985) (Friis et al. 2014). OIT was frequently
according to the rules of self-classification registered in “paint and varnishes” (60/111) with a
mean concentration of 177 ppm, which is in case showed that a patient with contact dermatitis
accordance with another Danish retrospective on the posterior sides of both legs had positive
analysis that showed that painters might be at patch test reactions to MI and OIT (Vandevenne
special risk of developing OIT contact allergy et al. 2014). Later exposure analysis showed that
(Mose et al. 2012). However, a recent Belgian the patient was continuously being exposed to MI
study showed that OIT could be found in leather from a newly purchased sofa but with no exposure
goods (Aerts et al. 2016). Investigation of OIT in to products containing OIT. The positive patch
different product categories is warranted, espe- test reactions were ascribed cross-reactivity
cially on a larger European scale. between MI and OIT (Vandevenne et al. 2014).
Further, another Belgian case report concluded
that cross-reactivity between MI and OIT exists,
6 Cross-Reactivity Between as two patients with allergic contact dermatitis and
Isothiazolinones positive patch test reactions to OIT and MI only
had relevant exposure to leather goods containing
Isothiazolinones have chemical similarities as OIT but no relevant exposures to MI (Aerts et al.
they all contain an isothiazolinone ring. Few stud- 2016). Additionally, it was concluded that the
ies have looked into cross-reactivity between recommended patch test concentration of OIT of
isothiazolinones. Swedish studies did in the 250 ppm pet. was too low to sufficiently detect
1980s investigate cross-reactivity between iso- OIT contact allergy; a patch- test concentration of
thiazolinones included in Kathon CG ® (Bruze 1000 ppm OIT pet. was needed (Aerts et al. 2016).
et al. 1987, 1988). These guinea pig maximization Another German observational study from
tests showed that potential cross-reactivity existed 2015 (n = 3938) showed that 8.5% (21/248) and
between methyldichloroisothiazolinone (as pri- 6.0% (15/248) of patients with MI contact allergy
mary sensitizer) and MCI (Bruze et al. 1987, also had OIT contact allergy and BIT contact
1988). MI was considered a weak sensitizer in allergy, respectively (Geier et al. 2015). Although
the guinea pig maximization test with no cross- the included patients were aimed patch tested with
reactivity to MCI (Bruze et al. 1987, 1988). the specialized series, it was concluded that the
In 1996, a German study suggested that found concomitant patch test reactions were due
observed coupled reactivity between MCI/MI, to concomitant sensitization rather than cross-
OIT, and BIT was due to co-sensitization rather reactivity (Geier et al. 2015).
than cross-reactivity (Geier and Schnuch 1996). In 2008, a Swedish study showed that workers
Other observational studies have briefly looked with a positive patch test reaction to MCI/MI in
into concomitant reactions between MI and other the European baseline series also reacted to
isothiazolinones, but no solid conclusions were to 1000 ppm MI aq. if they had a strong to extreme
be made on these data (Schwensen et al. 2014; patch test reaction to MCI as an individual sub-
Lundov et al. 2013). A Belgian patient study stance (Isaksson et al. 2008). This is in accordance
(n = 6599) did however conclude that cross- with several observational studies suggesting a
reactivity between MI and OIT existed (Aerts coupled reactivity between MCI/MI and MI, as
et al. 2014). All 199 patients that were aimed approximately 50–76% of those reacting to
patch tested with OIT in relatively low patch test MCI/MI also react to MI (Aerts et al. 2014;
concentrations (250 ppm) underwent full expo- Geier et al. 2012; Schwensen et al. 2014;
sure analysis (Aerts et al. 2014). Cross-reactivity Lundov et al. 2014).
between MI and OIT was deemed likely in Currently, the recommended and optimized
15 patients as the coupled reactions to MI and patch test dose of MI is 2000 ppm (Johansen
OIT were not explained by a simultaneous et al. 2015). Recently, two experimental studies
and/or an occupational exposure to OIT but investigated potential cross-reactivity between
should be ascribed cross-reactivity between MI isothiazolinones (Schwensen et al. 2017b;
and OIT (Aerts et al. 2014). In 2014, a Belgian Debeuckelaere et al. 2016). In a French study,
the in situ behavior of MCI and MI was investi- been driven mainly by the use of these iso-
gated (Debeuckelaere et al. 2016). Here it was thiazolinones in cosmetic products, but MCI/MI
concluded that cross-reactivity between MCI and MI are used in many industrial products and
(without the MI component) and MI would be are important allergens at the workplace as well. In
unlikely as the in situ behavior of the two sub- addition especially MI is volatile and may evapo-
stances were indifferent (Debeuckelaere et al. rate from surfaces, e.g., newly painted walls caus-
2016). In contrast to this, a Danish study ing airborne allergic contact dermatitis.
employing a modified local lymph node assay In the EU, steps to restrict the use of MI in
showed cross-reactivity between MI and OIT cosmetic products have been initiated, and stricter
and MI and BIT (Schwensen et al. 2017b). This criteria for labeling and warning of MI in chemical
latest experimental finding is in accordance with a products have been approved.
recent observational Finnish study that found that However, the unprecedented epidemic of con-
89% of patients with a positive patch test reaction tact allergy to MI has raised awareness on the risk
to OIT also had a (mainly extreme) positive patch assessment procedure in the EU (Schwensen and
test reaction to MI (Aalto-Korte and Suuronen Thyssen 2016; Bruze et al. 2015; Gonçalo and
2017). Further, exposure to products containing Goossens 2013).
OIT was only identified in 26% of the patients Other isothiazolinones, BIT, OIT, and DCOIT,
with a positive patch test reaction to OIT (Aalto- are used only in non-cosmetic consumer products
Korte and Suuronen 2017). and industrial products. These are also well-
Before observational studies can be used to known causes of occupational allergic contact
solid conclusions on potential cross-reactivity dermatitis from products like paints, glues,
between isothiazolinones, optimized patch test cutting oils, and leather. Cross-reactivity
concentrations need to be established. At the between MI and OIT and MI and BIT has been
moment the patch test concentration of BIT varies demonstrated in animal assays and broaden the
between 500 and 1000 ppm aq., and the patch test potential consequences of becoming sensitized to
concentration of OIT is 250 ppm pet. The patch an isothiazolinone.
test concentration of MI is optimized to 2000 ppm
aq. (Johansen et al. 2015).
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Formaldehyde and Formaldehyde-
Releasers 37
Anton C. de Groot and Mari-Ann Flyvholm
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
2 Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
2.1 Contact Allergy to Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
2.2 Occupational Allergic Contact Dermatitis from Formaldehyde . . . . . . . . . . . . . . . . . . 528
3 Formaldehyde-Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
4 Cosmetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
4.1 Contact Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
4.2 Relevance of Positive Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
4.3 Risk of Formaldehyde-Releaser Containing Products for Patients Allergic
to Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
4.4 Occupational Allergic Contact Dermatitis from Formaldehyde-Releasers
in Cosmetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
5 Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
5.1 Contact Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
5.2 Relevance of Positive Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
5.3 Risk of Formaldehyde-Releaser Containing Products for Patients Allergic
to Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
5.4 Occupational Contact Dermatitis from Formaldehyde-Releasers
in Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
6 Textiles and Clothes: Durable Press Chemical Finishes . . . . . . . . . . . . . . . . . . . . . . 538
6.1 Contact Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
6.2 Occupational Contact Dermatitis to Formaldehyde-Releasers in
Durable Press Chemical Finishes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
A. C. de Groot (*)
Acdegroot publishing, Wapserveen, The Netherlands
e-mail: antondegroot@planet.nl
M.-A. Flyvholm
National Research Centre for the Working Environment,
Copenhagen, Denmark
e-mail: maf@nrcwe.dk

https://doi.org/10.1007/978-3-319-68617-2_37
522 A. C. de Groot and M.-A. Flyvholm
7 Miscellaneous Formaldehyde-Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

7.1 Contact Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
7.2 Occupational Contact Dermatitis from Miscellaneous
Formaldehyde-Releasers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
Abstract reactions to formaldehyde; in these cases, the

This 31-page chapter in Kanerva’s Occupa- patch test to the releaser may be the result of an
tional Dermatology, 3rd edition (2018), dis- allergic reaction to the formaldehyde which
cusses contact allergy to and allergic is present in or released by the donor test
contact dermatitis from formaldehyde and material.
formaldehyde-releasers. Formaldehyde has With the exception of those used in cos-
many applications, which are shown in tabular metics (e.g., quaternium-15, imidazolidinyl
format in this publication. However, it is a urea, diazolidinyl urea, DMDM hydantoin,
ubiquitous and important allergen. Contact and 2-bromo-2-nitropropane-1,3-diol), there
allergy to formaldehyde occurs frequently in is little published information on the rele-
women with hand dermatitis. Sensitization vance of observed positive patch test
may also be caused by occupational exposure reactions to formaldehyde-releasers. Most
to formaldehyde, especially in metalworkers, reactions to releasers used in metalworking
nurses, other (para)medical professionals, and fluids appear not to be relevant with the
cosmetologists. Formaldehyde is widely dis- exception of N,N0 -methylenebis(5-methylox-
tributed in the environment and is difficult to azolidine). The presence of formaldehyde-
avoid completely. Thus, even in patients releasers used as durable press chemical
actively trying to avoid products containing finishes in clothes appears to be safe for con-
it, the dermatitis will infrequently heal sumers. None of the formaldehyde-releasers
completely and permanently. In 2013, the con- are important causes of occupational allergic
centration used for patch testing to detect form- contact dermatitis.
aldehyde sensitization was raised from 1% to
2% in water, as the latter reveals up to 80% Keywords
more cases of sensitization. Formaldehyde · Formaldehyde-releaser ·
Formaldehyde-releasers are chemicals, Preservative · Antimicrobial · Cosmetics ·
which release formaldehyde as a result of Metalworking fluids · Durable press chemical
decomposition and/or chemicals synthesized finish · Diazolidinyl urea · Imidazolidinyl
from formaldehyde that may still contain resi- urea · DMDM hydantoin · Quaternium-15 ·
dues of free formaldehyde. There are over 2-Bromo-2-nitropropane-1,3-diol · Bioban ® ·
30 formaldehyde-releasers with a wide array N,N0 -Methylenebis(5-methyloxazolidine) ·
of applications; most are used as preservatives tris(N-hydroxyethyl)hexahydrotriazine ·
in cosmetics, as antimicrobials in metalwork- tris(Hydroxymethyl)nitromethane · Urea-
ing fluids, paint, lacquers, and varnishes or as formaldehyde · Melamine/formaldehyde ·
durable press chemical finishes in textiles. Dimethylol dihydroxyethyleneurea ·
These are shown in this chapter in tabular Methenamine · N-Methylolchloracetamide
format with common names, IUPAC names, • Formaldehyde is a ubiquitous and important
synonyms, trade names, CAS numbers, and allergen. Contact allergy to formaldehyde
applications. occurs frequently in women with hand
Positive patch tests to formaldehyde- dermatitis. Sensitization may also be caused by
releasers are often accompanied by concomitant occupational exposure to formaldehyde,
37 Formaldehyde and Formaldehyde-Releasers 523
especially in metalworkers, nurses, other (para) 1 Introduction

medical professionals, and cosmetologists.
• Patch testing with formaldehyde 2% in water Formaldehyde is a common cause of contact
reveals up to nearly 80% more cases of sensi- allergy. Allergic contact dermatitis from this
tization than the 1% test substance. chemical is often chronic, presumably because
• Formaldehyde is widely distributed in the it is difficult to avoid exposure to the allergen
environment and is difficult to avoid completely. Indeed, formaldehyde may be found
completely. Thus, even in patients actively in cosmetics, toiletries, household products, and
trying to avoid products containing it, the in a great number of industrial applications
dermatitis will infrequently heal completely including adhesives, paints, lacquers, and metal-
and permanently. working fluids. Often, the products are not
• Formaldehyde-releasers are chemicals which preserved with formaldehyde itself but with
release formaldehyde as a result of decompo- agents that release formaldehyde under usage
sition and/or chemicals synthesized from form- conditions, the so-called formaldehyde-releasers
aldehyde that may still contain residues of free (or formaldehyde donors) (Table 1). In this
formaldehyde. chapter, (occupational) contact allergy to
• There are over 30 formaldehyde-releasers with formaldehyde and formaldehyde-releasers is
a wide array of applications; most are used as discussed. Details of the data presented here
preservatives in cosmetics; as antimicrobials in can be found in our 2009 and 2010 review
metalworking fluids, paint, lacquers, and var- articles on the subject (De Groot et al. 2009,
nishes; or as durable press chemical finishes in 2010a, b, c, d, e, f ) and – for formaldehyde and
textiles. formaldehyde-releasers used in cosmetics – in
• Positive patch tests to formaldehyde- the book Monographs in Contact Allergy,
releasers are often accompanied by con- Volume I. Non-fragrance Allergens in Cosmetics
comitant reactions to formaldehyde; in (De Groot 2018), which provides a full review of
these cases, the patch test to the releaser contact allergy to and other side effects from
may be the result of an allergic reaction to these chemicals. After the publication of this
the formaldehyde which is present in or chapter in the previous “Kanerva’s Occupational
released by the donor test material. For Dermatology” (De Groot and Flyvholm 2012),
many releasers, co-reactivity to formalde- only limited new information on the subject has
hyde is >50%. been published.
• There is very little published information on
the relevance of observed positive patch test
reactions to formaldehyde-releasers. Most 2 Formaldehyde
reactions to releasers used in metalworking
fluids appear not to be relevant with the Formaldehyde (methanal) is a colorless gas
exception of N,N0 -methylenebis(5-methyloxa- (HCHO) with a characteristic pungent odor.
zolidine). The lack of relevance of reactions Formalin is a 37–40% aqueous solution of form-
to the Bioban ® range of antimicrobials may aldehyde, to which 10–15% methyl alcohol has
partly be due to irritancy leading to false- been added to inhibit polymerization. This
positive reactions. simple aldehyde is ubiquitous in the environment
• None of the formaldehyde-releasers are and is generated in and released from the smoke of
important causes of occupational allergic burning wood, coal, charcoal, tobacco, natural
contact dermatitis. The presence of gas, and kerosene. Formaldehyde also occurs
formaldehyde-releasers as durable press naturally in certain foods such as coffee
chemical finishes in clothes appears to be (especially instant coffee), dried bean curd, cod-
safe for consumers. fish, caviar, maple syrup, shiitake mushrooms,
Table 1 Formaldehyde-releasers. (Adapted from De Groot et al. 2009)
524
Commonly used name IUPAC name Other synonyms Current trade namesc CAS
Formaldehyde-releasers used in cosmetics
Benzylhemiformal phenylmethoxymethanol (benzyloxy)methanol Akyposept B [Preventol D2; see 14548-60-8
(INCI) there]
2-Bromo-2-nitropropane- as in column 1 bromonitropropanediol; bronopol Bronopol; Chemynol BP; 52-51-7
1,3-diol (INCI) Myacide Pharma BP; Onyxide 500
Diazolidinyl urea (INCI) 1-[1,3-bis(hydroxymethyl)-2,5-dioxo- N,N’-bis(hydroxymethyl)urea Abiol Forte; Germall II; Liposerve 78491-02-8
imidazolidin-4-yl]-1,3-bis(hydroxy- DU; Nipa Biopure 200
methyl)urea
DMDM hydantoin 1,3-bis(hydroxymethyl)-5,5-dimethyl- dimethyloldimethylhydantoin; Cosept DM; Dekafald; Glydant 6440-58-0
(INCI) imidazolidine-2,4-dione 1,3-dimethylol-5,5-dimethyl-hydantoin; (2000, XL-1000); Lanodant DM;
DMDMH Mackstat DM; Microcare DH
Imidazolidinyl urea 3-[3-(hydroxymethyl)-2,5-dioxo- bis(methylolhydantoin urea)methane; Germall 115; Liposerve IU; Nipa 39236-46-9
(INCI) imidazolidin-4-yl]-1-[[[3-(hydroxy- imidurea Biopure 100; Protacide U-13;
methyl)-2,5-dioxo-imidazolidin-4-yl] Unicide U-13
carbamoylamino]methyl]urea
Quaternium-15 (INCI) 1-(3-chloroallyl)-3,5,7-triaza-1- N-(3-chloroallyl)hexaminium chloride; Cosept 200; Dowicide Q; Dowicil 4080-31-3
azoniaadamantane chloride chloroallylhexaminium chloride; (75,200);
hexamethylene tetramine chloroallyl
chloride
Sodium hydroxymethyl- sodium;2-(hydroxymethylamino) glycine, N-(hydroxymethyl)-, Sodium salt Suttocide A 70161-44-3
glycinate (INCI) acetate (1:1);
N-hydroxymethylglycine (mono)sodium
salt
Formaldehyde-releasers used in metalworking fluids
Bioban CS-1135 ® 4,4-dimethyloxazolidine; Bioban CS-1135 81099-36-7
3,4,4-trimethyl-oxazolidine (Ingred.75673-
43-7 and 51200-
87-4)
Bioban CS-1246 ® 5-ethyl-3,7-dioxa-1-azabicyclo[3.3.0] 7-ethylbicyclooxazolidine Bioban CS-1246; Chemtan A60; 7747-35-5
octane Oxazolidine-E; Zoldine ZE
Bioban P-1487 ® 4-[2-(morpholin-4-ylmethyl)-2-nitro- mixture of nitrobutylmorpholine and Bioban P-1487 37304-88-4
butyl] morpholine; 4-(2-nitrobutyl) ethylnitrotrimethylenedi-morpholine (Ingred.1854-23-
morpholine 5 and 2224-44-4)
Forcide 78 ® Ia (Z )-3-(bis(2-hydroxyethyl)amino)-2- 2-hydroxymethylaminoethanol- tri-N- Forcide 78 77044-78-1
(2- hydroxyethyl-(hydroxymethyl) ethylhydroxy-2-amino-methylene
A. C. de Groot and M.-A. Flyvholm
amino)prop-2-en-1-ol
37
Forcide 78 ® IIb 1,3,5-triethyl-1,3,5-triazinane (a) (a) hexahydro-1,3,5-triethyl-s-triazine; (a) Vancide-TH; Forcide 78 7779-27-3 (a)
(a) triethyl-trimethylenetriamine mixture of
(1) triazinetriethanol (see there) and
(2) hexahydro–1,3,5-triethyl-1,3,5-triazine
N,N’-Methylenebis 5-methyl-3-[(5-methyloxazolidin-3-yl) Grotan OX 66204-44-2
(5-methyloxazolidine) methyl]oxazolidine
4,4’-Methylenedimor- 4-(morpholin-4-ylmethyl)morpholine bismorpholinomethane; 5625-90-1
pholine dimorpholinomethane;
4,4’-methylenebis-morpholine
Preventol D2 ® phenylmethoxymethoxymethylbenzene bis(monobenzylether;menzyloxy)methane; Preventol D2, this trade name is 2749-70-4
mixture of hydroxymethylene and also often used for benzyl-
polyhydroxymethylene 1,1’-(methylenebis hemiformald
(oxymethylene)) bis-benzene
Tris(N-hydroxyethyl) 2-[4,6-bis(2-hydroxyethyl)- hexahydro-1,3,5-tris(hydroxy-ethyl) Forcide 78 (see there); 4719-04-4
hexahydrotriazine 1,3,5-triazinan- 2-yl]ethanol triazine;triazinetriethanol; Grotan (B, BK, HD);
trihydroxyethylhexahydro s-triazine;1,3,5- Onyxide 200;
Formaldehyde and Formaldehyde-Releasers
trihydroxyethylhexahydro- triazine Roksol T 1-7

Tris(hydroxymethyl)- 2-(hydroxymethyl)-2-nitropropane-1,3- nitromethylidynemethanol; Tris Nitro 126-11-4
nitromethane (INCI) diol trimethylolnitromethane; tris nitro
Formaldehyde-releasers used as durable press chemical finishes
Dihydroxydimethylol- 4,5-dihydroxy-1,3-bis dimethylolglyoxalurea, methylated Fixapret (various); Freerez PKF; 68411-81-4
ethyleneurea, methylated (hydroxymethyl)-imidazolidin-2-one, Knittex LE; Permafresh (various);
methylated Sumitex (various)
Dimethylol dihydroxy- 4,5-dihydroxy-1,3-bis 1,3-bis(hydroxymethyl)-4,5- dihydroxy-2- Fixapret (various); Permafresh 1854-26-8
ethyleneurea (hydroxymethyl)-imidazolidin-2-one imidazolidinone (various)
Dimethylolethyleneurea 1,3-bis(hydroxymethyl)imidazolidin-2- Fixapret AH 136-84-5
one
Dimethylolpropyleneurea 1,3-bis(hydroxymethyl)-1,3-diazinan- DMPU; tetrahydro-1,3-bis Fixapret PH; Knittex PRS 3270-74-4
2-one (hydroxymethyl)-1H-pyrimidin-2-one
Dimethylol urea (INCI) 1,3-bis(hydroxymethyl)urea N,N’-bis(hydroxymethyl)urea; Kaurit S; 140-95-4
carbamol; Methural;
dihydroxymethylurea; Permafresh 477;
N,N’-dimethylolurea; dimethylurea; Urofix
oxymethurea;
urea formaldehyde
Glyoxalurea 4,5-dihydroxyimidazolidin-2-one dihydroxyethyleneurea; 3720-97-6
glyoxalmonoureine
525
(continued)
526
Table 1 (continued)
Commonly used name IUPAC name Other synonyms Current trade namesc CAS
Methylol urea hydroxymethylurea N-(hydroxymethyl)urea; 1000-82-4
methyl hydroxyurea;
mono(hydroxymethyl)urea;
monomethylolurea
Polyoxymethylene 1,3,5-triazine-2,4,6-triamine, polymer melamine, polymer with formaldehyde; 9003-08-1
melamine (INCI) with formaldehyde melamine/formaldehyde resin; nanoplast
Polyoxymethylene urea formaldehyde;urea polynoxylin; urea-formaldehyde resin; Karbamol (B/M); Kaurit (285FL, 9011-05-6
(INCI) urea, polymer with formaldehyde 240); Uformite
Propylene glycol 1-(hydroxymethoxy)-2-propanol 199169-27-2 (?)
hemifor-mal
Tetramethylol acetylene- 2,4,6,8-tetrakis(hydroxymethyl)- tetrakis(hydroxymethyl)glycoluril; Fixapret 140 5395-50-6
diurea 2,4,6,8-tetraazabicyclo[3.3.0]octane- tetramethylolglycoluril
3,7-dione
Miscellaneous formaldehyde-releasers
Dimethyl hydantoin 5,5-dimethylimidazolidine-2,4-dione; formaldehyde, polymer with 5,5-dimethyl- 26811-08-5
formaldehyde resin formaldehyde 2,4-imidazolidinedione;
DMHF
MDM hydantoin (INCI) 1-(hydroxymethyl)-5,5-dimethylimi- 1-hydroxymethyl-5,5-dimethyl hydantoin; Glycoserve 116-25-6
dazolidine-2,4-dione MDMH; methylol dimethyl hydantoin;
monomethylol dimethyl hydantoin
Methenamine (INCI) 1,3,5,7-tetraazatricyclo[3.3.1.13,7] aminoform; formamine; Cystamine; Urotropine; Vulkacit 100-97-0
decane hexamethylene tetramine; H30
hexamine; methenamide
N-Methylolchloracetamide 2-chloro-N-(hydroxymethyl)acetamide chloroacetamide-N-methylol Grotan DF-35 2832-19-1
Paraformaldehyde formaldehyde paraform; poly(oxymethylene) Aldacide; Formagene 30525-89-4
CAS Chemical Abstract Service numbers (www.cas.org)
INCI INCI name
a
Description of Forcide 78 as by (Hamann 1980)
b
Description of Forcide 78 as by (Andersen et al. 1984)
c
Trade names used in 2009; not verified whether they are currently (January 2018) still in use
d
Preventol D2 also is used as a trade name for benzylhemiformal by Lanxess Energizing Chemistry (www.protectedbypreventol.com)
and smoked ham. It is an irritant as well as an found to detect far more cases of sensitization to
allergen and a potential respiratory carcinogen. formaldehyde (Pontén et al. 2013).
Formaldehyde can be used as a disinfectant as The former use of formaldehyde per se as a
it kills most bacteria and fungi. It was first com- preservative in cosmetics, as a disinfectant, as an
mercially used in embalming fluid and as a pre- antiperspirant, and in textile finish resins releas-
servative for laboratory specimens. The chemical ing large amounts of formaldehyde resulted in
is incorporated into a large variety of products and high sensitization rates into the 1980s. However,
reactants in many chemical processes, including its use in cosmetics has largely been abandoned
formaldehyde-releasers, polymerized plastics, and replaced with formaldehyde-releasers, and,
metalworking fluids, paints and lacquers, topical as a disinfectant, it was partly replaced by other
medicaments, fabrics, cosmetics, and detergents compounds like glutaraldehyde and glyoxal.
(Table 2). In finished products, there may be sev- Also, low formaldehyde textile resins were intro-
eral sources of formaldehyde, e.g., active ingredi- duced. Thus, since the 1980s, there has been a
ent for preservation or formaldehyde released decline in the frequency of sensitization in most
from a donor. Some sources, however, are “hid- countries. In recent multinational European
den” or “occult” (sometimes unknown to the man- investigations, it was on average below 2% in
ufacturer), such as formaldehyde used for the general patch test population (Uter et al.
preservation of raw materials used to prepare the 2012, 2017; Giménez-Arnau et al. 2017),
product, formaldehyde used to sterilize vessels although several countries had rates of over 3%
for storage of raw materials or products, formal- (Isaksson et al. 2014; Prodi et al. 2016). In the
dehyde released by package materials such as USA, where patients undergo stricter selection
formaldehyde resins coating cosmetic and phar- for patch testing, rates of 8–9% were the rule
maceutical tubes, or formaldehyde released from rather than the exception up to 2008; since
the non-woven material used for a disinfectant then, frequencies of sensitization have decreased
swab (Friis et al. 2014). to 5.5–6.5% and most recently, when tested with
Exposure to formaldehyde in the EU is subject formaldehyde 2% aqua, to 7% (Warshaw et al.
to restrictions because of its toxicological proper- 2013, 2015; DeKoven et al. 2017).
ties. The maximum allowed concentration in fin- Patients allergic to formaldehyde are often
ished cosmetic products is 0.2% for most products women (who are affected 1.2–1.5 times more
(oral cosmetics, 0.1%; nail-hardening products, frequently than men) with hand eczema, presum-
5%). All finished products containing formalde- ably (partly) from formaldehyde-releasers in
hyde or substances which release formaldehyde household products, frequently combined with
must be labelled with the warning “contains form- facial dermatitis from contact with formaldehyde
aldehyde” where the concentration of free formalin cosmetics (Flyvholm and Menné 1992; Trattner
dehyde in the finished product exceeds 0.05 wt% et al. 1998). Women are more often working in
(500 ppm). occupations with extensive wet work, e.g., hair-
dressing, catering, cleaning, and health-care work
(Meding 2000); irritant dermatitis increases the
2.1 Contact Allergy risk of contact allergy. Sensitization may also be
to Formaldehyde caused by occupational exposure to formaldehyde
(see below).
Patch testing with formaldehyde is not very reli- As formaldehyde is so widely distributed in the
able. Until recently, 1% aqua was the standard for environment, it is difficult to avoid. Thus, even in
patch testing. However, this concentration may patients actively trying to avoid products
result in both false-positive and in false-negative containing formaldehyde, the dermatitis will
reactions. In 2013, the concentration of formalde- infrequently heal completely. Most patients will
hyde in the European baseline series was still suffer from exacerbations of dermatitis (Cro-
increased to 2%, as this test substance had been nin 1991; Kang et al. 1995; Agner et al. 1999).
Table 2 Examples of applications of and products that Table 2 (continued)

may contain formaldehydea (De Groot 2018)
Reusable protective gloves
Adhesives (glues, pastes, cements) Starch (spray and powdered)
Agricultural chemicals (seed disinfectants) Surface active agents
Antifreeze agents Tanning agents
Asphalt shingles Tissue fixatives
Binders (polymers) Vaccines
Castings Urea plastics in adhesives and footwear
Cellulose esters a
Some uses mentioned here, found in literature, may have
Chipboard been abandoned
Cleaning products
Clothing and textiles (crease-resistant) Contact allergies to formaldehyde are signifi-
Coloring agents cantly associated with methylchloroisothia-
Construction materials zolinone + methylisothiazolinone (MCI/MI)
Corrosion inhibitors and/or methylisothiazolinone (MI) and with the
Cosmetics fragrance mixes I and II. This is not the result of
Dental preparations
cross-reactivity, but may be related to the use of
Deodorizers
products containing these allergens in different
Disinfectants
combinations (Pontén et al. 2016).
Dry cleaning materials
Embalming fluids
Fabric softeners
Filling agents (stopping, putty, etc.) 2.2 Occupational Allergic Contact
Flame retardant Dermatitis from Formaldehyde
Flooring materials
Footwear (resins and plastics) Occupational sensitization to formaldehyde is
Formaldehyde resins (melamine-, urea-, etc.) seen especially in metalworkers, nurses, other
Fumigants (para)medical professionals, and cosmetologists
Glues (Kadivar and Belsito 2015; Higgins et al. 2016;
Hardeners Cronin 1991), which usually presents as hand
Hydrocarbons (e.g., oil) eczema and is ascribed to the use and handling
Impregnating agents of skin cleansers, skin care products, and massage
Laboratory chemicals creams that may contain formaldehyde-releasers
Latex rubber as preservatives (Pesonen et al. 2015). Formalde-
Leather hyde allergy in plastic product machine operators
Medications: wart remedies
was ascribed to contact with formaldehyde resins
Metalworking fluids
(Pesonen et al. 2015).
Mildew preventatives (fruits, vegetables)
Published cases of occupational formalde-
Moistened baby toilet tissue
hyde-induced allergic contact dermatitis have
Orthopedic casts
Paints, lacquers, coatings
been caused by a photocopier toner, jeans and
Paint removers other textiles, bank notes, methylol urea present
Paper and paper industry in a laboratory diluent, a barrier cream, formalde-
Phenolic resins in adhesives and footwear hyde released by glycol diacetal present in a foun-
Photocopier toner tain solution, a photographic product containing
Photographic paper and solutions 35–40% formaldehyde, a pesticide containing a
Plywood polymerization product of formaldehyde and free
Polishes and finishes formaldehyde, and by repairing material for sand
Printing inks cores and sand cores (De Groot and Flyvholm
(continued) 2012, 2018).
3 Formaldehyde-Releasers and clothes as durable press chemical finishes,

and a rest group. For most releasers, their
Formaldehyde-releasers are substances which applications are not limited to one such class
release formaldehyde as a result of decompo- of products; possible applications for indivi-
sition and/or chemicals synthesized from form- dual formaldehyde-releasers are summarized in
aldehyde that may still contain residues of Table 4.
free formaldehyde (Table 1). Many patients
reacting to formaldehyde also have positive
patch tests to one or more formaldehyde-
releasers. It is often assumed that this is due
4 Cosmetics
to “cross-allergy” to formaldehyde (more cor-
An important source of human skin contact with
rectly termed “pseudo-cross-allergy”), i.e., that
formaldehyde is the use of cosmetics containing
the patch test reaction to the formaldehyde-
formaldehyde-releasers as preservatives. They
releaser is caused by the formaldehyde
are added to water-containing cosmetics
present in or released by the donor patch test
(which include personal care products/toilet-
material. In favor of this assumption is that
ries) to prevent the growth of microorganisms
often, more than one releaser reacts in
that may enter during manufacture or during
formaldehyde-allergic individuals, even when
their usage. Microbial contamination may
they are not structurally related (which makes
cause discoloration, malodors, and physical
cross-reactivity unlikely). There is also a sig-
and chemical degradation of products, in addi-
nificant patch test association between the
tion to the potential adverse events of pathogens
releasers themselves, including those that are
on consumers. Formaldehyde-releasers used in
structurally dissimilar; this also suggests an
cosmetics and permitted in the EU are shown
important role for formaldehyde.
in Table 5. In the USA, there is no relevant
The degree of co-reactivity to formaldehyde in
legislation, neither on the ingredients used in
eczema patients reacting to formaldehyde-releasers
cosmetics nor on their permitted concentration
is summarized in Table 3. 2-Bromo-2-nitropropane-
in the final product.
1,3-diol (15–18%), Bioban P-1487 ® (8%), tris
(hydroxymethyl)nitromethane (33%), and N,N0 -
methylenebis(5-methyloxazolidine) (42%) have
less than 50% co-reactivity to formaldehyde. The 4.1 Contact Allergy
other 14 have a co-reactivity score of >50% and
many >70% (especially in releasers used as The results of (routine) testing of eczema patients
durable press chemical finishes). This means with formaldehyde-releasers used in cosmetics
that the (great) majority of positive patch test are summarized in Table 3. In Europe, low fre-
reactions to these releasers may in fact be caused quencies of sensitization have been observed in
by formaldehyde sensitivity (Lundov et al. routine testing to all: 2-bromo-2-nitropropane-
2010). In these studies, patients were tested 1,3-diol 0.4–1.4%, diazolidinyl urea 0.5–1.4%,
with formaldehyde 1% aqua; as we know that imidazolidinyl urea 0.5–1.4%, and quaternium-
the currently used 2% may reveal up to 78% 15 0.7–1.9%. Comparison between Europe and
more positive reactions than the 1% test sub- the USA shows that there are (far) higher frequen-
stance (Isaksson et al. 2014), this means that the cies in the USA in patients suspected of contact
percentages mentioned above are in fact an dermatitis. This may partly be explained by
underestimation. stricter selection in the tertiary referral centers
Formaldehyde-releasers are presented here where the data come from (NACDG: North
in four groups: releasers mainly used in cos- American Contact Dermatitis Group (Warshaw
metics, releasers for antimicrobial activity in et al. 2013, 2015; DeKoven et al. 2017) and the
metalworking fluids, chemicals used in textiles Mayo Clinic (Wentworth et al. 2014) and a far
530
Table 3 Frequency of sensitization to formaldehyde and formaldehyde-releasers and co-reactivity to formaldehyde (De Groot et al. 2010a, b, c, d, e, f; De Groot 2018)a
Frequency of sensitization (range %)
Unselected patient Selected patient
populationb populationc Percentages co-reactivity to formaldehyde (mean, adjusted for sample
Formaldehyde releaser Europe USA Europe USA size)
Formaldehyde 0.7–3.4d 5.6–9.0d 0.2–5.0d 0.8–11d
Benzylhemiformal 1–2.9 76
2-Bromo-2-nitropropane- 1,3-diol 0.7–1.4d 1.0–3.4d 0.2–5.5e 2.0–9.0 15; 50 (2 patients)f; 18g
Diazolidinyl urea 0.5–1.4d 1.6–3.7d 0.2–3.0 1–7 59; 19f 43g
DMDM hydantoin 1.0–2.8d 0.1–1.1 1–4.1 71; 50f; 79g
d
Imidazolidinyl urea 0.5–1.4 1.6–3.0d 0.6–1.9 1.8–5 51; 29f; 34g
d
Quaternium-15 0.7–1.9 4.8–10.3d 0.7–4.7 56; 59h; 51f; 74g
Bioban CS-1135® 6.2 1.1–5.0 72
Bioban CS-1246 ® 6.2 0.8–3.0 68
Bioban P-1487 ® 1.5 0.5 0–2.2 8
Forcide ® 78 (II) 0.6 100 (in 4 patients)
N,N’-Methylenebis(5-methyloxazolidine) 2.9–6.7 42
4,4’-Methylenedimorpholine 4.9 29 (in 7 patients)
Propyleneglycolhemiformal 0.7–0.8 100
Tris(N-hydroxyethyl)hexahydrotriazine 3.3–4.5 0–8.1 4.6 60; 50f
Tris(hydroxymethyl)nitromethane 0–0.3 33 (in 6 patients)
Dihydroxydimethylolethyleneurea, 100 (1 patient only)
methylated
Dimethylol dihydroxyethyleneurea 0.7–1.2i,j 0.6–2.3 1.9 82
Dimethylol dihydroxyethyleneurea, modified 2.2i
Dimethylolpropyleneurea 2.1j 1.3–5.5k,l 0.4–1.1m 56
Dimethylol urea 100 (in 6 patients)
Ethylene urea, melamine/formaldehyde n 2.6–3.1i,j 2.1–7.2 0.6 l 1.5 86
37
Glyoxalurea 100 (in 6 patients)

Polyoxymethylene melamine 2.4–2.6i,j 1.7–1.9l 0.4–1.1m 85
Polyoxymethylene urea 2.3–2.4i,j 1.3l 1–2.2m 72
Tetramethylol acetylenediurea 2.4j 1.8k 0.2–0.8m 80
Methenamine 1d 0.3d 2.1d 66 (in 3 patients)f
N-Methylolchloracetamide 0.4 0.1–0.4
a
Literature reviewed back to 1990 unless otherwise indicated
b
Patients suspected of contact dermatitis (routine testing)
c
Selection procedures were sometimes specified (e.g., suspected of metalworking fluid dermatitis), but more often not adequately described; the frequency of sensitization
obviously depends on the degree of selection
d
2000–2014, data from De Groot 2018
e
All but two studies had scores <2%
f
Latorre et al. 2011
g
Lundov et al. 2010
h
Formaldehyde and Formaldehyde-Releasers
De Groot and Coenraads 2010

i
Study from Israel (Lazarov 2004)
j
Study from Israel (Lazarov et al. 2002)
k
Study from Israel (Lazarov et al. 2000)
l
(Includes the results of) Lisi et al. 2014
m
Frequency in an unselected test population, in which an unknown number of patients had been patch tested with these allergens
n
This is a commercial patch test preparation, not a durable press chemical finished used per se
531
Table 4 Uses and applications of formaldehyde-releasers a,b (De Groot et al. 2010a, b, c, d, e, f)
Formaldehyde-releaser Uses
Benzylhemiformal Preservative in rinse-off cosmetics. Biocide in metalworking fluids, slurries, filler
suspensions, adhesives, various emulsions and dispersions, paints and lacquers, the
paper industry, spinning baths in the textile industry, polishes, waxes and cleaning
products.
2-Bromo-2-nitropropane- Cosmetics, adhesives/glues, cleaning agents, binding agents, coloring agents,
1,3-diol construction materials, filling agents, flooring agents, humidifiers, impregnating
agents, metalworking fluids, milk processing plants, paints/lacquers, paper mills,
water circulating systems, pharmaceutical products, polishes, printing inks, slurries,
surface treatment for paper, cardboard and other non-metals, viscosity adjustors, and
washing detergents.
Quaternium-15 Cosmetics, metalworking fluids, detergents and soaps, floor waxes and polishes, inks,
latex-based paints, laundry starch, paper and pulp products, textile finishing solutions,
spinning emulsions, printing pastes, joint cements, and photocopier toner.
Sodium Cosmetics, neutralizing agent for acids/acrylics polymers, in cleaning/washing agents,
hydroxymethylglycinate and in rinsing agents.
Bioban CS-1135 ® Bactericide in metalworking fluids, fluids for oil and gas production, and mineral
slurries. Also used as an in-can preservative for paints, inks, emulsions, non-food
contact adhesives, surfactants, and in consumer household and institutional products
such as dish-washing and laundry detergents, fabric softeners, household and
industrial cleaners and polishes. Also provides quick clean-up for contaminated
process water and finished formulations.
Bioban CS-1246 ® Bactericide in metalworking fluids, adhesives, consumer and household products
(including dishwashing and laundry liquids, surface cleaners and polishes), industrial
products, wax and resin emulsions, inks, non-food contact adhesives, mineral slurries,
paints, and surfactants. Also used for leather tanning.
Bioban P-1487 ® Bactericidal and fungicidal agent used in metalworking fluids, paints, inks, emulsions,
slurries, non-food contact adhesives, die cast lubricants, mold-release agents, and also
in consumer, household, and institutional products.
N,N0 -Methylenebis Biocide in metalworking fluids, in nylon spin finish, technical emulsions, and system
(5-methyloxazolidine) cleansers.
Tris(N-hydroxyethyl) Bactericide and fungicide in adhesives, industrial cleaning systems, polymer
hexahydrotriazine emulsions, latex emulsions, soluble lubricants, paints and metalworking fluids, in
oilfield water systems, drilling muds, and in workover and completion fluids. In-can
preservation of water-based products like paints, glues, emulsions, inks, pigment
dispersions, cutting oils, and water-soluble cleaners. Fuel protection during storage.
Tris(hydroxymethyl) Antimicrobial agent in industrial applications such as household and institutional
nitromethane products, oil field water system and drilling muds, recirculating water systems,
chemical toilets, and metalworking fluids.
Dimethylol urea Production of urea-formaldehyde resins as an unisolated intermediate, also used as
textile finish.
Glyoxalurea In paper coating compositions and as a textile finish.
Methylol urea Used to treat textiles and woods and is mixed with fillers for use in molding adhesives.
In disinfectants and other biocidal products methylol urea is used for disinfection of
air, surfaces, materials, and equipment. It is a preservative for liquid-cooling and
processing systems and is also used as slimicide, e.g., on wood and paper pulp. Present
in urea –formaldehyde resins as residual starting material or breakdown product.
Polyoxymethylene melamine Surface coating and glues in the furniture and wood industry, bonding agents in
plywood and particle board (MDF), plastic composites manufacturing, printing,
dyeing or finishing of textiles, pulp and paper processing, in water-resistant orthopedic
plaster, surface coatings, and baking enamels and treatment of leather.
(continued)
Table 4 (continued)
Formaldehyde-releaser Uses
Polyoxymethylene melamine increases the wet and folding strength of paper essential
for the manufacture of currency, maps, shipping bags, towels, facial tissue, etc.
Polyoxymethylene urea Textile finishes, in cosmetics as bulking agent, and to form the outer shell of
microcapsules, adhesives, in polymers having incidental contact with food.
MDM hydantoin Preservative in paints, room deodorizers, and dishwashing detergents. Used as
“antimicrobial” in cosmetics according to the EU cosing database but is not included in
the annex of allowed preservatives.
Methenamine Used in the rubber industry to prevent vulcanized rubber from blocking, as an
accelerator and together with resorcinol and silica as adhesion promoter; as a curing
agent for thermosetting resins (particularly phenolformaldehyde and urea-
formaldehyde resins); in foundry mold casting as part of binder resins; in the
production of nitrilotriacetic acid; for use in the manufacture of adhesives and
coatings; as an anti-corrosive agent in steel; in the absorption of poisonous gases; in
the synthesis of explosives; in flame-retardant materials, paints and lacquers, rubber
textile adhesives, the photographic industry; in the production of deodorants and hair
fixers, in methenamine solid fuel tablets; as a protein modifier and as a reagent in
chemical analysis. Pharmaceutical for intestinal infection and preservative in the food
(especially fish) industry. Permitted in cosmetics in the EU in a maximum
concentration of 0.15%.
N-Methylolchloracetamide Preservative in glues, in metalworking fluids, and spin-finishes applied to nylon.
Paraformaldehyde Used as a fumigant, disinfectant, and fungicide, in root-canal therapy and as a curing
agent for phenol-formaldehyde resins. Higher molecule homopolymer is a hard
engineering plastic (polyoxymethylene plastic). As paraformaldehyde is essentially a
solid form of formaldehyde, it therefore has the same uses as formaldehyde. Permitted
in cosmetics in the EU in a maximum concentration of 0.2% (0.1% for products for
oral hygiene).
a
Formaldehyde-releasers mentioned in table 1 but not here are used mainly in the class of products under which they are
classified (cosmetics, metalworking fluids, durable press chemical finishes)
b
Uses in 2009; not verified whether the data are still valid in 2018
higher frequency of formaldehyde contact allergy tested. Their percentages have ranged widely. In
in the USA. Whether differences in composition these “prevalence studies,” the alleged causative
of cosmetics and/or the use pattern of these prod- products were never specified. In one detailed
ucts (US individuals might for example be heavier study, the great majority of 60 relevant reactions
users of cosmetics) play a role is unknown to quaternium-15 were caused by cosmetic prod-
(De Groot and Veenstra 2010). ucts: moisturizers (n = 46), hair preparations
(non-coloring, n = 19), and makeup (n = 4).
Three occupational cases were caused by similar
4.2 Relevance of Positive Reactions products (Parker and Taylor 1991). Most reac-
tions to other releasers used in cosmetics such as
Only in a small minority of studies, in which diazolidinyl urea and imidazolidinyl urea are
selected or unselected patient groups have been probably also due to cosmetic products. In a
tested, has data on relevance been provided. German study, relevance was found in 31% of
Many such investigations were performed by positive patch test reactions to DMDM
the North American Contact Dermatitis Group hydantoin. Causative products were mainly
or the Mayo Clinic. Relevance was usually cosmetics (30%) and topical drugs (22%); the
divided into “definite,” “probable,” and “possi- other products were not mentioned (Uter and
ble” and expressed as a percentage of the patients Frosch 2002).
534
Table 5 Formaldehyde-releasers permitted in cosmetics in the EU with their maximum concentration

Preservative Maximum allowed conc. (%) Comments
Benzylhemiformal 0.15 Permitted in rinse-off products only
2-Bromo-2-nitropropane-1,3-diol 0.1 Formation of nitrosamines must be avoided
Diazolidinyl urea 0.5
4,4-Dimethyloxazolidine 0.1 Present in Bioban CS 1135 ®, a preservative mainly used in
metalworking fluids
DMDM hydantoin 0.6
5-Ethyl-1-aza-3,7-dioxabicyclo-[3.3.0]octane 0.3 Prohibited in oral hygiene products and products intended to
come into contact with mucous membranes. present in Bioban
CS-1246 ®, a preservative in metalworking fluids
Formaldehyde 0.2 Maximum 0.1% for products for oral hygiene, 5% for nail
hardeners
Imidazolidinyl urea 0.6
Methenamine 0.15
Paraformaldehyde 0.2 Maximum 0.1% for products for oral hygiene, 5% for nail
hardeners
Quaternium-15 0.2
Sodium methylhydroxyglycinate 0.5
4.3 Risk of Formaldehyde-Releaser stay-on cosmetics preserved with quaternium-

Containing Products 15, diazolidinyl urea, DMDM hydantoin, or
for Patients Allergic imidazolidinyl urea, especially when they are
to Formaldehyde to be used regularly and/or on “sensitive” or
damaged skin (De Groot 2010b). Rinse-off
Whether cosmetic products containing for- products in general will have a low risk of caus-
maldehyde-releasers will cause allergic contact ing allergic contact dermatitis.
dermatitis in patients who are sensitive to form-
aldehyde depends on various factors (Table 6).
The amount of free and releasable formaldehyde 4.4 Occupational Allergic Contact
in a product is determined – inter alia – by the Dermatitis from Formaldehyde-
nature of the releaser, its concentration, the prod- Releasers in Cosmetics
uct composition, and the storage conditions.
However, the pH of the product, its age, and 4.4.1 Quaternium-15
presence of other ingredients may heavily influ- Health-care workers are more often contact aller-
ence the concentration of free formaldehyde. gic to quaternium-15, which is ascribed to the
Although it is unknown what level of formalde- more frequent use of handwashing preparations
hyde in products is safe, concentrations of over and moisturizers (Kadivar and Belsito 2015;
200 ppm probably are not (at least for some Higgins et al. 2016). Other occupations with
formaldehyde allergic subjects) (De Groot et al. overrepresentation of contact allergy to
2009). All releasers used in cosmetic products quaternium-15 include the food industry, hair-
(with the exception of 2-bromo-2-nitropropane- dressers, and cosmetologists, presumably from
1,3-diol, for which adequate data are lacking) similar preparations and cosmetics (Warshaw
can – in the right circumstances of concentration et al. 2007). Yet, occupational allergic contact
and product composition – release >200 ppm dermatitis from quaternium-15 is relatively rare.
formaldehyde, which may result in a number Among 60 positive patch tests to quaternium-15
of patients in allergic contact dermatitis. considered to be relevant, there were only 3 cases
Whether this is actually the case in any particu- of occupational contact dermatitis, caused by
lar product, cannot be decided on the basis hair products and a barrier cream (Parker and
of ingredient labelling. It is thus prudent Taylor 1991). Also, in a Finnish occupational
that patients allergic to formaldehyde avoid contact dermatitis clinic, in a period of 6.5
years, only one case of occupational contact
Table 6 Factors that determine the risk for patients hyper- dermatitis from quaternium-15 was seen, a main-
sensitive to formaldehyde to develop allergic contact
dermatitis from contact with products containing formal-
tenance man reacting to the preservative in a
dehyde-releasers protecting cream (Aalto-Korte et al. 2008).
Strength of the allergy to formaldehyde in the individual
Published cases of occupational quaternium-
patient 15 allergic contact dermatitis were caused by an
Amount and concentration of free and (upon passage electroencephalography skin preparation in a neu-
through the skin) releasable formaldehyde in the rophysiology technician, photocopier toner, a bar-
particular product rier cream (Parker and Taylor 1991), and an
Nature of the product (e.g., stay-on versus rinse-off industrial cleaner, leading to hand dermatitis and
products)
occupational nail dystrophy (De Groot and
Frequency and duration of skin contact with the products
Localization of skin contact (e.g., thin skin of eyelids or
Flyvholm 2012; De Groot 2018).
thick skin of the trunk)
Skin status (normal, dry with impaired barrier function, 4.4.2 2-Bromo-2-nitropropane-1,3-diol
dermatitis) 2-Bromo-2-nitropropane-1,3-diol has been re-
Concomitant or successive contact with other products ported as occupational allergen in nylon spin
containing formaldehyde or -releasers finish, in milk recorders, in a veterinary surgeon
by its presence in a lubricant, and in a heavy duty sensitization in unselected contact dermatitis
cleaner in a motor mechanic (De Groot and patients (routine testing) remains largely
Flyvholm 2012; De Groot 2018). unknown. The high percentages of positive reac-
tions to Bioban ® CS-1135 and Bioban ® CS-1246
4.4.3 Other Formaldehyde-Releasers (Anderson et al. 2007) and to tris
in Cosmetics (N-hydroxyethyl)hexahydrotriazine (Davis et al.
A female nurse working in a neonatal intensive 2008) in two tertiary US referral centers should
care unit developed occupational allergic con- not be taken as representative. They may be due to
tact dermatitis of the hands from diazolidinyl stricter selection before being patch tested, form-
urea in an antimicrobial hand gel (Cahill aldehyde sensitivity as a cause of positive patch
and Nixon 2011). A nurse had occupational tests, and possibly false-positive reactions.
allergic contact dermatitis from formaldehyde Most studies have been performed in selected
released by benzylhemiformal in a liquid deter- patients in contact with MWF suspected of occu-
gent and a sweet worker from a dishwashing pational contact dermatitis. In these groups,
liquid containing benzylhemiformal (Aalto- mean prevalences of contact allergy were 2.8%
Korte et al. 2008). for Bioban ® CS-1135, 1.9% for Bioban ®
CS-1246, 1.9% for Bioban ® P-1487, 4.0% for
N,N0 -methylenebis(5-methyloxazolidine), 4.9%
5 Metalworking Fluids for 4,40 -methylenedimorpholine (one small study
with 144 patients), 1.6% for tris(N-hydroxyethyl)
The functions of metalworking fluids (MWF) are hexahydrotriazine, and 0.2% for tris(hydrox-
primarily those of cooling and lubrication. For ymethyl)nitromethane. In larger groups of
these purposes, MWF are directed at the interface selected patients (selection procedure usually
of the metal workpiece and the cutting edge of the unknown but not patients suspected of MWF der-
machine tool. Traditionally, MWF may be classi- matitis), generally the same or lower prevalences
fied as insoluble (neat) oils or soluble oils. Soluble were observed. It thus appears that most
oils are usually oil in water emulsions but some- formaldehyde-releasers in MWF cannot be con-
times true aqueous solutions. Biocides such as the sidered frequent and important contact allergens.
formaldehyde-releasers are mixed into water- Even in highly selected patients groups – i.e.,
soluble oils to inhibit the overgrowth of bacterial metalworkers in contact with MWF suspected of
and fungal populations. Such overgrowth, which occupational contact dermatitis – generally mod-
occurs particularly at oil-water interfaces, is est prevalence rates have been observed. In the
responsible for problems of foul odor (“Monday case of the Biobans, it should further be noted that
morning stink”) and results in decreased tool life most patch test reactions are only weakly positive
(metal corrosion), loss of cutting oil function, (+) and that they are often not reproducible, which
increased frictional heat, increased power con- suggests that many may be irritant (false-positive)
sumption, and rust. Bacterial growth in these (Brinkmeier et al. 2002). The most frequent con-
fluids can also cause emulsion breakdown, poor tact sensitizer appears to be N,N0 -methylenebis
surface finish, excessive solid loads on filters and (5-methyloxazolidine).
clarifiers (i.e., slimes and deposits), and discolor-
ations (De Groot et al. 2010e).
5.2 Relevance of Positive Reactions
5.1 Contact Allergy Relevance data on positive patch tests to Bioban ®

CS-1135, Bioban ® CS-1246, and \tris(hydroxy-
The results of patch testing with formaldehyde- methyl)nitromethane are not available; positive
releasers used in MWF in selected patient groups patch test reactions to Bioban ® P-1487 and
are summarized in Table 3. The frequency of 4,40 -methylenedimorpholine appear to be rarely
relevant. In the case of N,N0 -methylenebis metalworkers with occupational dermatitis

(5-methyloxazolidine), the relevance of positive exposed to water-based MWF had a significantly
patch reactions has been stated in one study only increased risk of sensitization to formaldehyde
and was found to be 47% (7/15 patients) (Madan (odds ratio 4.1) compared to men not working in
and Beck 2006). There is extensive literature on the metal industry (Geier et al. 2004b).
contact allergy to tris(N-hydroxyethyl)hexa-
hydrotriazine, but relevance has been addressed
in a mere two studies. Of 24 patients with 5.4 Occupational Contact
positive reactions to tris(N-hydroxyethyl)hexa- Dermatitis from Formaldehyde-
hydrotriazine seen at the Finnish Institute of Releasers in Metalworking
Occupational Health, only 2 were exposed to Fluids
a MWF containing tris(N-hydroxyethyl)hexa-
hydrotriazine (Aalto-Korte et al. 2008). Occupational hand dermatitis is common in met-
The lack of data on the clinical relevance of alworkers exposed to MWF. In one study, current
contact allergy to formaldehyde-releasers in skin symptoms were reported by 10% of metal-
MWF may partly be explained by the difficulty workers (Mirabelli et al. 2009). The prevalence or
of establishing exposure. Also, in the safety data 3-year incidence of hand eczema has also been
sheets (SDS) of other chemicals, the information found to be 20–25% (Berndt et al. 2000). Irritant
on the sensitizing substances has sometimes been contact dermatitis is more frequently observed
found to be deficient (Henricks-Eckerman et al. than allergic contact dermatitis. Skin irritation by
2008). In the case of the Biobans, another expla- MWF is not only caused by wet work but also by
nation for the lack of established relevance may be the alkaline pH usually ranging from 8.5 to 9.6
that a number of the patch test reactions were and by emulsifiers and biocides in the fluids.
actually false-positive (Brinkmeier et al. 2002). Irritant dermatitis promotes and may precede con-
tact sensitization, often caused by biocides, par-
ticularly formaldehyde-releasers (Geier et al.
5.3 Risk of Formaldehyde-Releaser 2004a, b; Suuronen et al. 2007).
Containing Products In several studies, patients suspected of occupa-
for Patients Allergic tional contact dermatitis and/or metalworkers in con-
to Formaldehyde tact with metalworking fluids have been patch tested
with formaldehyde-releasers. In only a few of these
Most metalworking fluid concentrates contain studies were positive patch tests often related to
formaldehyde in concentrations ranging from occupational contact with metalworking fluids, nota-
0.002% to 1.3% (free and easily released formal- bly with N,N0 -methylenebis(5-methyloxazolidine)
dehyde) (Henricks-Eckerman et al. 2008). There (Madan and Beck 2006). This formaldehyde-
appear to be no data on the free and releasable releaser has also caused occupational contact derma-
formaldehyde content in fresh and used MWF in titis in nylon spin finish (Batta et al. 1999).
dilutions of actual use. As a consequence, there is Hand eczema in an engine fitter was (not quite
insufficient information to estimate the risk of convincingly) ascribed to Forcide ® 78 I (see
sensitization in workers exposed to MWF and of Table 1 for details) (Hamann 1980). Two machin-
elicitation of dermatitis in individuals previously ists with hand eczema, who had contact with
sensitized to formaldehyde. However, it is well products containing tris(hydroxymethyl)nitro-
known that sensitization to formaldehyde from methane, reacted to this releaser 1% pet (Robert-
these sources does occur and is by no means son and Storrs 1982). A male fitter working in an
rare. In a recent Finnish study, for example, 40% engineering company had dermatitis of the hands
of new occupational sensitizations to formalde- from N,N-methylenebismorpholine in a cutting
hyde were seen in metalworkers (Aalto-Korte oil, probably the result of formaldehyde contact
et al. 2008). In a German/Austrian/Swiss study, allergy (Field et al. 2010).
6 Textiles and Clothes: Durable In the USA, most cases of allergic contact der-
Press Chemical Finishes matitis were attributed to formaldehyde released
from the DPCF; in Israel, however, only about
Durable press chemical finishes (DPCF) have one-third of the patients with positive patch test
been used on fabrics since the mid-1920s to reactions to DPCF co-reacted to formaldehyde
impart wrinkle resistance during wear and laun- (tested at 1%, so many cases of formaldehyde
dering. Their application primarily concerns cot- sensitization may have gone unnoticed). This
ton, viscose, linen, and their blends with synthetic leads to the conclusion that the DPCF per se must
fibres. DPCF can also facilitate bleaching and be sensitizers as well. However, all studies had one
dyeing, make fabrics waterproof, nonshrinkable or more (serious) flaws in design and/or interpreta-
and moth-proof; they can ameliorate nylon and tion. Recent testing of clothes for formaldehyde in
make it electrically antistatic. They give textile the USA, Europe, New Zealand, and other coun-
body and improve their quality, touch and tries demonstrated low levels of formaldehyde.
appearance. Such amounts (nearly always <200 ppm) are con-
sidered too low to cause sensitization to formalde-
hyde and also too low to elicit allergic contact
6.1 Contact Allergy dermatitis in individuals already allergic to formal-
dehyde (with the possible exception of a few
The early DPCF based on polyoxymethylene urea patients exquisitely sensitive to formaldehyde).
(urea-formaldehyde resin) and polyoxymethylene The concept of formaldehyde in clothes as the
melamine (melamine/formaldehyde resin) released cause of recent cases of dermatitis has not been
large amounts of formaldehyde in clothes; proven beyond doubt in a single case, and the
levels of 5000–12,000 ppm (0.5–1.2%) of same applies to DPCF as a putative allergen.
formaldehyde were found in rayon and cotton. Thus, the current use of durable press chemical
Consequently, allergic contact dermatitis due finishes in clothes is considered to be safe by
to formaldehyde present in textiles was com- some authors (De Groot and Maibach 2010; De
monly reported in the 1950s and 1960s, Groot et al. 2010d). The results of (routine) testing
especially in Europe. Formaldehyde from with DPCF are summarized in Table 3. A useful
deodorants and repeated exposure to fabrics review on the topic of allergic contact dermatitis
treated with DPCF served as the primary sen- from formaldehyde textile resins was provided in
sitizer in many of the cases. 2010 (Reich and Warshaw 2010).
As a result, the textile industry in the 1960s
started using finishes releasing less formaldehyde,
notably dimethylol dihydroxyethyleneurea. By 6.2 Occupational Contact
1981, the US textile industry claimed that levels Dermatitis to Formaldehyde-
of formaldehyde release had decreased so that Releasers in Durable Press
100–200 ppm was standard; these levels would Chemical Finishes
appear to be safe (Fisher et al. 1962). In spite of
this, there has been a resurrection of reports of Reports of occupational allergic contact dermatitis
allergic contact dermatitis to clothes from 1990 in to DPCF in the textile industry and to clothes in an
the USA (Sherertz 1992; Fowler et al. 1992; occupational setting are infrequent in the past
Scheman et al. 1998; Metzler-Brenckle and 30 years. A US pediatrician developed dermatitis
Rietschel 2002) and in Israel (Lazarov et al. attributed to a hospital gown and a face mask,
2000, 2002; Lazarov 2004). The availability of unconvincingly attributed to formaldehyde (Dono-
DPCF for patch testing, including the test mix van and Sloynicki-Grant 2006). Of 17 patients
ethylene urea, melamine/formaldehyde, facili- reacting to ethylene urea, melamine/formaldehyde
tated the investigation of patients suspected of resin (EUMF) investigated in the USA, there were
textile dermatitis. 6 occupational cases: 3 male retirees (one may
Table 7 Occupational allergic contact dermatitis to melamine/formaldehyde resin

No No. allergic to
pat formaldehyde Occupation/work activities Responsible products References
1 0 Melamine paper impregnating line Melamine/formaldehyde Gavin et al. 2008
1 0 Compositor in chipboard factory Melamine/formaldehyde Aalto-Korte et al.
resin coating 2003
1 0 Laboratory technician Melamine/formaldehyde Aalto-Korte et al.
glue 2003
1 0 Plywood worker Melamine/formaldehyde Aalto-Korte et al.
glue 2003
5 0 Workers in plant producing resin- Melamine/formaldehyde Isaksson et al. 1999
fibre composites resin
1 ? ? ? Holness and
Nethercott 1997
1 0 Orthopedic plaster technician Orthopedic plaster Ross et al. 1992
1 1 Production of clay pots Gypsum moulds for clay Fregert 1981
pots
wonder how can this be occupational) and dermatitis; not a single case was caused by either
3 women, an office worker, a dialysis technician, formaldehyde or a DPCF (Gasperini et al. 1989).
and a machinist (Carlson et al. 2004). Among Investigators in Spain ascribed petechial facial der-
83 Israeli patients reacting to either a DPCF or a matitis in a patient working in a textile plant to
color used in clothes, there were 4 occupational contact with wool on the basis of a positive patch
cases (occupation not specified) (Lazarov 2004). A test reaction to formaldehyde and 2 high-
man handling new ready-made clothes in a ware- formaldehyde DPCF (Romaguera et al. 1981). The
house had eczema on the hands that improved dur- validity of many if not most of these reports may be
ing weekends and holidays. Patch tests were doubted, as confirmation of the presence of the
positive to formaldehyde, quaternium-15, and eth- incriminated DPCF and/or formaldehyde in the
ylene urea, melamine/formaldehyde (Cockayne alleged culprit products was nearly always lacking.
et al. 2001). From Spain one (atopic) patient was There have been several reports of occupa-
reported with hand eczema that got worse when tional contact dermatitis from melamine/formal-
replacing clothes in a store (Bracamonte et al. dehyde resin but all outside the textile industry;
1995). She reacted to formaldehyde and several their details are summarized in Table 7.
(high-formaldehyde) DPCF. In the USA, between
1989 and 1994, 19 patients were investigated with
dermatitis who were occupationally involved with 7 Miscellaneous Formaldehyde-
finished textile products. Six were diagnosed as Releasers
suffering from allergic contact dermatitis to DPCF
on the basis of a positive patch test to formaldehyde 7.1 Contact Allergy
or a DPCF (Soni and Sherertz 1996). Between 1975
and 1993, the average annual incidence of A rest group of formaldehyde-releasers (Table 1)
formaldehyde-related occupational contact dermati- has various applications and functions (Table 4).
tis in the Finnish textile and clothing industries was None of these is an important cause of allergic
0.66/10.000 (Priha 1995). In a US case series (Fow- contact dermatitis (Table 3). Methenamine has
ler et al. 1992), there were 4 cases of occupational structural similarities to quaternium-15, and about
contact dermatitis (2 garment workers, 1 printer, and one in three patients allergic to quaternium-15 will
1 chemical worker) among 16 patients sensitized to also have positive patch tests to methenamine. This
DPCF. From Italy came a report on 62 textile and is presumably unrelated to formaldehyde sensitiv-
garment industry workers with allergic contact ity (Aalto-Korte 2000).
7.2 Occupational Contact Batta K, McVittie S, Foulds IS (1999) Occupational aller-

Dermatitis from Miscellaneous gic contact dermatitis from N,N-methylene-bis-3-
methyl-oxazolidine in a nylon spin finish. Contact
Formaldehyde-Releasers Dermatitis 41:165
Berndt U, Hinnen U, Iliev D et al (2000) Hand eczema in
7.2.1 Methenamine metalworker trainees – an analysis of risk factors. Con-
A Japanese foundry worker had hand eczema tact Dermatitis 43:327–332
Bracamonte BG, Ortiz de Frutos FJ, Iglesias Diez L (1995)
caused by occupational contact with methenamine Occupational allergic contact dermatitis due to formal-
in a core moulding process (De Groot 2018). Two dehyde and textile finish resins. Contact Dermatitis
patients developed eczema (located at exposed skin 33:139–140
areas in one subject and generalized in the other) Brinkmeier T, Geier J, Lepoittevin J-P et al (2002) Patch
test reactions to biobans in metalworkers are often
and conjunctivitis probably caused by contact weak and not reproducible. Contact Dermatitis
allergy to methenamine (Merget et al. 1999). In 47:27–31
early years, methenamine was a frequent sensitizer Cahill JL, Nixon RL (2011) Allergic contact dermatitis in
in the rubber industry (De Groot 2018). health care workers to diazolidinyl urea present in
antimicrobial hand gel. Med J Aust 194:664–665
Carlson RM, Smith MC, Nedorost ST (2004) Diagnosis
and treatment of dermatitis due to formaldehyde resins
7.2.2 N-Methylolchloroacetamide
in clothing. Dermatitis 15:169–175
In older literature, N-Methylolchloroacetamide Cockayne SE, McDonagh AJ, Gawdrodger DJ (2001)
has been reported as a cause of occupational Occupational allergic contact dermatitis from formal-
allergic contact dermatitis from its presence in dehyde resin in clothing. Contact Dermatitis
44:109–110
“spin finish” (Savage 1978), plasticine (Farli
Cronin E (1991) Formaldehyde is a significant allergen in
et al. 1987), preservative (Ågren et al. 1980), women with hand eczema. Contact Dermatitis
coolant oil (Hjorth 1979), and glue (Pereira et al. 25:276–282
1999). Patients allergic to N-Methylolchlora- Davis MD, Scalf LA, Yiannias JA et al (2008) Changing
trends and allergens in the patch test standard series. A
cetamide may co-react to formaldehyde and/or
Mayo Clinic 5-year retrospective review, January
chloroacetamide, from which N-Methylolchlora- 1, 2001, through December 31, 2005. Arch Dermatol
cetamide is synthetized. 144:67–72
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Fiberglass, Dusts
38
Daniel J. Hogan, Megan Morrison, and Anand Desai
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
2 Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
2.1 Centrifugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
2.2 Blowing Through Hot Gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
2.3 Thinning by Flame . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
3.1 Irritant Contact Dermatitis (ICD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
3.2 Allergic Contact Dermatitis (ACD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547
3.3 Airborne Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
3.4 Atopic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
4 Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550
5 Hardening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
6 Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554
6.1 Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554
6.2 Alternative Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
7 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
8 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
Abstract
Production of fiberglass is increasing.
D. J. Hogan (*)
Internal Medicine (Dermatology) NOVA Southeastern Airborne dermatitis may be caused by
University College of Osteopathic Medicine, Davie, FL, fiberglass.
USA Irritant contact dermatitis is usually caused
e-mail: daniel.hogan@va.gov by fibers greater in diameter than 4.5 μm.
M. Morrison Hardening is not prominent and may be less
Stones River Dermatology, Murfreesboro, TN, USA likely to develop in atopics.
A. Desai Histopathology of dermatitis is nonspecific
University of Central Florida College of Medicine, unless the fiberglass is itself visualized in the
Orlando, FL, USA
e-mail: AnandDesai@Knights.ucf.edu skin biopsy or skin tape stripping.

https://doi.org/10.1007/978-3-319-68617-2_38
544 D. J. Hogan et al.
Treatment is nonspecific except for taking Table 1 Classification and mean diameter of MMVF.
measures to curtail exposure to fiberglass and (Modified from Stam-Westerveld 1995)
where possible to identify sources of exposure. Mean diameter
Classification Material (μm)
Keywords Glass filament Glass 6–25
fibers
Airborne contact dermatitis
Mineral wool Glass wool 4–9
Rock wool 4–6
Slag wool 4–6
1 Introduction Refractory ceramic Ceramic 2.5–4
fibers fibers
Fiberglass is a type of man-made vitreous fiber Fibers for special Glass 0.2–1.5
(MMVF). There are four general groups of purposes fibers
MMVF (Table 1): glass filament, mineral wool
(glass wool, rock wool, and slag wool), refractory
Table 2 Uses of MMVF. (Adapted from Stam-
ceramic fibers, and fibers for special purposes Westerveld 1995)
(Jolanki et al. 2002).
Classification Uses
We will be focusing on glass filament MMVF,
Glass filament Textiles
also known as fiberglass. Fiberglass is the most Reinforcement of plastics,
commonly used mineral fiber because of its wide cement, papers, and roofing
variety of uses. It has replaced asbestos as the materials
insulation of choice because the health risk Mineral wool Thermal insulation
involved is less. As opposed to asbestos which Acoustic insulation
breaks longitudinally to make many finer thin Fire protection
fibers, the fiberglass breaks transversely to give Horticultural growing media
rise to many smaller fibers of the same diameter Refractory ceramic High temperature insulation
fibers
(Sertoli et al. 1992). Also, compared to asbestos,
Fibers for special Aircraft insulation
which is a natural mineral, fiberglass can be pro- purposes (textile Spacecraft insulation
duced in various dimensions and is best suited to fibers) Filtration applications
meet the required use. Curtains
Since 2002, the demand for fiberglass has been
rapidly growing. Between 2002 and 2006, the
production capacity increased dramatically at an workability (Sertoli et al. 2000). Glass fibers and
annual growth rate of 33%. China is the main other MMVP products have a variety of uses
supplier of fiberglass and provided 76% of (Tables 2 and 3). Depending on their function,
the global fiberglass output in 2011. Due to a they can be made into wool or fibers. Glass wool
continued anticipated increase in demand at this is commonly used to reinforce polymer products
time, China planned to increase growth in the and make heat and sound insulation. Glass fibers
fiberglass industry during 2014–2015. In 2011 are used in the textile industry to make curtains
the global output of fiberglass was 4.88 million and draperies. These thin fibers are friable and
tons, while the demand was 4.66 million tons. The easily break into microscopic particles. Dust is
estimated fiberglass demand increased in 2012 to made up of fragmented glass fibers and plastic
4.94 million tons (ReportLinker 2012). particles, which are easily carried in the air
Fiberglass is made from thin strands of glass, due to their microscopic size, causing airborne
the basis of which is silica, SiO2. These strands are diseases or dust mechanical irritation of the skin
produced through fusion at temperatures ranging and lungs. Contact with the dust can lead to mild
from 1000 C to 1500 C, after which point they respiratory symptoms, itching, and eczema
are filtered of the siliceous-based mixtures which (Minamoto et al. 2002; Cusano and Mariano
contain earthy alkaline additives to improve their 2007).
38 Fiberglass, Dusts 545
Table 3 Uses of fiberglass. (Adapted from Sertoli et al. Table 4 Resins used with fiberglass leading to ACD.
2000) (Adapted from Björnberg 1985)
Use Type Product Epoxy resin
Acoustic Glass wool Used for the Phenyl-formaldehyde resin
insulators internal setting of Polyvinyl acetate
public buildings, Silicones
usually in the form
Urea
of panels
Starch
Thermal Glass wool Mattresses
insulators Ammonium hydroxide
Felts
Mineral oil
Fiberglass tissues
Dyes
Insulation for
water pipes,
stoves, under-roof
coverings in A variety of resins are added to assist in the
houses various functions of the fiberglass, which can
with wave-form induce allergic contact dermatitis. Commonly
ceiling boards used additives are listed in Table 4.
Aircraft industry Fiberglass dermatitis occurs primarily
Printed circuit
in the workplace and was first described
boards (PRCB)
Electrical Glass fibers Insulation of
in the 1940s by Sulzberger and Baer (1942). Expo-
insulators motors sure is almost impossible to avoid in the building
Insulation of wires industry and glass wool factories.
Insulation
of electric
cables 2 Production
Reinforcing Glass fibers/wools Reinforced plastic
material with polyester, Used in the As mentioned earlier, glass fibers are pro-
epoxy and aircraft, duced at extremely high temperatures ranging from
melaminic resins automotive, naval
and railway
1000 C to 1500 C. Three methods are curren-
industries to make tly still in use for the production of glass fibers:
doors, hulls, centrifugation, blowing with hot gasses, and thin-
boards, etc. ning by flame (Sertoli et al. 2000).
Sportswear
Printed material
Filtering Glass fibers Shaping tissues 2.1 Centrifugation
material for air filters, gas
filters and liquid
filters for Special rotating drums are utilized to churn the
chemistry labs, vitreous mixture. As the mixture exits the furnace,
food and drunk it is melted at high temperatures and percolates
industries through small holes in the shape of the primary
Air filters for filaments, which are then thinned by a high-pressure
private and public
air circulating fluid flux. This enables fibers to maintain a diameter
systems between 6 and 7 μm (Sertoli et al. 2000) (Fig. 1).
Fiberglass is also used to make casts and den- 2.2 Blowing Through Hot Gases
tures. Fiberglass casts require less maintenance
than the plastic casts, so are the preferred material, This technique is similar to centrifugation, but
and are excellent additives for dentures because instead of exiting through a rotating drum,
it solidifies dental implants. the melted magma exits by gravity out of the
3 Pathogenesis
The fiberglass is not only a primary irritant but

may also contain a sensitizer. Because of this
it can induce either an irritant contact dermatitis
(ICD) or an allergic contact dermatitis (ACD).
It is mainly transmitted directly, but because
of its small size and ease of breakage, it
often travels airborne to lead to cutaneous and
respiratory problems. Atopics have been identi-
fied as susceptible targets for the effects
of fiberglass.
3.1 Irritant Contact Dermatitis (ICD)
While it is suspected that the pathogenesis of

ICD is due to inflammatory mechanisms, the spe-
cifics of this process are not known (Patterson
Fig. 1 Fiberglass inline centrifugal blower (http://www.
2016). Polymorphisms compromising function
troymfg.com/fans/blow_inline.html)
of filaggrin predispose to chronic irritant contact
dermatitis (Patterson 2016). Since glass itself
special crucible. In this method a gaseous jet
is chemically inert, the dermatitis is actually due
is used, instead of a fluid jet, to thin the fibers to
to the fiberglass fragments breaking through the
a diameter of 15 μm (Sertoli et al. 2000). This
epidermis, leading to direct microtrauma. The
method produces more fiberglass dusts due to the
severity of the irritant is inversely proportional to
blowing process, which can lead to respiratory
length and directly proportional to the diameter of
problems. These effects are discussed later.
the fiber. It has been reported that irritation
is mainly caused with fibers exceeding 4.5 μm
(Stam-Westerveld 1995; Hogan 2008). These
2.3 Thinning by Flame
microscopic fibers can be seen in the stratum
corneum or dermis (Patterson 2016). They pene-
In this technique, after the vitreous substance is
trate through the stratum corneum, leading to
thinned into the primary filaments, it is transferred
epidermal cellular changes and cytokine release
to an inner combustible chamber where high-
(Hogan 2008). The particles can be transferred to
speed gas jets thin the filaments to 1 μm or less
the worker by direct contact with the fiberglass,
in diameter using high temperatures. The length of
contact with contaminated surfaces, contact with
this continuous filament is 10 cm at most. After
garment embedded with fibers, indirect contact
this process of thinning the glass, the fibers are
with fiber dust on the skin, and inhalation of
treated with different resins to bind, protect, and
the fiber dust. The clinical appearance of ICD
lubricate the fiberglass, especially if it is to be used
resembles other eczematous reactions and is
for reinforced plastics (Sertoli et al. 2000).
almost indistinguishable from ACD (Frosch and
After this process is complete, the fiberglass is
John 2006).
reinforced with resins. Glass wool is produced by
spinning a vitreous mixture into wool and is used
in acoustic and heat insulation (Tables 2 and 3) 3.1.1 Acute
with a maximum operating temperature of 450 C Acute ICD elicits keratinocytic changes that vary
(Sertoli et al. 1992). based on the irritating substance.
3.1.2 Chronic shows nonspecific changes due to minor trauma and

Chronic ICD is also referred to as “cumulative features of eczema. In a study of 410 patients with
insult dermatitis” and by definition persists for chronic eczematous dermatitis reported by
a considerable time period with a minimum of Rietschel, it was established that atopic patients
6 weeks (Frosch and John 2006). Histologically were just as likely to have allergic contact dermatitis
the keratinocytic changes have been described as as nonatopic patients and that they would also ben-
one of hyperkeratosis with areas of parakeratosis, efit from patch testing. Also, atopic dermatitis
moderate to marked acanthosis and elongation patients had significantly more positive patch tests
of the rete ridges, with increased numbers of (2.7 vs. 2.0) than nonatopic dermatitis patients.
Langerhans cells in the epidermis and dermis Patch testing done on 66 fiberglass spinners in
(Willis 1996). The ICD is usually aggravated Germany showed epoxy resin to be the most com-
by hand washing with water, which directly dis- mon allergen in 54% of the workers (Cronin
rupts the stratum corneum lipid lamellar bilayers 1980). Patch testing to epoxy resin can help dis-
(Frosch and John 2006). Fiberglass rarely causes tinguish allergic contact dermatitis to epoxy from
a chronic ICD due to hardening of the skin. cutaneous irritation caused by fiberglass (James
et al. 2016), but a negative result does not exclude
the resin product as the cause of the allergic der-
3.2 Allergic Contact Dermatitis matitis. There may be a different epoxy resin in
(ACD) the product or another compound in the resin such
as dyes, fillers, plasticizers, or the hardener that
Sensitization causes an ACD reaction, which is not could be causing the allergy. In a PRCB factory,
directly caused by the fiberglass trauma but is a 19 workers were tested, and 6 were positive in a
response to the body’s sensitization to resins and patch test for epoxy resin (Sertoli et al. 2000).
additives in the fiberglass (Table 4). The most com- Also, in a ski factory where the plastics were
mon causes of ACD are cobalt, peroxides, para- fiberglass reinforced, 6 out of 22 workers pre-
tertiary butyl catechol (PTBC), and unsaturated sented with sensitization to epoxy, and all had
polyester (UP) base resin which are commonly dermatitis on the back of their hands (Jolanki
used in the production of fiberglass-reinforced plas- et al. 1996). Conversely, many patients test pos-
tic (Minamoto et al. 2002). After an allergen enters itively to epoxy resin in patch testing without
the skin, it binds a hapten to create a complete having a history of contact (Andersen et al.
antigen which is then shown to T lymphocytes 1992). This can be due to exposure to uncured
as part of the induction phase (Patterson 2016). resin in common plastic products on a daily
As a result, as opposed to ICD, ACD may not basis. Another resin to produce a positive patch
present with symptoms until at least the second test was discovered in a case by Kalimo et al. A
exposure, after the Langerhans cells have migrated 46-year-old glass wool delivery truck driver in
and matured. The initial sensitization takes Finland had a positive patch test to p-tert-
10–14 days, after which a subsequent exposure butylphenol-formaldehyde resin after presenting
can produce a response in several hours or days with loss of voice (1980).
(Hogan and May 2007; Hogan 2008). Trace
amounts of contaminants such as arsenic, mercury, 3.2.2 Rubbing Tests
lead, or cadmium can be found in fiberglass and This test has been used to establish the diameters
rock wool insulation (Adams 1999). and lengths at which the MMVF is the most
irritating. Assessment of the reaction can be ana-
3.2.1 Patch Testing lyzed using laser Doppler flowmetry and ery-
Patch testing has shown that the irritation caused by thema scores. Studies using this test have
fiber glass and glass wool is transient in nature and is established that the smaller diameter fibers (less
directly related to the diameter of the fiber (Stam- than 4.5 μm) are less irritating to the skin (Stam-
Westerveld 1995). The histology of the patch test Westerveld et al. 1993).
3.2.3 Resins upholstery. It is also used for construction mate-

rials, such as laminated floors, and in the produc-
Epoxy Resin tion of fiberglass and mineral fiber insulation. It
Epoxy resins are used daily as additives in various acts as a modifier in resin manufacturing (Ander-
materials to act as an adhesive. Epoxy resins are sen et al. 1992).
not alone in the materials they harden. They are In the case mentioned earlier studied by
combined with fillers, pigments, plasticizers, reac- Kalimo et al., a 46-year-old truck driver had
tive diluents, and solvents, which are all mixed been loading and delivering glass wool rolls
together with a hardening agent to cure the resin. used for thermal insulation and air filters since
The higher the molecular weight of the epoxy 1972. He developed aphonia without any cutane-
resin, the less sensitizing the compound is. After ous symptoms and tested positive for both a type
hardening, the cured resins are less sensitizing, 1 and delayed type 4 hypersensitivity reactions to
but hardened resins are known to contain some PTBP resin. Sixty minutes after patch test appli-
uncured molecules which lead to sensitization cation, an urticarial reaction was seen, and after
(Andersen et al. 1992). 3 days a delayed type 4 reaction also developed
One of the most common routes of epoxy resin (Rietschel and Fowler 2008b) (Fig. 3).
sensitization is the epoxy resin used in fiberglass.
This combination produces strong sheets with
many uses, such as hulls for boats and ships 3.3 Airborne Contact Dermatitis
and electrical insulation (Andersen et al. 1992).
Another common use for the combination of Any fibrous material can give rise to an airborne
epoxy resin and fiberglass is in the production contact dermatitis when it is circulated in the work
of printed circuit boards (PRCB). In this, the fire- place. Glass fiber, rock wool, and grain dust are
proof core made up of fiberglass is soaked in bro- examples of some fibrous materials that can lead
minated epoxy resin and wrapped in an outer layer to mechanical dermatitis. These dusts impregnate
of copper sheets (Wang et al. 1993). In the produc- themselves in the fabric of clothing and accumu-
tion of skis, plastic sheets that are reinforced with late in skin folds (Veien 1992). These areas, for
glass fibers are laminated with sheets in epoxy example, the eyelids and neck (beside the shirt
resins (Jolanki et al. 1996) (Fig. 2). line), are irritated by friction and can sometimes
mimic photo contact dermatitis.
p-Tert-Butylphenol-Formaldehyde Resin Airborne contact dermatitis that affects the
(PTBP) lung has been correlated with the length and
PTBP is a very adhesive substance which is dura- diameter of the glass fiber. The hazard is inversely
ble and pliable and has good strength and high proportional to the diameter and length. Fibers
temperatures. Because of its pliability, it is mainly with a length between 5 pm and 80 μm with
utilized as an adhesive or glue in the manufactur- a diameter less than 3 μm can reach the peripheral
ing of rubber shoes and leather goods, neoprene areas of the lung to create a potential bronchop-
adhesives, and glues for furniture and auto neumopathy hazard (Sertoli et al. 2000).
Fig. 2 Epoxy resin

Fig. 3 PTBP in patients with AD and may thus also play a role
(Irvine et al. 2016). Antigen-presenting cells in
both epidermis and dermis express IgE on their
surface significantly more than patients with irri-
tant contact dermatitis or allergic contact dermati-
tis. There is some evidence that substances from
the horny layer of skin may induce reactions in
people with atopic skin. Such substances include
skin’s own constituents, soil, and products of
microorganisms that colonize the skin (e.g., staph-
ylococci) (Rietschel and Fowler 2008b). It has
been observed that there is an inverse relationship
related to the clinical severity of atopic dermatitis
and contact sensitization in atopic dermatitis
3.4 Atopic Dermatitis (Rietschel and Fowler 2008b). A female predom-
inance has been reported in atopic patients. In a
The cause of atopic dermatitis (AD) has yet to be study reported by Rietschel and Fowler, out of
firmly established. Genetic research suggests 74 atopic dermatitis patients with persistent facial
filaggrin loss of function mutations can be associ- dermatitis, 39.2% had one or more positive patch
ated with AD (Irvine et al. 2016). The “hygiene test, while 31 out of the 40 positive tests were
hypothesis” attributes the sensitivity to reduced females (2008).
microbial exposure in childhood, which helps to Atopic patients have been advised in the past to
explain why people from well-developed coun- not work with glass fibers because of a low thresh-
tries are more prone to AD. The allergens that are old for itch and an increased risk of being affected
most important to AD patients are aeroallergens by the fiberglass (Adams 1999). Atopic eczema
and food allergens in children (Darsow and Ring renders skin vulnerable to nonspecific irritants
2003). The airborne spread of fiberglass dusts such as dust and dander, so when faced with an
particles puts AD patients at a heightened risk. abrasive irritant such as fiberglass, it is under-
The estimated prevalence of AD is 10–30%, standable as to why an atopic individual would
which is imprecise due to the disagreement have a heightened reaction. This decreased pru-
between physicians about criteria to make a firm ritic threshold is attributed to the innate perception
diagnosis. A set of criteria that can be agreed upon of mild mechanical stimulation as itch instead of
is the presence of atopy, pruritus, eczema, and as touch. Once the scratch has been itched, the
altered vascular reactivity (Beltrani and surrounding skin has increased liability to react to
Boguneiwicz 2003). It can also be loosely defined light stimuli with an itch sensation – a phenome-
as a susceptibility to start an itch and occurs when non called allokinesis (Beltrani and Boguneiwicz
usually harmless substances in the stratum 2003). A study done by Björnberg showed that
corneum meet and react with specific circulating rubbing tests may be a reliable way to determine
antibodies, presumably IgE (Rietschel and Fowler which workers are more sensitive to glass fiber-
2008b). It has been established that some patients induced itching. Despite this, a history of itching
with AD have elevated levels of IgE in their serum from synthetic textile fibers, wool, and hot baths
which may correlate with the disease severity. was of no value to predicting itching from
One proposed hypothesis reported by Darsow fiberglass (1985).
and Ring states that Langerhans cells bind to and Studies reported by Cronin have shown that
present “immediate-type” allergens, which then patients with a history of irritant contact dermatitis
penetrate the impaired epidermal barrier in AD have a high chance of reoccurrence from a new
patients (2003). Type 2 innate lymphoid cells irritant. This has led to the understanding that
have also been found to be drastically increased some people are predisposed to irritant contact
dermatitis, or AD, and despite job changes and most likely due to large glass fibers. This has
different chemical exposures, the dermatitis is been reported as a familial fiberglass micro-
likely to recur. Because of this, not all irritant epidemic and appears clinically as scabies when
hand eczemas heal when the precipitating factor the workers’ clothes are mixed with underwear
is removed (1992). (Stam-Westerveld 1995).
In one case, a 36-year-old woman and her
husband had been treated for scabies for 3 months
4 Clinical Picture without results. The woman had a mild presenta-
tion with a pruritus follicular eruption, while the
Initial symptoms are most commonly intense husband presented more similarly to scabies with
pruritus and tingling at the site of exposure and marked folliculitis, popular urticaria, and linear
skin folds. Skin lesions are not always initially erosions in the creases. It was soon established
present but can appear within hours or days. that the husband had recently started a job at a
The characteristic dermatitis appears as pinpoint- fiberglass factory and had been washing his work
sized erythematous papules, which are often clothes at home with his wife’s. To determine if
follicular (Björnberg 1985; Stam-Westerveld this was the culprit, the husband was instructed to
1995). It appears like papular urticaria without apply talcum powder to his body every day before
papules. Irritation is most common on the hands, he put on his work clothes and to wash his cloth-
forearms, face, neck, and flexural areas where ing separately from his wife’s. One week after
clothing rubs. Other skin lesions can appear as these changes were made, the eruption on both
purpura, urticaria, petechiae, erosions, nummular the husband and wife completely subsided
eczema, and rarely paronychia due to penetration (Rietschel and Fowler 2008b). Scabies is distrib-
of glass spicules beneath the nail fold (Björnberg uted bilaterally on the wrists, elbows, ankles, and
1985; Stam-Westerveld 1995). The fragments and feet. The lesion is identified by the primary bur-
dust can penetrate clothing, so it is not uncommon row, which presents as a gray straight line. Itching,
for the dermatitis to be in a covered area. With the most common symptom, is more intense at
continued irritation, secondary changes may night, as opposed to fiberglass dermatitis which is
occur. These consist of lichenification, bacterial pruritic throughout the day. The main differenti-
infections, and excoriations (Björnberg 1985; ating features between scabies and fiberglass der-
Stam-Westerveld 1995). When present, an exco- matitis are the distribution of the lesions and the
riated folliculitis is most commonly located type of itching that it induces. Also scabies pruri-
on the arms, face, neck, and sometimes legs tus rarely relapses after treatment. In fiberglass
(Sertoli et al. 1992). Glass fibers and resins may dermatitis, the pruritus may improve when the
less commonly penetrate leather footwear leading irritant is removed but quickly relapses when
to maceration and dermatitis of the feet (Rietschel reintroduced.
and Fowler 2008b). Clothing purpura has been reported and pre-
Different environmental changes can aggra- sented as petechial and purpuric eruptions caused
vate the symptoms of the dermatitis. High tem- by woolen garments such as underwear and from
peratures and humidity in the summer or relative the water-soluble formaldehyde urea finish
low humidity in the winter can make diagnosis applied to the woolen khaki skirts worn by British
more difficult. The humidity is protective in the soldiers (Rietschel and Fowler 2008b). Many
fact that it prevents the airborne mechanism from other problems can present similarly to fiberglass
being started up while also supporting the sponta- dermatitis and are listed in Table 5.
neous elimination of fibers by gravity (Sertoli The transmission of fiberglass in the laundry
et al. 2000). is not limited to workers’ clothing. There have
The irritant dermatitis may appear “conta- been reports of family outbreaks of fiberglass
gious,” as the fibers can be transferred to family dermatitis when fiberglass curtains were
members by mixing laundry. This dermatitis is washed with the clothes (Cronin 1980). Laundry
Table 5 Differential diagnosis with fiberglass dermatitis. A 37-year-old man experienced an intense pruritic
(Modified from Sertoli et al. 2000) eruption on his forearms after crawling through
By external cause an insulated attic (Chen et al. 2000).
Pediculosis Two waitresses in contact with serving trays in a
Swimmers prurigo restaurant (Cusano and Mariano 2007).
Phytodermatitis by thorns A 22-year-old man working in a scrap yard
Prurigo by irritant solid airborne particles removing heating pipes (Bordel-Gómez and
Actinic prurigo Miranda-Romero 2008).
Eczema prurigo
Five individuals employed by companies
Improper or excessive use of detergents
making aerogenerators in Spain (Larraga-
Side effects of drugs
Pinones et al. 2013)
By internal cause
A fiberglass epidemic occurred in Italy and was
Pruritus senilis
Psychosomatic pruritus
reported by Cusano and Mariano. Ten 8- to
Biliary stasis 9-year-old children and two female teachers
Diabetes mellitus experienced an acute skin itching eruption
Uremia with excoriated follicular papules and mild
Pregnancy (PUPP) respiratory symptoms after being exposed for
Dysthyroidisms 10 months to fiberglass felt from a hole kicked
Cancers in the wall of the classroom. History of atopy
Hodgkin’s disease or chronic leukemias was only present in one child (2007).
Myeloma The penetration of glass fragments into the hands
PUPP “pruritic urticarial papules and plaques of preg- of employees causing glass-hand syndrome
nancy.” This is an uncommon cause of third trimester which was first reported by Grzegorczyk in
itching with a polymorphous rash
1982. In this syndrome, there is a painful
sensation in the hands, without any skin
mats are often utilized by the public to lesions. These glass fragments can be visual-
wash fiberglass curtains, so caution must be ized by x-rays and computed axial tomogra-
exercised when using one for family clothing. phy. The fragments were shown to have
Because of this problem, the Department of penetrated into the hands reaching the subcu-
National Health and Welfare recommended for tis among the tendons and the interossei
curtains containing fiberglass to not be washed in (Sertoli et al. 2000).
the same laundry machine as clothing Several studies have recently been reported exam-
(National Institute of Occupational Safety and ining ocular injury due to fiberglass. Mostafavi
Health 1977). The proper way to wash et al. reported the first case of fiberglass as an
fiberglass curtains or fiberglass-laden clothing intraocular foreign body (2014). The patient
is with rubber gloves separately in a tub or reported no symptoms for 3 months, but the
basin that can be rinsed thoroughly after use foreign body was eventually identified upon
(Rietschel and Fowler 2008b). evaluation for preretinal hemorrhage. Because
Other rare cases of fiberglass dermatitis have fiberglass is an inert material that does not
been reported, and a few examples are listed: cause ocular inflammation, identification of
fiberglass intraocular foreign bodies can be
An 8-year-old girl experienced chronic ICD on difficult. Baile et al. report three cases of
the posterior thighs from sitting in fiberglass- glass wool foreign bodies in the eye (2014).
reinforced plastic chairs at school (Cronin These three patients were initially mis-
1980). diagnosed with conjunctivitis due to minimal
A 6-year-old girl came into contact with glass findings on slit-lamp exam, suggesting the
fiber when playing in a barn, leading to the need for thorough evaluation of occupational
formation of nodules (Sertoli et al. 1992). factors that could produce an intraocular
foreign body (Baile et al. 2014). Fiberglass small to cause any dermatologic symptoms. As
dermatitis has also been found to affect the stated earlier, cutaneous manifestations of fiber-
eyelids (Larraga-Pinones et al. 2013). glass irritation are not apparent until the fiber-
glass is 4.5 μm or larger.
Exposure to fiberglass has been associated A study done on rats and hamsters by
with various cancers. Mukhammadiyeva et al. McConnell showed that all vitreous fibers stimu-
suggest a relationship between skin cancer and late an inflammatory response, which is charac-
TP53 polymorphisms in individuals exposed to terized by the increase in the number of
fiberglass (2014). Further, asbestos is a well- pulmonary macrophages at the level of the termi-
established occupational carcinogen, and nal bronchioles and proximal alveoli (1994).
because of the similarities, a relationship of Hancu et al. performed a study on fiberglass in
MMVF and cancer has been suspected. In the rats’ respiratory tracts and demonstrated that, as
1950s a timeline of lung cancer and mesotheli- levels of IL8 increase, the number of lymphocyte
oma caused by asbestos was determined. It was in bronchoalveolar lavage fluid decreases, but
established that the average latency interval for the presence of lung pathology such as fibrosis
lung cancer caused by chronic asbestos exposure or emphysema increases. The only vitreous fiber
was 20 years and 25–50 years for mesothelioma in this study to show carcinogenic activity was
(Warheit et al. 2001). It was thought in the past refractory ceramic fibers, which produced a dose-
that MMVFs were nonrespirable because they related increase in primary lung neoplasms and
are generally manufactured as a continuous fila- mesotheliomas (McConnell 1994).
ment and the diameters usually exceeded 3 μm. A follow-up cohort study done in Ontario of
They were thought to be too large to penetrate the 2557 fiberglass workers between 1955 and 1997
distal lung, and if inhaled they would be trapped showed a significant increase in lung cancer
in the upper lung (Warheit et al. 2001). It has deaths, with a nonsignificant increase in chronic
since been determined that in the production of obstructive pulmonary disease and bronchitis.
fiberglass, small fractions of airborne fibers and The study focused on three groups of workers:
dusts can be generated during the blowing or workers only in the plant (Table 6), workers only
extruding process. These particles can travel in the office, and workers with mixed exposures.
into the alveoli to induce an airborne bronchop- There were slightly more respiratory disease
neumopathy. Glass fibers have also been shown deaths than expected, and the standardized mor-
to cause oxidative stress on alveolar cells, which tality ratio (SMR) was lower for office workers
can injure these cells and their DNA (Rapisarda for all selective causes. The study also focused
et al. 2015). Toxicological research done on syn- on establishing a relationship between the dura-
thetic vitreous fibers (fiberglass, mineral wool tion of employment and the time since first
and refractory fiber) has shown that the pulmo- employment (TSFE). Although it seems there
nary effects of these dusts are directly related to would be correlation, there was no clear pattern
the fiber dose in the lung over time and have been
generally grouped into the three “Ds”: (a) Dose – Table 6 Mortality by selective causes for plant workers,
the number of fibers deposited in the distal lung 1955–1997. (Adapted from Shannon et al. 2005)
over time. (b) Dimension – the thinner fibers are SMR
more respirable, while the longer fibers are more All cancers 115
toxic to the pulmonary cells. The thinner the Lung cancer 163a
fibers are, the more efficiently they deposit in Respiratory diseases 119
the lower lungs. (c) Durability – the severity is Kidney cancer 146
related to the biopersistance, which is related to Ischemic heart disease 81
the fiber length and inversely related to the dis- SMR = (observed number of deaths/expected number of
solution and fragmentation rates (Warheit et al. deaths) 100
2001). The dusts that can irritate the lung are too
a
P < 0.05
for mortality and incidence in relation to dura- the overall mortality risk for malignant mesothe-
tion of employment and TSFE (Shannon et al. lioma was not elevated in this cohort (2001).
2005). Recent studies have suggested that Exposure to fiberglass with styrene resins can
while continuous fiberglass filaments are not also cause obliterative bronchiolitis (Cullinan
linked with lung cancer and mesothelioma, et al. 2013); however, obstructive lung disease is
biopersistant glass fibers are associated with unlikely associated with fiberglass exposure (Fire-
mesothelioma and lung cancer (Costa and man 2014). Some other symptoms of fiberglass
Orriols 2012). Buchanich et al. established in a exposure are dry hacking cough, sore throat or
study that the males and females working in blood in the sputum, bloody nose, persistent
fiberglass factories had higher rates of ever sinusitis and rhinitis, persistent respiratory infec-
smoking than the corresponding general tions; headaches; nausea; dizziness; insomnia;
populations of the USA (2001). This differenti- irritability; depression; asthma-like breathing
ating factor could further explain the reasoning attacks or constant wheezing; allergy-like symp-
behind the elevated levels of respiratory system toms that do not respond to allergy treatment;
cancers that are found in these workers. reactive airway disease; swollen, red, watery
Shannon et al. also found that the number of infected eyes; and extreme sensitivity to everyday
kidney cancers was nearly double than expected. amounts of ambient pollutants. Many of these
Literature reviewed by Goldsmith and Goldsmith symptoms overlap with symptoms of allergies,
(1993) concluded that silica was likely to be the common cold, asthma, and conjunctivitis, making
cause of the excess renal diseases in fiberglass the diagnosis difficult.
workers. Fiberglass can be silica based, which
gives it more dexterity in production. Silica
has no real melting point but has a softening 5 Hardening
point at 2000 C at which point the silica-based
fiberglass can be extruded out into thin strands In most cases, after 1–4 weeks of exposure,
suitable for textile processing (Loewenstein workers may become unaffected by the irritant, or
1973). Thus the finding of increased renal cancer hardened, allowing individuals to continue with
is unlikely to be related directly to the glass fibers their work. The term “hardening” is mainly in
(Shannon et al. 2005). Despite these findings, in regard to the itching, not the visible dermatitis,
2002 the International Agency for Research on and has been defined by some as an adaptation of
Cancer classified glass and mineral fibers as the skin to the cause of the ICD (Björnberg 1985;
class 3, which is not classifiable as to carcinoge- Watkins and Maibach 2009). After hardening,
nicity to humans. They established this based on the skin is less vulnerable to the secondary effects
insufficient evidence in humans and limited evi- of the dermatitis and less prone to secondary infec-
dence in experimental animals (Pintos et al. tion. Because of this, most workers do not request
2008). Two subsequent studies published in to be transferred after experiencing an acute ICD
2008 from Canada and 2009 from Italy showed since the symptoms disappear without any conse-
no evidence that continuous glass filament quences (Sertoli et al. 2000). The gross appearance
workers experience a significant increased risk of hardened skin has been described in some exper-
of cancer (Pintos et al. 2008; Pira et al. 2009). imental models as having a slight sheen and glossy
A strong relationship between asbestos and appearance with a mild scale. Upon manipulation it
mesothelioma has been well established. Because has been documented to show a decrease in skin
of this relationship, and the similarities between elasticity (Watkins and Maibach 2009). This adap-
asbestos and MMVFs, the mortality rate from tive measure is not permanent though, as a break in
mesothelioma has been studied by Marsh et al. exposure for more than 4 weeks will result in the
in a group of MMVF factory workers. After same irritant response on reintroduction of
reviewing data from a 1992 follow-up study of the fiberglass (Stam-Westerveld 1995; van der
32,110 fiberglass workers, it was concluded that Valk 1996).
The mechanism of hardening is not completely Table 7 Alterations in hardened skin. (Modified table
understood, most likely because research usually from Watkins and Maibach 2009)
does not focus on mechanisms of nondisease Alteration Experimental findings
or illnesses that self-resolve. However, it is Physical changes Thicker stratum granulosum;
suspected to be due to hyperkeratosis of the hyperkeratotic stratum corneum
stratum corneum, thickening of the stratum Skin Adapted skin is more permeable to
permeability irritants; accommodated skin is
granulosum, and a diminished inflammatory reac- changes more erythematous after irritant
tion (Park et al. 2014). Hardening was first exposure versus
described in 1982 by Samuel, who showed that non-accommodated skin
repeated exposure of rabbit ears to croton oil Systemic Locally induced hardening can alter
changes skin’s response on reexposure to
resulted in decreased levels of inflammatory
irritant systemically in previously
response (Watkins and Maibach 2009). Since unexposed areas
then the adaptive effects of hardening have been Immunologic Localized hardening is
studied on humans. Theories have been formu- changes accompanied by changes in the
lated to determine the cause of the hardening. One expression of various inflammatory
mediators and markers
theory pertains to altered barrier function, which
holds that morphological changes in skin structure
and composition decreases irritant access to skin
(Watkins and Maibach 2009). On histological Less commonly a worker may not adapt to the
exam of accommodated skin, it is shown to have irritant, leading to chronic ICD. This can lead
a thicker layer of stratum granulosum. It was to emotional, physical, and financial distress for
reported by Van der Valk and Maibach that the affected individuals (Watkins and Maibach 2009).
thickening of the horny layer was directly propor- Chronic ICD can appear as erythematous or dry,
tional to a decrease in transepidermal water loss scaly, and fissured skin, usually on the hands, and
(TEWL), which is a method of estimating skin is difficult to treat. The only cure is to withdraw
water barrier function. TEWL fluctuates through- exposure to the irritating substance.
out the evolution of hardening. Upon initial
exposure to the irritant, the TEWL increases.
With chronic irritation, the TEWL subsequently 6 Histopathology
decreases with emergence of hardening (Watkins
and Maibach 2009). There have also been reports 6.1 Biopsy
of altered lipid composition in the stratum
corneum layer, which could be a contributing If fiberglass dermatitis is suspected, a biopsy of
factor to the accommodation effect of hardening the irritated skin can aide in the diagnosis. The
(Watkins and Maibach 2009). fragments produce microtrauma and perforate
Hardening has also been described to produce the skin. Under the microscope, the fiberglass
global effects of cutaneous adaptation. In this particles show up as birefringent fragments in
process, an individual can be exposed to the irri- the cornified layer of the skin (Bordel-Gómez
tant, or fiberglass, on their hands and become and Miranda-Romero 2008). The histopathology
“hardened.” When the fiberglass is introduced induced by glass fiber dermatitis is indistinguish-
after the initial hardening to another area of their able to that of rock wool dermatitis. This has
body, i.e., their feet, there is no irritant reaction been described by Björnberg to display the fol-
because of the global adaptation. The studies done lowing features: subcorneal vesicles containing
on this provide evidence that chronic exposure to neutrophils, sometimes developing into superfi-
an irritant in low doses can induce a globally cial erosions; spongiosis with mononuclear-
hyporeactive state (Watkins and Maibach 2009). polynuclear infiltrate in the epidermis; and a
A summary of the alterations in hardened skin is perivascular lymphocytic infiltration in the der-
provided in Table 7. mis (Björnberg 1985).
The lesions are almost equal to those produced best treatment is to avoid excessive contact with
by contact eczema, which present with spongiosis, water, aggressive cleaning materials and abra-
sometimes diastasis at the basal layer, and lympho- sives, and use topical emollients until the skin
cytic perivascular and perifollicular infiltrate. The heals. This in combination with protective skin
lesions can sometimes persist into a foreign body practices will help in the alleviation and avoid-
granuloma due to the continuous stimulation from ance of any future ICD outbreaks (van der Valk
the penetration (Sertoli et al. 2000). 1996). Topical emollients should contain no irri-
tating ingredients and must contain enough fatty
substances to hydrate the skin. Topical corticoste-
6.2 Alternative Methods roid therapy is controversial, as it is known to thin
the epidermis and make it more vulnerable to
Alternatively, particles may be observed through trauma. Tar is often known for its anti-eczematous
skin stripping or skin scraping. In skin stripping, effect on the hands but is undesirable due to the
which can also be used as a treatment, tape is appearance and smell. This can be masked by
applied to the irritated area and peeled away. It is wearing cotton gloves (van der Valk 1996).
then mounted on a glass slide and visualized
under polarized light microscopy. If fiberglass is
the cause of the dermatitis, the tape would show 8 Prevention
transparent fine fragments of glass. The tape-
stripping method can also be used to demonstrate Workers in direct contact with fiberglass and the
the presence of fiberglass fragments on clothing. resins should wear gloves, long sleeves, and loose-
With skin scraping, the sample is prepared with fitting clothes. Any clothing that is exposed to fiber-
one or two drops of potassium hydroxide at 20% glass should be washed separately to avoid transfer-
and visualized microscopically to look for the ring the fibers to other clothes. To avoid transfer to
presence of fibers in the horny layer of the epider- family members, the washing machine should be
mis (Stam-Westerveld 1995). Microscopy of wiped out after each washing or run through an extra
affected areas may exhibit rod-shaped fibers that cycle to clean out all the fibers. Also, workers should
are a pale greenish color of similar width to hair shower right after work to prevent the fibers from
(Paller and Manicini 2016). Also when the pres- being rubbed in (Stam-Westerveld 1995).
ence of fibers is suspected in tissue, an x-ray Preventative measures can be taken by the
should be taken to confirm the results of the workplace to minimize exposure to fiberglass by
biopsy (Sertoli et al. 1992). frequent cleaning of the floor and work surfaces to
decrease the amount of indirect dust exposure.
Direct contact can be minimized by decreasing
7 Treatment the amount of hands on exposure that workers
have with the fiberglass. This can be done by mak-
Treatment of acute fiberglass dermatitis is primarily ing some of the machines a closed cycle, so that the
symptomatic. Oral antihistamines or low-power transfers are done automatically. Also, when felts
corticosteroids can be applied, along with antibi- are cut, hand tools would be more ergonomic than
otics to eradicate any overlapping bacterial infec- power-driven tools, because they would release
tion. Fibers can be removed from the skin to relieve less fibers and powders (Sertoli et al. 2000). Air
irritation by using scotch tape or plumbers’ duct quality can be improved by increasing ventilation
tape and peeling it away (Sertoli et al. 2000). and adding filters and providing masks. Latent
The only way to successfully treat chronic ICD dermatitis can be avoided by providing protective
is to adhere to a strict avoidance of the irritating clothing that can be left at work and washed, which
substance, in this case, fiberglass. This is not a would also help in avoiding fiberglass exposure to
practical treatment in most cases, as this is how the the family, and providing a shower room to allow
workers earn their livelihood. Because of this, the the worker to rinse off the fiber dust as soon as
possible. Washable leather gloves could also be Baile RB, Meghana SC, Pattiwar MS (2014) Glass wool
provided, which are less permeable to the fibers tripod foreign bodies in the eye: first ever reported case
series. Middle East Afr J Ophthalmol 21(4):363–365
(Schwartz et al. 1947). When spraying insulation Beltrani VS, Boguneiwicz M (2003) Atopic dermatitis.
containing fiberglass, the wet method would pro- Dermatol Online J 9(2):1
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(Sertoli et al. 2000). The removal of non-resined effect of repeated mechanical trauma to the skin. Alan
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man-made citreous fiber production workers:
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39:372–274
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Drug Allergens
39
Andreas J. Bircher
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
2.1 Immediate-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
3 Contact Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
3.1 Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
3.2 Analgesics and Nonsteroidal Anti-inflammatory Drugs . . . . . . . . . . . . . . . . . . . . . . . . 567
3.3 Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
3.4 Antiasthmatic Drugs and Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
3.5 Antibiotics and Tuberculostatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
3.6 Anti-infectious Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
3.7 Cardiovascular and Vasoactive Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
3.8 Central Nervous System Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569
3.9 Gastrointestinal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
3.10 Herbal Drugs and Plant Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
3.11 Immune Modulators and Cytostatic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
3.12 Intermediate Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
3.13 Veterinary Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
3.14 Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
3.15 Miscellaneous Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572

Drugs · Metabolites · Hapten · Allergic contact
dermatitis · Urticaria · Occupational • Many drugs from very different drug classes
and categories have been reported to elicit
allergic contact dermatitis by direct contact or
airborne exposure.
• More rarely, immediate-type reactions with
A. J. Bircher (*) asthma, urticaria, or anaphylaxis have been
Allergy Unit, Department of Dermatology, University observed.
Hospital, Basel, Switzerland
e-mail: andreas.bircher@unibas.ch

https://doi.org/10.1007/978-3-319-68617-2_39
560 A. J. Bircher
• Employees in the development, production, the final products. This group may be exposed –
and maintenance in the pharmaceutical indus- directly or by airborne contact – to precursor sub-
try and workers in health care are typically stances, highly reactive intermediates, and final
affected. drugs, as well as to other agents used in the syn-
• Most drugs are haptens and therefore need to thesis, such as accelerators, catalysts, enzymes,
become reactive to be able to bind to proteins etc., which may also act as allergens (Altomare
to form a complete antigen. et al. 1992; Sherertz 1994). The second group
• Some prodrugs and intermediate substances in encompasses health-care workers, such as nurses,
the synthetization process are highly reactive physiotherapists, physicians, dentists, pharma-
and more prone to be allergenic. cists, masseurs, herbal therapists, veterinarians,
animal caretakers, and farmers preparing or apply-
ing medicaments for animals. These particular
2 Introduction occupations are discussed in depth in other
respective chapters of this book.
With few exceptions, such as peptides and hor- Apart from drugs for topical use, where contact
mones, drugs and their precursors are typically is possible during treatment of a patient, exposure
low-molecular-weight compounds and, therefore, to systemically applied agents, e.g., to powdered
haptens. Some drugs, then called prohaptens, substances or aerosols from vials, may happen by
have to be metabolized to become reactive and negligence or accident and results in direct or
therefore sensitizing. To build a complete antigen, airborne contact with the skin or the mucosae or
they must bind to macromolecules, e.g., to human takes place by inhalation or, rarely, by ingestion.
tissue or serum proteins. Some drugs are primarily Typical situations involving dust or nebulization
reactive, while in others, reactive metabolites are exposure occur during the manufacturing of hand-
only generated in vivo. Recently, the concept of compounded medications by pharmacists, during
prehaptens has been proposed, where a molecule, the preparation of animal feed in farmers, or in
e.g., oxidizes to become a hapten (Lepoittevin nurses crushing tablets or preparing lyophilized
2006). For drugs, however, this is unusual and drugs for injection (Barbaud 2002). Some health
only feasible if they are inappropriately stored. professionals, such as dentists, physiotherapists,
Oral administration of a drug is usually well or masseurs, directly apply medications to the
tolerated and is typically associated with toler- patient by hand, thus facilitating sensitization by
ance. However, particularly intermittent exposure repeated unprotected skin contact. Sometimes, a
or application by the epidermal, intradermal, sub- member of such an occupation needs pharmaco-
cutaneous, or inhalatory route, as it typically therapy himself and suffers from an adverse drug
occurs in occupational settings, carries a higher reaction, e.g., to carbamazepine, which, however,
risk of sensitization (Bircher 1996; Merk et al. 2007). is not necessarily linked to his occupation
Occupationally related allergic reactions to (Altomare et al. 1992). Another occasionally
drugs mainly occur in two groups of employees overlooked way of exposure may happen by con-
exposed in different settings. The first group nubial contact (Newton and White 1987).
involves workers of pharmaceutical and chemical Typical clinical manifestations include
companies occupied in the production of drugs; allergic and irritant contact dermatitis, airborne
the second group consists of professionals using dermatoses, photo-induced reactions (Björkner
the final drugs in a therapeutic setting. The former 1994; Winkler et al. 2015), immunologic and
includes chemists and laboratory technicians non-immunologic contact urticaria, rhinocon-
involved in the development of new agents, junctivitis, asthma and, rarely, anaphylaxis
workers exposed during the manufacturing and (Bause and Kugelman 1990), or severe skin
synthetization processes, technicians or cleaning disorders, such as toxic epidermal necrolysis
staff employed in the maintenance of equipment, (Valsecchi et al. 1987). Irritant agents are numer-
and employees involved in handling and packing ous and may cause symptoms on the skin or the
39 Drug Allergens 561
mucosal surfaces (Testud et al. 1994). Examples called Baboon syndrome (Menné et al. 1989) or
are potassium salts, chloroquine phosphate, eth- SDRIFE (Häusermann et al. 2004). Therefore,
ylene oxide and, particularly, the cytostatic the exact identification of a presumed occupa-
drugs. Usually, the exposed workers know the tional allergy and the offending allergens has
hazards of these substances, and preventive mea- implications beyond the scope of occupational
sures are used. Accidental contact, however, safety. In this chapter, an overview on drugs and
causes rapidly irritant or toxic skin damage in intermediate substances reported as occupational
most or all exposed individuals. The causal rela- allergens is given (Tables 1 and 2). Two recent
tionship is easily recognized, and an extensive reviews give further detailed information on
diagnostic work-up is often not necessary; there- particular drugs (Goossens and Hulst 2011;
fore, such cases may be underreported. How- Whitaker 2016).
ever, patients with sensitization to an unusual
compound are often published as single case
reports and dominate the literature. 2.1 Immediate-Type Reactions
As a practical consequence of sensitization,
an allergic individual must therefore meticu- Symptoms of such reactions include rhinocon-
lously avoid contact with the allergen or, in a junctivitis, asthma, contact urticaria, and, rarely,
more severe case, change the workplace or even anaphylaxis (Belsito 1993). In some patients,
his profession. In cases of drug allergens, a fur- urticaria and later eczema may be present, in
ther problem may arise. Occupationally sensi- analogy to protein contact dermatitis (Keller and
tized individuals may encounter their allergen Schwanitz 1992); patients may also have concom-
in drug therapy (Bircher 1996). Topical treat- itant skin and respiratory symptoms (Moscato et
ment with the occupational allergen or with al. 1995; Stejskal et al. 1986). Pharmaceutical
cross-reacting substances, e.g., the “caine workers and farmers exposed to airborne dust,
group,” may elicit contact dermatitis. Systemic nurses and veterinarians crushing tablets or pre-
exposure to an allergen, e.g., antibiotics, to paring vials for injection, farmers exposed to
which the patient has been sensitized by epider- animal feed, and individuals exposed to the dust
mal contact may result in a flare-up of formerly of medicines derived from plants are typically
affected sites; it may also result in systemic affected. Common allergens include particularly
(“hematogenic”) contact dermatitis or the so- penicillins and cephalosporins. Chloramine-T is
Table 1 Selected drug allergens eliciting immediate-type skin symptoms on contact

Allergen Symptom References
Benzalkonium chloride Urticaria, asthma Bernstein et al. (1994)
Cefotiam Anaphylaxis Miyahara et al. (1993) and Tadokoro et al. (1994)
Chloramine-T Urticaria Dooms-Goossens et al. (1983) and Kanerva et al. (1997)
Cisplatin Urticaria Schena et al. (1996)
Colistin Asthma Gómez Ollés et al. (2010)
Etoposide Rhinosinusitis Meyer and Stahl Skov (2010)
Labetalol Anaphylaxis Bause and Kugelman (1990)
Levomepromazine Urticaria Johansson (1988)
Mezlocillin Urticaria Keller and Schwanitz (1992)
Mitoxantrone Asthma Walusiak et al. (2002)
Penicillin Urticaria Rudzki and Rebandel (1985) and Stejskal et al. (1986)
Pentamidine isethionate Urticaria Belsito (1993)
Piperacillin sodium Urticaria, asthma Moscato et al. (1995)
Tafenoquine Asthma Cannon et al. (2015)
Vancomycin Asthma Choi et al. (2009)
562 A. J. Bircher
Table 2 Drug and intermediate compounds eliciting occupational contact dermatitis

Allergen References
Additives
Benzoyl peroxide Quirce et al. (1993)
Dicyclohexylcarbodiimide (CAS 538-75-0) Davies (1983) and Poesen et al. (1995)
Ethoxyquin (CAS 91-53-2) Mancuso et al. (1990) and Savini et al. (1989)
Ethylenediamine Corazza et al. (1994), Rudzki (1990), and Rudzki et al. (1989b)
Tosyl chloride Watsky et al. (1993)
Analgesics and nonsteroidal anti-inflammatory drugs
Benzydamine hydrochloride (CAS 132-69-4) Foti et al. (1992) and Rademaker (1994)
Paracetamol (acetaminophen) Swinnen et al. (2014)
Piroxicam Arévalo et al. (1995)
Propacetamol (prodrug of paracetamol) Mathelier-Fusade et al. (1997) and Szczurko et al. (1996)
Pyrazinobutazone Dorado Bris et al. (1992)
Pyrazolone Vanuytrecht-Henderickx et al. (1986)
Anesthetics
Isoflurane (1-chloro-2,2,2-trifluoroethyl Finch et al. (2000)
difluoromethyl ether)
Pantocaine Rudzki (1990)
Procaine Bruijn et al. (2009), Rudzki et al. (1989a, b)
Propanidid Gastelain and Piriou (1980)
Proxymetacaine Riddell et al. (2000)
Tetracaine (amethocaine) Condé-Salazar et al. (1988, 1989), Rudzki (1990), and Rudzki et al.
(1989a)
Antiasthmatic drugs
Aminophylline Rudzki (1990), Rudzki et al. (1989a), and Tas and Weissberg (1958)
Budesonide Baeck and Goossens (2009)
Metaproterenol Fung et al. (1996))
Tixocortol pivalate Schwensen et al. (2016)
Antibiotics and tuberculostatics
Aminopenicillins Gamboa et al. (1995), Møller and Jeppesen (1987), Møller et al.
(1986, 1990), Møller and Von Würden (1992), Rudzki and Rebandel
(1991), Rudzki et al. (1989b), and Stejskal et al. (1986)
Cefazolin Straube et al. (2000)
Cefradine Rudzki et al. (1989b)
Ceftiofur García-Bravo et al. (1995)
Cephalosporins Condé-Salazar et al. (1986), Filipe et al. (1996), and Foti et al. (1994,
1997)
Chloramphenicol Rudzki (1990), Rudzki et al. (1989b), and Schwank and Jirásek
(1963)
Colistin Rudzki et al. (1989b)
Doxycycline Rudzki et al. (1989b)
Ethambutol Holdiness (1986a)
Gentamicin Altomare et al. (1992)
Isoniazid Holdiness (1986b) and Rudzki et al. (1989a)
Kitasamycin (leucomycin) Dooms-Goossens et al. (1990)
Metronidazole Madsen et al. (2009)
Mezlocillin Keller and Schwanitz 1992)
Midecamycin Dooms-Goossens et al. (1990)
Oxytetracycline Rudzki (1990)
(continued)
Table 2 (continued)
Allergen References
Penicillin Møller et al. (1986), Pecegueiro (1990), Rudzki et al. (1989a, b), and
Stejskal et al. (1986)
Pristinamycin Blancas-Espinosa et al. (2006)
Streptomycin Altomare et al. (1992), Holdiness (1986b), and Rudzki et al. (1989b)
Sulfathiazole Foussereau et al. (1982), Rudzki (1990), and Rudzki et al. (1989a)
Tetracyclines Rudzki et al. (1989a, b)
Vibramycin Rudzki (1990)
Other anti-infectious agents
Albendazole Macedo et al. (1991)
Benzalkonium chloride Kanerva et al. (2000)
Chloramine-T (CAS 127-65-1) Lombardi et al. (1989)
Chlorhexidine Sato et al. (2004)
Chloroquine Kellett and Beck (1984)
Fentichlora Norris et al. (1988)
Foscarnet Testud et al. (1994)
Griseofulvin Testud et al. (1994)
Hydroxychloroquine Meier et al. (1999)
Metronidazole Madsen et al. (2009)
N-benzyl- N,N-dihydroxyethyl- N-cocosalkyl- Placucci et al. (1996)
ammonium chloride
Nifuroxazide Kiec-Swierczynska and Krecisz (1998)
Piperazine Calnan (1975), Rudzki and Grzywa (1977), and Rudzki et al. (1989b)
Quinidinea Wahlberg and Boman (1981)
Quininea Hardie et al. (1978)
Cardiovascular and vasoactive drugs
Alprenolol Ekenvall and Forsbeck (1978) and Stejskal et al. (1986)
Bisoprolol Swinnen et al. (2014)
Captopril Dziuk et al. (1994)
Carbocromen Martin et al. (1973) and Rudzki et al. (1989b)
Carvedilol Neumark et al. (2009)
Enalapril Swinnen et al. (2014)
Homatropine Marcos et al. (1997)
Lisinopril Swinnen et al. (2014)
Metoprolol Swinnen et al. (2014)
Nicergoline (CAS 27848-84-6) Fumagalli et al. (1992)
Nitroglycerin Kanerva et al. (1991)
Oxprenolol Rebandel and Rudzki (1990)
Perindopril Swinnen et al. (2014)
Phenoxybenzamine hydrochloride Mitchell and Maibach (1975)
Phenylephrine Marcos et al. (1997)
Pirmenol Bennett et al. (2016)
Propranolol Rebandel and Rudzki (1990), Rudzki (1990), and Swinnen et al.
(2014)
Quinidine sulfatea Stejskal et al. (1986) and Wahlberg and Boman (1981)
Sotalol Swinnen et al. (2014)
Spironolactone Klijn (1984)
Central nervous system drugs
Apomorphine Dahlquist (1977)
(continued)
564 A. J. Bircher
Table 2 (continued)
Allergen References
Chlorpromazinea Björkner (1994), Foussereau et al. (1982), and Rudzki (1990)
Chlorprothixen Schwenck et al. (1994)
Codeine Coenraads et al. (2001), Conde-Salazar et al. (1991), Romaguera and
Grimalt (1983), and Waclawski and Aldrige (1995)
Cyanamide (CAS 420-04-2) Goday Buján et al. (1994)
Diamorphine (heroin) Coenraads et al. (2001)
Meclofenoxate Foussereau et al. (1982)
Morphine Conde-Salazar et al. (1991)
Olanzapine Lowney et al. (2010)
Oxolamine (CAS 959-14-8) Coenraads et al. (2001) and Condé-Salazar et al. (1989)
Perazine Rudzki et al. (1989a)
Pyritinol Dooms-Goossens et al. (1986b) and Wigger-Alberti and Elsner
(1997)
Tetrazepam Ferran et al. (2005) and Ortiz-Frutos et al. (1995)
Thebaine Waclawski and Aldrige (1995)
Ziprasidone Bennett et al. (2016)
Zolpidem Neumark et al. (2009)
Gastrointestinal drugs
Famotidine Monterseirín and Conde (1990)
Lactase Laukkanen et al. (2007)
Lansoprazole Vilaplana and Romaguera (2001)
Omeprazole Altomare et al. (1992), Bennett et al. (2016), and Meding (1986)
Pantoprazole Neumark et al. (2011)
Ranitidine Alomar et al. (1987) and Romaguera et al. (1988, 1990)
Herbal drugs and plant derivatives
Arnica Hausen (1980)
Essential oils Cockayne and Gawkrodger (1997) and Selvaag et al. (1995)
Eugenol Kanerva et al. (1994) and Rudzki et al. (1989a)
Lavender Rademaker (1994)
Pyrethrum Schmidt (1986)
Vincamine tartrate Van Hecke (1981)
Immune modulating and cytostatic drugs
Azathioprine Burden and Beck (1992) and Soni and Sherertz (1996)
Cisplatin Dastychová and Semrádová (2000)
Dinitrochlorobenzene Garcia-Perez (1978) and Lubbe (1993)
Dinitrofluorobenzene Garcia-Perez (1978)
Diphencyprone Bircher et al. (1999) and Sansom et al. (1995)
Imatinib Bennett et al. (2016)
Methotrexate Dastychová (2003)
Squaric acid dibutyl ester Frattasio et al. (1997) and Noster et al. (1976)
Intermediate products and precursors
1-(Methylamino)-1-(methylthio)-2- Romaguera et al. (1990)
nitroethylene
2-Aminothiophenol Bonamonte et al. (2002)
2,6-Dichloropurine Rycroft (1981)
5-1-(2-Aminoethyl)-thiomethyl- N,N- Goh and Ng (1984) and Rycroft (1983)
dimethyl-2-furanmethanamine
Allopurinol (ethyl ethoxymethylene Hsu et al. (1992)
cyanoacetate)
(continued)
Table 2 (continued)
Allergen References
Azaerythromycin Milković-Kraus et al. (2007)
Azathioprine (5-chloro-1-methyl-4- Jolanki et al. (1997)
nitroimidazole)
Bumetanide (sulfonyl benzoic acids) Møller and Kromann (1989)
Chlordiazepoxide (2-chloromethyl-4-phenyl- Rebandel and Rudzki (1986a, b)
6-chlorquinazoline-3-oxide)
Chloroquine (4,7-dichloroquinoline) Pickering and Ive (1982)
Cistofur (2-[([(1-Dimethylaminomethyl)] Romaguera et al. (1990)
furan-5-1methyl)thio] ß-amino ethane)
Clenbuterol (4-amino-(x-bromo-3,5- Romaguera et al. (1990)
dichloroacetophenone))
Cytosine arabinoside Conde-Salazar et al. (1984)
Dichlorobenzoyl chloride De Boer and Van Joost (1988)
Diethyl-p-chloroethylamine Deschamps et al. (1988)
Erythromycin A iminoether Milković-Kraus et al. (2007)
Erythromycin A oxime hydrochloride Milković-Kraus et al. (2007)
Famotidine Guimaraens et al. (1994)
H2 antagonist (2-(4(5)-methyl-5(4)- Camarasa and Alomar (1980)
imidazolyl-methyl-thio)-C13)
Histamine antagonist (heterocyclic Sonnex and Rycroft (1986)
chloromethyl compounds)
Methotrexate (2,4-di-amino-6-6- Lahti et al. (1990)
chloromethylpteridine)
N-(3-trifluoromethyl-4-nitrophenyl) Jungewelter and Aalto-Korte (2008)
phthalimide (flutamide)
Nitrosourea (3-taurinyl-1-(2-chloroethyl)-1- Niklasson et al. (1990)
nitrosourea, carbamates)
Oxprenolol (epichlorhydrin) Rebandel and Rudzki (1990)
p-Aminophenol Walker et al. (2005)
Procaine ( p-nitrobenzoyl chloride) Foussereau (1989)
Propranolol (epichlorhydrin) Rebandel and Rudzki (1990)
Pyridoxine (2-methyl-3-nitro-4- Wigger-Alberti and Elsner (1997)
methoxymethyl-5-cyano-6-chloropyridine)
Radiocontrast medium (3,4- Niklasson and Björkner (1990)
dicarbethoxyhexane-2,5-dione)
Ranitidine (cistoran) Valsecchi et al. (1989)
Tetramisole (3rd intermediate) Valsecchi et al. (1987)
Virostatic 6-aza-uracil (3,4,6- Dooms-Goossens et al. (1986a)
trichloropyridazine)
Veterinary drugs
Avoparcin Barroga et al. (1992)
Bacitracin Mancuso et al. (1990)
Carprofen Kerr et al. (2008), Kiely and Murphy (2010), and Walker et al.
(2006)
Furaltadone Vilaplana et al. (1990)
Furazolidone De Groot and Conemans (1990)
Lincomycin Vilaplana et al. (1991)
Methylchlorpindol Mancuso et al. (1990)
Monensin (CAS 17090-79-8) Mancuso et al. (1990)
Morantel tartrate (CAS 26155-31-7) Newton and White (1987)
(continued)
566 A. J. Bircher
Table 2 (continued)
Allergen References
Neomycin Mancuso et al. (1990)
Nitrofurazone Ancona (1985) and Lo et al. (1990)
Olaquindoxa Francalanci et al. (1986) and Schauder et al. (1996)
Oxytetracycline Guerra et al. (1991)
Penethamate Hjorth and Weismann (1973)
Penicillin Guerra et al. (1991) and Hjorth and Weismann (1973)
Phenothiazines Schauder et al. (1996)
Spectinomycin Dal Monte et al. (1994) and Vilaplana et al. (1991)
Spiramycin Guerra et al. (1991) and Veien et al. (1980)
Streptomycin Gauchía et al. (1996)
Thiabendazole Mancuso et al. (1990)
Tylosin Barberá and De La Cuadra (1989), Caraffini et al. (1994), Guerra et
al. (1991), Malaiyandi et al. (2012), Tuomi and Räsänen (1995), and
Veien et al. (1980)
Virginiamycin Tennstedt et al. (1978)
Vitamins
Cyanocobalamin (vitamin B12) Rodriguez et al. (1994) and
Rudzki et al. (1989b)
Menadione sodium bisulfite (vitamin K3) Camarasa and Barnadas (1982), Dinis et al. (1988), and Romaguera
et al. (1980)
Pyridoxine (vitamin B6) Wigger-Alberti and Elsner (1997)
Retinyl acetate (vitamin A acetate) Heidenheim and Jemec (1995)
Thiamine (vitamin B1) Ingemann Larsen et al. (1989)
Miscellaneous drugs
Abacavir Bennett et al. (2016)
Benzoin Klein et al. (2009)
Carbimazolea (CAS 22232-54-8) Goh and Ng (1985)
Disulfiram (CAS 97-77-8) Mathelier-Fusade and Leynadier (1994) and
Rudzki et al. (1989b)
Ethylene oxide (CAS 75-21-8) Haddar et al. (1993) and Lerman et al. (1995)
Fluvastatin Bennett et al. (2016)
Meglumine diatrizoate (CAS 131-49-7) Verschaeve et al. (1984)
Mesna (CAS 19767-45-4) Benyoussef et al. (1996)
Minoxidil Veraldi et al. (1992)
Mitomycin C Fisher (1991)
Simvastatin Bennett et al. (2016), Neumark et al. (2009), and Peramiquel et al. (2005)
Thiomersal De Groot et al. (1990)
Tubocurarine Rudzki (1990)
a
Photosensitivity
known to induce immunoglobulin E (IgE) anti- (e.g., latex, formaldehyde, chlorhexidine, penicil-
bodies (Kanerva et al. 1997; Piirilä et al. 2002). lins, cefaclor, ethylene oxide) should be determined.
A list of selected allergens having elicited urti- Suspected allergens should be first tested by open
caria or anaphylaxis by contact, with or without application in high dilutions on intact skin and only
respiratory symptoms, is shown in Table 1. In later by prick and, if necessary, intradermal tests.
such patients, if available, initially specific IgE Patients should be carefully monitored during these
diagnostic procedures since severe anaphylactic (Dorado Bris et al. 1992). Benzydamine, a topical
reactions may be elicited by skin tests alone and systemic nonsteroidal anti-inflammatory drug,
(Bause and Kugelman 1990; Tadokoro et al. 1994; has caused two cases of occupational sensitization
Wang and Maibach 2013). (Foti et al. 1992). An unusual case of a multilocular-
fixed drug eruption upon inhalation of pyrazolones
with positive oral provocation has also been
3 Contact Allergens described (Vanuytrecht-Henderickx et al. 1986).
3.1 Additives
3.3 Anesthetics
Some examples of common additives are given
which may be used as drugs themselves (such Occupational problems with topically applied
as benzoyl peroxide for acne), in the synthesis local anesthetics, particularly ester derivatives,
of drugs (dicyclohexyl carbodiimide), or as anti- have been known for many years (Altomare et
oxidants in final products. Ethylenediamine is al. 1992). Contact allergy to procaine used to be
present in topical drugs and in aminophylline a typical professional disease of dentists due to
and is the allergen in the latter compound. Several direct handling (Kanerva et al. 1994). Other
cases of occupational contact dermatitis have been affected professionals include ophthalmologists
reported (Corazza et al. 1994). and veterinary surgeons. An extensive dissemi-
nated contact allergy from procaine has been
seen in a veterinarian (Bruijn et al. 2009). Allergic
contact fingertip dermatitis secondary to pro-
3.2 Analgesics and Nonsteroidal xymetacaine has been reported in an ophthalmol-
Anti-inflammatory Drugs ogist (Riddell et al. 2000).
There is an extensive cross-reactivity among all
With the exception of photoallergy, nonsteroidal p-aminobenzoic acid derivatives, such as pro-
anti-inflammatory drugs rarely induce immuno- caine, benzocaine, and tetracaine, but not to
logically mediated adverse reactions; more com- amide derivatives, such as lidocaine. Since the
monly, a pseudoallergic pathogenesis is involved, less allergenic amide local anesthetics are gener-
reflected by non-immunologic urticaria, asthma, ally used today, the number of occupational cases
or non-immunologic anaphylaxis. has declined. The intravenous anesthetic pro-
Nurses have been reported who have developed panidid, a derivative of eugenol (Gastelain and
contact dermatitis and, in one case, an airborne Piriou 1980), has caused sensitization in anesthe-
contact dermatitis (Mathelier-Fusade et al. 1997) tists by direct and probably also airborne contact
to propacetamol (Barbaud et al. 1995, 1997), an (Altomare et al. 1992). Other anesthetic drugs
injectable prodrug which is rapidly hydrolyzed by causing occupational dermatitis were succinyl-
esterases to paracetamol and diethylglycine. Para- choline (Newman and Goel 2010) and the gas
cetamol and diethylglycine were patch test nega- sevoflurane (Burches et al. 2015).
tive, and oral administration was tolerated
(Szczurko et al. 1996). Later, diethylglycine has
been identified as eliciting moiety, explaining why 3.4 Antiasthmatic Drugs and
propacetamol-sensitized individuals tolerate para- Corticosteroids
cetamol (Berl et al. 1998). However, in another
patient paracetamol was strongly positive in patch Compared to the widespread and long-term use of
tests (Swinnen et al. 2014). β-mimetic drugs, typically by nebulization, the
A patient sensitized to another prodrug, few reports involving antiasthmatic drugs indicate
pyrazinobutazone, a piperazine salt of phenylbuta- that they are weak allergens (Fung et al. 1996).
zone, reacted with a flare-up to oral provocation Aminophylline is of importance since it consists
568 A. J. Bircher
of ethylenediamine and theophylline; therefore, tuberculostatics and tetracyclines is of minor rel-

positive patch tests to ethylenediamine are evance today; however, in some countries it was a
present in patients sensitized to aminophylline common problem. Several workers with contact
(see Sect. 3.1) (Rudzki 1990; Rudzki et al. dermatitis from azithromycin and some also from
1989a). Corticosteroids and particularly intermediate products such as erythromycin A
budesonide has resulted in 15 subjects, not them- oxime hydrochloride 5% in pet., erythromycin A
selves treated by budesonide-containing aerosols iminoether 5% in pet., and azaerythromycin A 5%
but taking care of or living together with patients in pet. were reported (Milković-Kraus et al. 2007).
who used them, in sensitization by airborne expo-
sure and airborne allergic contact dermatitis
(Baeck and Goossens 2009). Also, tixocortol 3.6 Anti-infectious Agents
pivalate has caused occupational dermatitis in
health-care workers (Schwensen et al. 2016). Common occupational allergens are quinine (an
antimalarial) and its D-stereoisomer quinidine
sulfate or gluconate, used as anti-arrhythmic
3.5 Antibiotics and drug. Both substances have elicited contact
Tuberculostatics allergy without cross-reactivity between the two
compounds (Stejskal et al. 1986; Wahlberg and
By far, the largest number of affected workers has Boman 1981), indicating stereoselectivity for
symptoms due to antimicrobials for human or contact allergy (Isaksson et al. 1994). However,
animal use (see Sect. 3.13). Among the antibi- photocontact allergy cross-reactivity between the
otics, the natural and the semisynthetic penicillins two isomeric substances is present (Ljunggren et
are the most common drug allergens causing al. 1992), due to practically identical photoprod-
symptoms, particularly in pharmaceutical workers, ucts after ultraviolet irradiation (Isaksson et al.
followed by cephalosporins and tuberculostatic 1994). An outbreak of irritant quinine dermatitis
agents in pharmaceutical industry workers and has been observed in a factory (Hardie et al.
medical employees. Contact urticaria and anaphy- 1978), whereas allergic reactions to quinine have
laxis have also been reported (see Sect. 2.1). In the declined in recent years. Contact allergy to chlo-
penicillin group, aminopenicillins have elicited roquine sulfate, another chemically closely related
occupational skin problems; cross-reactivity to antimalarial, has been observed in a maintenance
natural penicillins (penicillins G and V) was not apprentice in a drug-packing firm; cross-reactivity
always present, indicating an antigenic determi- to quinine was not present. Quinidine was not
nant on the side chain and not on the β-lactam ring tested (Kellett and Beck 1984). Also, cases of
(Gamboa et al. 1995; Møller and Von Würden sensitization to a precursor of chloroquine (4,7-
1992; Rudzki and Rebandel 1991). Contact dichloroquinoline) have been published (Pickering
allergy to cephalosporins has been particularly and Ive 1982). Nifuroxazide, a compound used in
observed in nurses. The problem of cross-reactiv- diarrhea, elicited a prurigo-like eruption in an
ity is more complex, since the antigenic determi- employee filling bottles with the drug (Kiec-
nants for cephalosporins in IgE- and T cell- Swierczynska and Krecisz 1998).
mediated reactions are not as well established. Chloramine-T, which should not be confused
Several structures, e.g., aminobenzyl or metho- with (mono)chloramine (NH2Cl) or chlorhexidine
xyimino side chains, have been more recently (Krautheim et al. 2004) (Fig. 1), is a recognized
identified as relevant allergens (Kim and Lee IgE-antibody-inducing immediate-type allergen,
2014). Cases of contact allergy to ceftiofur which causes occupational contact urticaria and
(García-Bravo et al. 1995) and several structurally asthma (Kanerva et al. 1997). However, allergic
different cephalosporins and also a case from contact dermatitis to chloramine-T was identified
cefazolin (Straube et al. 2000) have been in a nurse who was also sensitized to quaternary
described. Occupational contact allergy to ammonium compounds and mercury derivatives
Fig. 1 Chemical formulas

of (a) chloramine-T,
(b) monochloramine, and
(c) chlorhexidine
(Lombardi et al. 1989). Chlorhexidine was a com- ACE inhibitors enalapril, lisinopril, and peri-
mon contact allergen among physicians in one ndopril were positive, whereas captopril was neg-
study (Sato et al. 2004). Another quaternary ative in patch tests in one patient (Swinnen et al.
ammonium compound caused contact dermatitis 2014).
in a dental nurse (Placucci et al. 1996). The alpha- and beta-blocking agent carvedilol
Also, benzalkonium chloride, a disinfectant with (Neumark et al. 2009) has also caused occupa-
irritant potential, has been identified as occupational contact dermatitis.
tional contact allergen (Kanerva et al. 2000). In a patient with contact sensitization to the α-
Other anti-infectious drugs include albendazole blocker phenoxybenzamine, cross-reactivity to
(which induced contact urticaria and der- chemically related haloalkylamines was demon-
matitis), fentichlor (eliciting a photoallergic strated (Mitchell and Maibach 1975). Contact
reaction with positive patch and photopatch dermatitis has been observed to nicergoline
tests) (Norris et al. 1988), piperazine (another and spironolactone in pharmaceutical employees
anthelmintic), foscarnet (an antiviral), and griseo- and to carbocromen (a vasodilator), captopril (an
fulvin (an old antifungal drug) (Testud et al. angiotensin-converting enzyme inhibitor), and the
1994). Also, topical metronidazole has rarely ophthalmologic agents homatropine and phenyl-
elicited contact allergy. In two nurses, therapeutic ephrine in nurses. Quinidine sulfate has elicited
use for rosacea elicited within 1 day severe con- contact allergy in production workers, and patch
tact dermatitis of the face (Madsen et al. 2009). tests with quinine were negative (Wahlberg and
Sensitization has likely taken place during previ- Boman 1981) (see Sect. 3.7). The vasodilator
ous occupational exposure. nitroglycerin (Kanerva et al. 1991) was also
reported to cause occupational contact dermatitis.
3.7 Cardiovascular and Vasoactive

Drugs 3.8 Central Nervous System Drugs
Antihypertensive drugs, which have elicited occu- Among the drugs acting on the central nervous
pational dermatitis in pharmaceutical workers, system, the opium alkaloids and the phenothia-
include the β-blocking agents, e.g., alprenolol, zine derivatives have caused most occupation-
propranolol, and oxprenolol, and their precursors related cases. Apart from contact dermatitis in
(Rebandel and Rudzki 1990). Cross-reactivity pharmaceutical employees and nurses, the opiates
between alprenolol and metoprolol was present have also caused respiratory symptoms. In an IgE-
(Ekenvall and Forsbeck 1978). In another patient mediated reaction to papaveretum, the allergenic
cross-reactivity among four beta-blockers meto- determinant has been located at the N-methyl-
prolol, bisoprolol, propanolol, and sotalol hydro- cyclohexenyl ring in combination with a hydroxyl
chloride was present (Swinnen et al. 2014). The group on the C atom in position 6 (Harle et al.
570 A. J. Bircher
1989). For contact allergy, the antigenic determi- also been observed (Vilaplana and Romaguera
nant is not clear, since cross-reactivity between 2001). Also, pantoprazole (Neumark et al. 2011)
the opiates is present; thebaine has an –OCH3 has been reported to cause airborne contact der-
group and hydromorphone an oxygen at this posi- matitis. More often, pharmaceutical workers with
tion (Waclawski and Aldrige 1995). It also skin problems from the production of the H2
remains unexplained why most of the patients antagonists (famotidine, ranitidine) have been
allergic to opioids were also sensitized to described. Typically, the patients are not only
p-group substances, since there are no apparent sensitized to the final products but also to inter-
cross-reacting structures (Conde-Salazar et al. mediate products from the synthesis process (see
1991). Workers preparing heroin from cap- Sect. 3.12). In another case with an airborne pat-
sules developed contact sensitivity to heroin tern, co-sensitization to omeprazole and ranitidine
(diamorphine), morphine, and codeine (Coen- was present. Patch tests were positive to both,
raads et al. 2001). prick test positive to omeprazole (Herrera-Mozo
The phenothiazines may elicit contact derma- et al. 2017). Lactase has caused protein contact
titis, airborne dermatitis (Schwenck et al. 1994), dermatitis and rhinoconjunctivitis in an occupa-
and photoallergic dermatitis. In particular, chlor- tional setting (Laukkanen et al. 2007).
promazine was a potent contact and photocontact
allergen upon direct skin contact (Björkner 1994;
Rudzki 1990). Other centrally active drugs such 3.10 Herbal Drugs and Plant
as olanzapine (Lowney et al. 2010), ziprasidone Derivatives
(Bennett et al. 2016), and zolpidem (Neumark et
al. 2009) have been identified as occupational Plant derivatives are used as fragrances and as
contact allergens. drugs in aromatherapy and phytotherapy. Contact
There have also been cases of occupational allergy and exanthematous reactions to herbal
contact dermatitis to other benzodiazepine com- remedies have been observed (Bircher 1996); air-
pounds, such as tetrazepam (Ferran et al. 2005) borne contact dermatitis and photosensitivity
and cyanamide. In some cases cross-reactivity to are well-known reactions to members of the
other benzodiazepines and sensitization to other Asteraceae (Compositae) family. Occupational
non-related drugs was demonstrated (Swinnen allergies have been observed to Arnica montana
et al. 2014). In another benzodiazepine chlordiaz- (Hausen 1980); to essential oils in aroma- and
epoxide, its precursor quinazoline oxide has phytotherapists; to pyrethrum, which is still used
caused sensitization (Rudzki and Rebandel 2001). as acaricide, in factory workers; and to the alka-
A rare case of airborne allergy from isoflurane loid vincamine tartrate from Vinca minor L. (used
(1-chloro-2,2,2-trifluoroethyl difluoromethyl for cerebral perfusion problems) (Van Hecke
ether) was identified in an anesthetist. A ROAT 1981). Eugenol, the essential constituent of
only identified the culprit; patch tests were clove oil, which is present in impression pastes
negative possibly due to its volatile nature and cements, may be an allergen for dentists
(Finch et al. 2000). (Kanerva et al. 1994).
3.9 Gastrointestinal Drugs 3.11 Immune Modulators and

Cytostatic Drugs
Two pharmaceutical employees with contact
allergy to the proton pump inhibitor omeprazole Highly reactive chemicals (and, therefore, potent
have been reported (Meding 1986). Another contact sensitizers) include dinitrofluorobenzene,
employee with contact dermatitis from lanso- dinitrochlorobenzene (DNCB), diphenylcyprone,
prazole and cross-reactivity to omeprazole has and squaric acid dibutyl ester. These sensitize
practically all exposed individuals, and therefore, in the synthesis of flutamide, an antiandrogen,
probably only unusual cases are published. caused an early onset of an itchy erythema; patch
The three latter agents have been used in the test was positive (Jungewelter and Aalto-Korte
treatment of alopecia areata, but DNCB has 2008).
become obsolete due to its mutagenic potential An unusual case of toxic epidermal necrolysis
(Happle et al. 1980). The main exposed pro- upon skin contact with an intermediate of tetra-
fessionals are accidentally exposed chemical misole, an anthelmintic and immunostimulatory
workers, dermatologists, and pharmacy agent, has been described. Patch tests were not
employees (Bircher et al. 1999). performed (Valsecchi et al. 1987). Recently, p-
Azathioprine, an immunosuppressant, is aminophenol, a breakdown product of paraceta-
widely used in transplantation and autoimmune mol (acetaminophen), has been identified as con-
diseases; cutaneous reactions to it are rare (Soni tact allergen in two employees of a production
and Sherertz 1996). Two pharmaceutical workers plant (Walker et al. 2005). After accidental expo-
have been described who had a contact allergy sure without protection to 2-aminothiophenol,
to azathioprine; the role of impurities, such as an intermediate pharmaceutical substance, a
mercaptopurine and chloromethyl-nitroimidazole, technician developed recurrent contact dermatitis
could not be elucidated (Burden and Beck at his working place, even when exposed to
1992). Also cytostatic agents such as metho- minute amounts (Bonamonte et al. 2002). An
trexate (Dastychová 2003), and cisplatine intermediate (N-(3-trifluoromethyl-4-nitrophenyl)
(Dastychová and Semrádová 2000) have been phthalimide) of flutamide, an antiandrogen,
implicated in occupational dermatitis. Etoposide elicited a disseminated erythema despite exten-
has caused rhinosinusitis in an occupational set- sive protective measures. Patch tests were positive
ting (Meyer and Stahl Skov 2010). in very high dilutions to this substance only
(Jungewelter and Aalto-Korte 2008).
3.12 Intermediate Agents

3.13 Veterinary Drugs
Intermediate products are often highly reactive
chemicals and bind readily to proteins, a prereq- Farmers, animal caretakers, and veterinarians are
uisite for sensitization. Contact allergy to inter- particularly at risk. The majority of the eliciting
mediates is not uncommon and occurs practically agents are anti-infectious and antibiotic drugs,
exclusively in individuals involved in the devel- which are used as growth promoters or for
opment and production of drugs or in mainte- therapy.
nance employees in chemical or pharmaceutical Contact takes place by skin contact while
plants. Patch testing may be difficult or treating or vaccinating (Vilaplana et al. 1991)
imposible because of safety and availabil- animals or through dust during feeding or the
ity issues. Allergic reactions to intermediates of production of feed. Important allergens are
H2 antagonists are well established, e.g., for tylosin, a macrolide antibiotic (Malaiyandi et al.
ranitidine (Romaguera et al. 1990), famotidine, 2012; Veien et al. 1980) that sometimes induced
and others. Also, synthesis of cytostatic drugs airborne contact dermatitis, and olaquindox, a
apparently produces allergenic intermediates, as growth promoter for pigs, which induced severe
demonstrated for cytosine arabinoside, metho- photoallergic contact dermatitis and, in some
trexate, nitrosoureas, and the immunosuppres- patients, a persistent light reaction (Schauder et
sant azathioprine. The intermediates of a al. 1996). Carprofen, an analgetic drug, caused
number of other drugs have been reported as photoallergic contact dermatitis in occupationally
contact allergens (Table 2). The intermediate N- exposed workers (Kerr et al. 2008; Kiely and
(3-tri-fluoromethyl-4-nitrophenyl) phthalimide) Murphy 2010; Walker et al. 2006).
572 A. J. Bircher
3.14 Vitamins immediate-type hypersensitivity, has caused an

epidemic of irritant contact dermatitis due to eth-
Thiamine (vitamin B1) (Ingemann Larsen et al. ylene oxide-sterilized overalls (Lerman et al.
1989) is a typical occupational sensitizer, 1995). Two patients, a male and a female with
whereas, e.g., cyanocobalamin has rarely caused an airborne contact dermatitis on the face from
occupational problems. In some patients, oral simvastatin with positive patch tests, have been
administration of thiamine resulted in a flare observed; patch tests were positive, and ten con-
of contact dermatitis. Few cases of occupational trols were negative (Peramiquel et al. 2005).
contact dermatitis have been reported to pyritinol, Also other statins such as atorvastatin and
a compound of two pyridoxine (vitamin B6) mol- fluvastatin may cause occupational dermatitis
ecules; pyritinol and two bases containing pyri- (Bennett et al. 2016). A male anesthesiologist
doxine induced airborne occupational contact used a tincture of benzoin aerosol spray to improve
allergy (Wigger-Alberti and Elsner 1997). The adhesion of a small bandage immediately before
retinols (vitamin A) elicit irritant reactions in performing a spinal anesthesia. He experienced
higher concentrations more often; a case of allergy severe pruritus and dermatitis in the affected hand
to vitamin A acetate has been reported. However, 48 h after benzoin exposure (Klein et al. 2009).
occupational contact allergy (in several pharma-
ceutical workers and a pig feeder) to the synthetic,
water-soluble form of vitamin K3 (menadione 4 Summary
sodium bisulfite) has been observed, with cross-
reactivity to vitamin K4 (menadiol sodium A considerable number of drugs have been
diphosphate) (Dinis et al. 1988). reported as occupational allergens. Drugs are not
the most common occupational allergens, but, for
the above mentioned reasons, they may be of
3.15 Miscellaneous Drugs considerable importance. Cutaneous and/or respi-
ratory symptoms (and, rarely, systemic reactions)
Several drugs have caused single cases of occu- may be elicited. Of particular importance is the
pational contact dermatitis. Carbimazole, a thio- possibility of reexposure to a particular drug for
urea used as an antithyroid drug, has induced medical purposes in an occupationally sensitized
photoallergic reactions in a pharmaceutical individual. Diagnosis of an occupational allergy
laboratory worker. Disulfiram (tetraethylthiuram and allergen recognition can lead to appropriate
disulfide) used for adjunctive therapy in alcohol- control and prevention in many situations
ism has elicited contact dermatitis in a nurse (Sherertz 1994).
handling tablets. A clinically relevant cross-reac-
tivity to other thiurams (eczema under rubber
gloves) has been reported (Mathelier-Fusade and
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Fragrances and Essential Oils
40
Anton C. de Groot
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
2 Fragrances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
2.2 The Composition of Perfumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
2.3 Contact with Fragrances and Fragranced Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582
2.4 Detecting Fragrance Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
2.5 Frequency of Contact Allergy to Fragrances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
2.6 Clinical Picture of Allergic Contact Dermatitis from Fragrances . . . . . . . . . . . . . . . . 588
2.7 Products Causing Contact Allergy to and Allergic Contact Dermatitis from
Fragrances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
2.8 Other Fragrance Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
2.9 Occupational Allergic Contact Dermatitis to Fragrances . . . . . . . . . . . . . . . . . . . . . . . . . 589
3 Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
3.1 Definition and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
3.2 Chemistry of Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
3.3 Contact Allergy to Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
3.4 Frequency of Contact Allergy to Essentials Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
3.5 Clinical Relevance of Positive Patch Test Reactions to Essential Oils . . . . . . . . . . . 595
3.6 Clinical Picture of Allergic Contact Dermatitis from Essential Oils . . . . . . . . . . . . . 600
3.7 Occupational Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
3.8 The Allergens in Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
3.9 Patch Testing with Essential Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Abstract perfumes; Contact with fragrances and

This chapter discusses occupational and fragranced products; Detecting fragrance
non-occupational contact allergy to and aller- allergy; Frequency of contact allergy to fra-
gic contact dermatitis from fragrances and grances (general population, patch test popula-
essential oils. The following topics are pre- tion, fragrances markers in the baseline series,
sented for fragrances: The composition of individual fragrances); Clinical picture of aller-
gic contact dermatitis from fragrances; Prod-
ucts causing contact allergy to and allergic
A. C. de Groot (*) contact dermatitis from fragrances; Other
Acdegroot Publishing, Wapserveen, The Netherlands

https://doi.org/10.1007/978-3-319-68617-2_40
580 A. C. de Groot
fragrance allergens; Occupational allergic con- absolute), hydroxyisohexyl 3-cyclohexene

tact dermatitis to fragrances. carboxaldehyde (Lyral ®), Evernia prunastri
For essential oils, the following topics are extract (oakmoss absolute), cinnamyl alcohol,
discussed: Definition and applications; cinnamal and isoeugenol; unoxidized linalool
Chemistry of essential oils; Contact allergy and limonene are virtually non-sensitizing
to essential oils; Frequency of contact allergy • Fragrances are not important occupational sen-
to essential oils; Clinical relevance of posi- sitizers; in the case of eczema of the hands,
tive patch test reactions to essential oils; fragrance allergy may complicate previous irri-
Clinical picture of allergic contact dermatitis tant or atopic hand dermatitis from their pres-
from essential oils; Occupational allergic ence in cleansers, hand lotions etc.
contact dermatitis to essential oils; The aller- • Contact allergy to essential oils as a group is
gens in essential oils; Patch testing with not very frequent; the highest rates of sensiti-
essential oils zation to individual oils in routine testing have
been observed for turpentine oil (4.2%), orange
Keywords oil (3.2%), oxidized lavender oil (2.8%), tea
Fragrance · Perfume · Essential oil · Evernia tree oil (2.7%), ylang-ylang oil (2.6%), citro-
prunastri extract · Oakmoss absolute · Evernia nella oil (2.5%), sandalwood oil (2.4%) and
furfuracea extract · Treemoss absolute · clove oil (2.1%)
Hydroxyisohexyl 3-cyclohexene • Determining relevance of positive patch tests
carboxaldehyde · Lyral ® · Hydroxycitronellal · to essential oils is often difficult; relevant cases
Isoeugenol · Cinnamal · Farnesol · Limonene · may be caused by pure essential oils (notably
Linalool · Tea tree oil · Fragrance mix I · tea tree oil), massage products (mostly occu-
Fragrance mix II · Limonene hydroperoxides · pational), cosmetic products, perfumes, tooth-
Linalool hydroperoxides pastes and other oral preparations, and
pharmaceutical products
• Essential oils are not important occupational
1 Core Messages sensitizers, but contact allergy may increas-
ingly be detected in aromatherapists, physio-
• Fragrances are ubiquitous and are present in therapists and others massaging with products
cosmetics, household products, industrial containing essential oils
products and many other applications; they
are also used as flavors in foods and drinks
• Contact allergy to fragrance materials is fre- 2 Fragrances
quent, both in the general population
(2–3.5%) and in patients seen by dermatolo- 2.1 Introduction
gists for suspected allergic contact dermatitis
(12–17%) Perfumes (fragrances) are so much a part of
• The fragrances and fragrance markers in the our daily life that we take them for granted,
baseline series do not detect all cases of fra- but if they were suddenly taken from us, our
grance sensitization; in patients suspected of culture would suffer immeasurably. We do pay
fragrance allergy, it is advised to test an addi- a price for their service, part of which are
tional fragrance series with individual fra- dermatologic and other medical reactions,
grance allergens most often allergic contact dermatitis. This
• Frequent fragrance sensitizers include oxidized chapter discusses occupational and non-
limonene (limonene hydroperoxides), oxi- occupational contact allergy to and allergic
dized linalool (linalool hydroperoxides), contact dermatitis from fragrance materials
Evernia furfuracea extract (treemoss and essential oils. For a full review of this subject
40 Fragrances and Essential Oils 581
up to 1997 the reader is referred to De Groot and Table 1 Concentrations of perfume in various products
Frosch (1997). Very useful reviews were (De Groot and Frosch 1997; Johansen 2002)
published in 2002 and 2003 (Johansen 2002, Aerosol freshener 0.5–2%
2003) and 2013 (Uter et al. 2013a). Contact Bathroom cleaners 5%
allergy to and chemical composition of Body lotion 0.4%
essential oils has been extensively reviewed by Compressed powder 0.5%
De Groot and Schmidt (2016a, b, c, d, e, f, g, Deodorant/antiperspirant 1–3%
2017). Many older literature references for Dishwashing liquid 0.1–0.5%
Eau de cologne 3–5%
the data in this chapter can be found in the
Eau de parfum 8–15%
▶ Chap. 40, “Fragrances and Essential Oils” in
Eau de toilette 4–8%
the previous 2000 and 2012 Editions of this book
Facial make-up 1.0%
(De Groot 2000, 2012).
Hair pomade 0.5%
Hair spray 0.1–0.3%
Laundry powder 0.1–0.3%
2.2 The Composition of Perfumes Lipstick 1.0%
Liquid detergents 0.1–1%
Perfumery is the art of making individuals Masking perfume 0.1%
and products attractive to the olfactory sense. Perfume (proper) 15–30%
Of the thousands of chemical substances that Shampoo (undiluted) 0.5%
have an odor, about 3000 (of which 300–400 Skin care products (emulsions) 0.3–0.5%
are of natural origin), are used in the fragrance Soap (undiluted) 0.5–2%
industry. A perfume is a creative composition
of a few to over 300 fragrance materials.
‘Proper’ perfumes contain approximately parameters (country, period of investigation,
15–30% of the fragrance compound. They are product types, sample sizes, methods of selec-
expensive and too concentrated. The more tion), the results are very difficult to compare.
diluted products (eau de parfum, eau de toilette, Neverthess, when each fragrance in individual
colognes) are therefore much more popular. studies is assigned a rank number (chemical
Approximate concentrations of fragrance with the highest percentage presence in the
materials in cosmetics and other products are investigated products rank number 1, lowest
given in Table 1. percentage rank number 26), a fairly constant
Details of the composition of a particular per- picture of the relative use of each fragrance
fume are closely guarded by industry, which becomes evident. By far most commonly
maintains that secrecy of the formulae is fully encountered were linalool and limonene,
commensurate with investment in the develop- followed by citronellol, geraniol, hexyl-
ment and marketing of a product. Since cinnamal, butylphenyl methylpropional and
2005 however, in the EU, cosmetic products benzyl salicylate. In fragranced cosmetic
and detergent products are required to be products (Buckley 2007; Bennike et al. 2017b)
labelled for the presence of 26 individual they were present in 50–63% (linalool), 49–63%
fragrance chemicals, if present at >10 parts per (limonene), 29–48% (citronellol), 24–42%
million (ppm, 0.001%) in leave-on products (geraniol), 22–42% (hexylcinnamal), 21–42%
and >100 ppm (0.01%) in rinse-off (butylphenyl methylpropional) and 18–38%
products (Table 2) (EU 2003). Several recent (benzyl salicylate). The least frequently used
studies have investigated the presence of these chemicals in fragranced cosmetics were
fragrances in cosmetics and household cinnamal (1–6%), Evernia prunastri extract
detergents by checking the labels. Their results (oakmoss absolute) (0.1–4%), Evernia
are summarized in Table 2. Due to differing furfuracea extract (treemoss absolute)
582 A. C. de Groot
Table 2 Presence of 26 fragrances in cosmetics and household productsbased on ingredient labelling

Buckley Uter et al. Yazar et al. Bennike
2007a 2013bb 2011c et al. 2017bd
Fragrance % (rank nr.) % (rank nr.) % (rank nr.) % (rank nr.) Rank number overall
Linalool 63 (1) 31 (1) 29 (1) 50 (1) 1
Limonene 63 (1) 30 (2) 27 (2) 49 (2) 2
Citronellol 48 (3) 20 (3) 17 (5) 29 (3) 3
Geraniol 42 (4) 18 (4) 9 (7) 24 (4) 4/5
Hexyl cinnamal 42 (4) 13 (6) 26 (3) 22 (6) 4/5
Butylphenyl methylpropional 42 (4) 15 (5) 23 (4) 21 (7) 6
Benzyl salicylate 38 (7) 12 (7) 11 (6) 18 (8) 7
α-Isomethyl ionone 35 (8) 12 (7) 8 (8) 16 (9) 8
Benzyl alcohol 20 (14) 9 (11) 7 (9) 23 (5) 9
Coumarin 30 (9) 10 (10) 5 (10) 13 (11) 10
Citral 25 (12) 11 (9) 3 (13) 15 (10) 11
HICCe 29 (10) 9 (11) 5 (10) 7 (14) 12
Benzyl benzoate 23 (13) 9 (11) 3 (13) 9 (12) 13
Eugenol 27 (11) 7 (14) 1 (16) 8 (13) 14
Hydroxycitronellal 17 (15) 7 (14) 2 (15) 7 (14) 15
Amyl cinnamal 7 (19) 3 (16) 4 (12) 4 (16) 16
Farnesol 8 (17) 3 (16) 0.3 (18) 3 (17) 17
Isoeugenol 9 (16) 2 (19) 0.3 (18) 2 (18) 18
Cinnamyl alcohol 8 (17) 3 (16) – (21) 2 (18) 19
Cinnamal 6 (20) 1 (20) – (21) 1 (20) 20
Evernia prunastri extract 4 (21) 0.7 (21) 0.3 (18) 0.1 (24) 21
Evernia furfuracea extract 3 (22) 0.7 (21) – (21) 0.3 (22) 22
Benzyl cinnamate 3 (22) 0.8 (23) – (21) 0.6 (21) 23
Anise alcohol 0.3 (24) 0.2 (25) – (21) 0.3 (22) 24
Methyl 2-octynoate – (25) 0.1 (26) 0.7 (17) 0.1 (25) 25
Amycinnamyl alcohol – (25) 0.3 (24) – (21) – (26) 26
a
UK (2006), 300 fragranced cosmetics and household cleaning products available on the shelves of UK retailers
b
Germany (2006–2009), 4991 cosmetics product sampled for an official investigation of conformity of cosmetic products
with legal provisions
c
Sweden (2008–2010), 204 frequently used cosmetics and 97 household detergents
d
Denmark (2015–2016), 5588 fragranced cosmetic products examined with a smartphone application
e
HICC hydroxyisohexyl 3-cyclohexene carboxaldehyde
(0.3–3%), benzyl cinnamate (0.6–3%), anise 2.3 Contact with Fragrances

alcohol (0.3%), methyl 2-octynoate (0–0.1%) and Fragranced Products
and amycinnamyl alcohol, which was
present in 0.3% of products in one study, The use of fragrances is ubiquitous and not limited
but in none of the other three investigations to those cosmetic products that are used primarily
(Table 2). for their scent such as perfumes, eau de cologne,
Over 70% of the investigated products eau de toilette, deodorant and aftershave. Virtually
contained 3 or more of the 26 fragrances (Bennike all cosmetics and toiletries contain fragrance mate-
et al. 2017b). In one study, the mean number of rials; even ‘unscented’ or ‘fragrance-free’ products
listed fragrances in a product was 5.9 (mean for may contain a masking perfume or an essential oil.
perfumes 12, deodorants 7.8, products for men Flavours used in oral hygiene products - toothpaste,
6.5, household products 3, dental products 1) mouthwash, and dental floss - are fragrance
(Buckley 2007). chemicals. Scented household products include
detergents, cleaners, softeners, fabric conditioners, (fragrance mix I and fragrance mix II and two
deodorising sprays, polishes, solvents and waxes. markers (indicators) of fragrance allergy:
In industry, cutting fluids, electroplating fluids, Myroxylon pereirae resin (balsam of Peru) and
paints, rubber, plastics, insecticides, herbicides colophonium (Table 3).
and additives used in air conditioning water may The FM I, which has been part of most routine
all be scented. Eugenol is occasionally used by series since the late 1970s, although very useful,
dentists. Paper and paper products – including dia- is far from ideal. It causes irritant reactions,
pers, facial tissues, moist toilet paper and sanitary false-negative reactions (positive reaction to
napkins – may be scented. Fabrics and clothes may one or more of the ingredients but negative reac-
contain fragrance materials, especially after they tion to the mix), and leaves up to 50% of fra-
are laundered or treated with a fabric softener grance sensitivities undetected. In addition, it is
(although this never results in sensitization or elic- rather common for patients with positive reac-
itation of allergic contact dermatitis). Topical drugs tions to the fragrance mix to have a negative
often contain perfumes or essential oils, and venti- break-down, i.e., no positive reactions to one or
lating systems and diffusers may spread fragrances more of its ingredients (Mowitz et al. 2017). This
through the air.
The distinction between fragrances and
spices is often vague. Many synthetic fragrances Table 3 Fragrances, fragrance mixes and markers of fra-
are used as spices and flavours. Natural grance contact allergy in the European baseline series
fragrances like cinnamon, clove, vanilla and Concentration%
Chemical (w/w) & vehicle
cardamom are added to foods, soft drinks,
Colophonium (rosin) 20% pet.
lozenges, chewing gum, candies, ice cream and
Fragrance mix I (incl. 5% 8% pet.
tobacco. Thus, it can be stated that virtually sorbitan sesquioleate)
everyone is in daily contact with fragrance Amyl cinnamal
materials. (α-amylcinnamic aldehyde)
Contact with fragrances may be from direct (1%)
product application to the skin or mucous mem- Cinnamal (cinnamic
branes, by occasional contact with an allergen- aldehyde) (1%)
Cinnamyl alcohol (1%)
contaminated product such as towels and pil-
Eugenol (1%)
lows, contact with products used by partners,
Evernia prunastri extract
friends or co-workers (consort or connubial (oakmoss absolute) (1%)
contact dermatitis), airborne contact, and sys- Geraniol (1%)
temic exposure by inhalation and ingestion (fra- Hydroxycitronellal (1%)
grances, flavours and spices in foods and Isoeugenol (1%)
drinks). Any part of the body may come in Fragrance mix II 14% pet.
contact with fragranced cosmetics. Citral (1%)
Citronellol (0.5%)
Coumarin (2.5%)
2.4 Detecting Fragrance Allergy Farnesol (2.5%)
Hexyl cinnamal
A perfume may contain as many as 300 or (α-hexylcinnamic aldehyde)
(5%)
more individual ingredients. This makes the
Hydroxyisohexyl
diagnosis of perfume allergy by patch test pro- 3-cyclohexene carboxaldehyde
cedures complicated. The European baseline (Lyral ®) (2.5%)
series, which is routinely tested in all patients Hydroxyisohexyl 3-cyclohexene 5% pet.
suspected of contact dermatitis, contains a spe- carboxaldehyde (Lyral ®)
cific fragrance (hydroxyisohexyl 3-cyclohexene Myroxylon pereirae resin 25% pet.
(balsam of Peru)
carboxaldehyde), two mixtures of fragrances
584 A. C. de Groot
may indicate an irritant reaction to the mix or a (including mixes and indicators) are commer-
false-negative reaction to its ingredients. How- cially available for patch testing (Table 4). In
ever, another explanation for this phenomenon cases of suspected fragrance allergy, therefore,
(assuming that the reaction to the mix was not testing an additional ‘fragrance series’ is advis-
false-positive) may lie in the observation that able, which should also be performed (in a second
mixtures of fragrance sensitizers can result in session) when fragrance sensitivity is strongly
increased challenge responses to specific aller- suspected, but the fragrance test substances in
gens within the mixture (Bonefeld et al. 2017). the baseline series remain negative. Of course,
Another draw-back is that the mix may occasion- all suspected products used by the patients
ally cause active sensitization. In addition, should also be patch tested. This goes especially
sorbitan sesquioleate present in the mix may for perfumes, deodorants and shaving lotions,
induce an allergic response. Therefore, this as in about half the cases of positive reactions
emulsifier should always be routinely tested to to these personal products the fragrance allergens
avoid misinterpreting a positive reaction to in the baseline series are negative, and positive
sorbitan sesquioleate in the mix as fragrance reactions to the products strongly suggest
allergy. relevancy (Uter et al. 2007).
The fragrance mix II was added to the
European baseline series in 2008. It certainly has
added value, as in 35–50% of the patients with a 2.5 Frequency of Contact Allergy
positive reaction, the fragrance mix I is negative to Fragrances
(Mowitz et al. 2017). Similar to the FM I,
one-third of the patients reacting to the FM II Although fragrances are mostly moderate
have no positive reactions to any of its ingredients sensitizers (Lidén et al. 2016), they are among
(Mowitz et al. 2017). At the same time, the most frequent causes of contact allergy,
hydroxyisohexyl 3-cyclohexene carboxaldehyde presumably from their extremely widespread
(Lyral ®) (HICC), the predominant sensitizing use. Some fragrances with low allergenic
constituent of the FM II, was added as single potency turn into stronger allergens after auto-
allergen to the baseline series in the higher con- oxidation by which sensitizing hydroperoxides
centration of 5%. The rate of sensitization to this are formed, e.g., limonene, linalool, linalyl
fragrance, which is strongly associated with con- acetate and geraniol. In the case of geraniol, the
tact allergy to deodorants, is one of the higher in main products in common after autoxidation
the baseline series. are the sensitizing isomeric aldehydesgeranial
Nevertheless, some authors suggest that it can and neral, which together constitute the
be deleted from the baseline series (it actually fragrance chemical citral (Bråred Christensson
was deleted from the Swedish baseline series et al. 2016a).
in 2014), as by far most reactions to this
fragrance are also picked up by a positive
reaction to the FM II (Engfeldt et al. 2017; 2.5.1 General Population
Isaksson et al. 2014), leaving undetected allergy Based on 13 studies performed in adults, the
to HICC in only 0.2–0.3% of the patients, a weighted average prevalence of FM I sensitization
prevalence too low to warrant its inclusion in a has been calculated to be 3.7% (Thyssen et al.
baseline series. 2009). However, other fragrance compounds
It is well known that the fragrances and indi- not detected by this mix can also cause contact
cators leave a considerable number of sensitiza- allergy, so the percentage of fragrance sensitiza-
tions to fragrances undetected. Indeed, testing tion is likely to be higher. It should be appreciated
with additional fragrances (and essential oils) that many such individuals, although sensitized
may reveal many additional cases of fragrance to certain fragrance materials, can tolerate per-
contact allergy. Sixty-one fragrance allergens fumes and scented products and do not suffer
Table 4 Fragrances commercially available for patch testing

Suppliers
Patch test allergen SPEurope Chemo SPCanada
Abietic acid 10% 10% 10%
Alantolactone 0.033%
Amyl cinnamal (α-amylcinnamic aldehyde) 1% 2% 1%
Amylcinnamyl alcohol 1% 5%
Anethole 5%
Anise alcohol 1% 10% 1%
Softisan
Atranorin 0.1% 0.1% 0.1%
Benzaldehyde 5% 5%
Benzyl alcohol 1% and 10% 1% and
5% Softisan 5%
Benzyl benzoate 1% 10% 5%
Benzyl cinnamate 5% 10% 5%
Benzyl salicylate 1% 10% 1%
Butylphenyl methylpropional (Lilial ®, p-tert-butyl-α-methyl- 10% 10%
hydrocinnamicaldehyde)
Carvone 5% 5%
Cinnamal (cinnamic aldehyde) 1% 1% 1%
Cinnamyl alcohol 1% 2% 1%
Citral 2% 2% 2%
Citronellal 2% 2%
Citronellol 1% 1% 1%
Colophonium (rosin)a 20% 20% 20%
Coumarin 5% 5% 1%
Dipentene (d,l- (R-S-)-limonene) 2%
Eugenol 1% 2% 1%
Evernia furfuracea extract (tree moss absolute) 1% 1% 1%
Evernia prunastri extract (oakmoss absolute) 1% 2% 1%
Evernic acid 0.1%
Farnesol 5% 5% 5%
Fragrance mix I (cinnamyl alcohol, cinnamal, hydroxycitronellal, amyl 8% 8% 8%
cinnamal, geraniol, eugenol, isoeugenol, Evernia prunastri extract)a
Fragrance mix II (citral, citronellol, coumarin, farnesol, hexyl cinnamal, 14% 14% 14%
hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral ®))a
Geraniol 1% 2% 1%
Hexyl cinnamal (α-hexylcinnamic aldehyde) 10% 10% 10%
Hydroabietyl alcohol (Abitol ®) 10% 10% 10%
Hydroxycitronellal 1% 2% 1%
Hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral ®) 5% 5% 5%
Isoeugenol 1% 2% 1%
α-Isomethyl ionone (γ-methylionone) 10% 1%
Lichen acid mix (atranorin, evernic acid, usnic acid)a 0.3% 0.3%
d-Limonene 2% 10% 2% and
3%
Limonene hydroperoxides 0.2% and 0.2%
0.3%
Linalool 10% 10% 10%
(continued)
586 A. C. de Groot
Table 4 (continued)
Suppliers
Patch test allergen SPEurope Chemo SPCanada
Linalool hydroperoxides 0.5% and
1%
Menthol 1% 1% and 1%
2%
Methyl anthranilate 5%
Methylcoumarin 1% and
1% alc.
Methyl-2-octynoate (methyl heptine carbonate) 0.2%
Methyl salicylate 2% 2%
Musk ambrette 5% 5%
Musk ketone 1%
Musk mix (xylene, moskene, ketone)a 3%
Musk moskene 1%
Musk xylene 1%
Myroxylon pereirae resin (Balsam of Peru)a 25% 25% 25%
Perfume mix (cinnamyl alcohol, cinnamal, hydroxycitronellal, eugenol, 6%
isoeugenol, geraniol)a
Phenyl salicylate 1% 1% 1%
α-Pinene 15% 15%
Propolisa 10% 10% 10%
Salicylaldehyde 2% 2%
Sesquiterpene lactone mix (alantolactone, costunolide, dehydrocostus 0.1% 0.1% 0.1%
lactone)a
Trimethylbenzenepropanol (Majantol ®) 5% 5%
Usnic acid 0.1% 0.1% 0.1%
Vanillin 10% 10% 10%
All test substances are in petrolatum unless otherwise indicated; alc.: alcohol
SPEurope: SmartPractice Europe, www.smartpracticeeurope.com; Chemo: Chemotechnique Diagnostics, www.
chemotechnique.se; SPCanada: SmartPractice Canada, www.smartpracticecanada.com
a
Not a fragrance ingredient per se, but an indicator of fragrance allergy
from, nor have a history of allergic reactions. 2.5.2 Patients Patch Tested because
Even continuous exposure to fragrances to of Suspected Contact Dermatitis
which contact allergy has been established will In consecutive patients patch tested because of
not necessarily lead to allergic contact dermatitis suspected contact dermatitis (routine testing),
(Schubert 2006). contact allergy to fragrances is frequent. In a
In a recent study in five European countries recent study in 12 European countries, 12.7%
in a random sample from the general population of a group of over 50,000 patients reacted to
aged 18–74 years, 2.6% reacted to the FM I, 1.9% the FM I, the FM II, HICC, Myroxylon pereirae
to the FM II and 1.5% to hydroxyisohexyl resin, oil of turpentine (a weak marker for fra-
3-cyclohexene carboxaldehyde. The conservatively grance allergy) or a combination of these (Frosch
estimated prevalence of clinically relevant fra- et al. 2015). However, these fragrances and
grance contact allergy was 1.9% (Diepgen markers fail to detect a large number of fragrance
et al. 2015). allergic individuals. In patients reacting to
oxidized linalool and/or limonene, for example, resin in Europe range from 2.9% to 5.7% and
which recently caused many reactions in several are slightly higher in the USA (7.2–7.9%) and
European and some other countries (limonene Thailand (6.8%). Colophonium, which is a
2.5–5.2% and linalool 3.9–7.4%), only 30–42% weaker marker for fragrance sensitization, cur-
co-react to the baseline fragrance markers rently has the lowest prevalence scores,
(Audrain et al. 2014; Bråred Christensson et al. 2.6–2.9% in Europe (Frosch et al. 2015; Uter
2016b; Deza et al. 2017; Ung et al. 2017). Of et al. 2017) and 1.9–2.3% in the USA (DeKoven
patients reacting to one or more of the 26 fra- et al. 2017, Warshaw et al. 2015).
grances that need to be labelled in the EU,
40–60% are not detected by a reaction to the 2.5.4 Individual Fragrances
markers in the baseline series (Mann et al. Contact allergy to limonene and linalool was
2014; Ung et al. 2017). And finally, even a con- long considered to be rare. In recent years,
siderable number of contact sensitizations to the however, limonene hydroperoxides and linalool
ingredients of the FM I and FM II are in patients hydroperoxides (in oxidized limonene and
with a negative patch test to the mixes them- linalool) have gained much attention and have
selves (Mann et al. 2014; Mowitz et al. 2017). been patch tested in several studies in consecu-
This means that the actual prevalence of fra- tive patients in European and some other
grance sensitivity in routinely tested patients countries. Prevalences of sensitization to
must be considerably or far higher than 12%. In limonene hydroperoxides have ranged from
Central Europe, an estimated 16.2% of consecu- 2.5% to 5.2% and to linalool hydroperoxides
tive patients reacted to FM I, FM II, HICC, from 3.9% to 7.4%. This would make these
Myroxylon pereirae resin, oil of turpentine or the most frequent fragrance sensitizers at
combinations (Uter et al. 2013a) and in this moment (Audrain et al. 2014, Bennike
Thailand (small population), a staggering et al. 2017a, Bråred Christensson et al. 2016b,
22.1% reacted to the FM I, FM II, Myroxylon Deza et al. 2017, Ung et al. 2017). The author
pereirae resin or combinations (Vejanurug thinks it likely that a number of these reactions
et al. 2016). have been false-positive (Audrain et al. 2014;
Bennike et al. 2017a). Nevertheless, in the UK,
2.5.3 Fragrance Mixes and Fragrance it has recently been advised to add them to the
Markers in the Baseline Series British baseline patch test series (Wlodek et al.
In Europe, current prevalences of sensitization to 2017), acknowledging that the optimal test con-
the FM I in consecutive patch tested patients centration for these chemicals has yet to be
range from 5.1% to 9.3% (Bennike et al. 2017a; determined.
Frosch et al. 2015; Mowitz et al. 2017; Ung et al. Hydroxyisohexyl 3-cyclohexene carbox-
2017; Uter et al. 2017). In the USA, prevalences aldehyde (HICC) is present in the European
are around 12% (DeKoven et al. 2017; Warshaw baseline series in the FM II and as single test
et al. 2015) and (in a small group of patients) in substance (Table 3). It is a frequent fragrance
Thailand, even an 18.3% frequency was allergen, strongly associated with deodorants,
observed (Vejanurug et al. 2016). The FM II with rates of 1.2–3.1% positive reactions, but
generally has lowers scores, ranging from 2.9% probably somewhat declining most recently
to 4.4% in Europe (Bennike et al. 2017a; (Bennike et al. 2017a; Carvalho et al. 2011;
Engfeldt et al. 2017; Frosch et al. 2015; Isaksson Engfeldt et al. 2017; Frosch et al. 2015;
et al. 2014; Mowitz et al. 2017; Ung et al. 2017; Heisterberg et al. 2011b, 2012; Isaksson et al.
Uter et al. 2017) to 5.2–5.7% in the USA 2014; Mann et al. 2014; Mowitz et al. 2017;
(DeKoven et al. 2017, Warshaw et al. 2015,) Ung et al. 2017; Van Oosten et al. 2009). HICC
and 8% in Thailand (Vejanurug et al. 2016). will be totally banned from cosmetic products in
Rates of sensitization to Myroxylon pereirae the EU from 23 August 2021 on.
588 A. C. de Groot
Several recent studies have tested the 26 fra- Table 5 Prevalence of sensitization to 26 fragrances
grances that need to be labelled in the EU in con- labelled in the EU in four studies in European countries
(Bennike et al. 2017a; Mann et al. 2014; Heisterberg et al.
secutive patients (Table 5) (Bennike et al. 2017a; 2011b; Van Oosten et al. 2009)
Mann et al. 2014; Heisterberg et al. 2011b; Van
Average
Oosten et al. 2009). These include the eight compo- Range of percentage of
nents of the FM I (indicated with*) and the six positive positive
constituents of the FM II (indicated with**). In Fragrance reactions reactionsa
groups of patients tested with theses 26 fragrances, Evernia furfuracea 2.3–3.3% 2.78%
approximately 10% react to one or more of them extract
(Mann et al. 2014; Van Oosten et al. 2009). The HICC** 1.3–3.1% 2.03%
Evernia prunastri 1.3–2.1% 1.75%
results are shown in Table 5. Evernia furfuracea
extract*
extract (treemoss absolute) is the most frequently Cinnamyl alcohol* 0.6–2.5% 1.58%
reacting fragrance, with prevalences of 2.2–3.3%. It Cinnamal* 1.3–1.6% 1.43%
is followed by HICC and 6 of the components of the Isoeugenol* 0.9–2.1% 1.35%
FM I: Evernia prunastri extract (oakmoss absolute) Hydroxycitronellal* 0.6–2.2% 1.18%
(1.3–2.1%), cinnamyl alcohol (0.6–2.5%), cinnamal Eugenol* 0.3–1.3% 0.65%
(1.3–1.6%), isoeugenol (0.9–2.1%), hydroxyci- Farnesol** 0.3–0.9% 0.6%
tronellal (0.6–2.2%) and eugenol (0.3–1.3%). The Citral** 0.3–1.0% 0.58%
FM II components farnesol (0.3–0.9%), citral Hexyl cinnamal** 0.5–0.6% 0.55%
(0.3–1.0%) and hexyl cinnamal (0.5–0.6%) follow. Butylphenyl 0.3–0.6% 0.43%
In Denmark and Germany, trimethylbenzen- methylpropional
epropanol (Majantol®) was positive in 0.7–0.8% Geraniol* 0–0.6% 0.35%
Coumarin** 0.1–0.6% 0.33%
of routinely tested patients (Frosch et al. 2015;
Linalool (not 0.1–0.6% 0.3%
Schnuch et al. 2017). Oxidized linalyl oxidized)
acetate scored 2.2% positive reacties in Sweden Amycinnamyl 0.1–0.6% 0.28%
(Hagvall et al. 2015) and in the USA, cinnamal alcohol
is an important cause of contact allergy Benzyl salicylate 0.1–0.3% 0.23%
with around 4% positive reactions in the Citronellol** 0.1–0.3% 0.2%
studies of the North American Contact Dermatitis α-Isomethyl ionone 0–0.6% 0.2%
Group (DeKoven et al. 2017; Warshaw et al. 2015). Benzyl alcohol 0.1–0.3% 0.18%
Methyl 2-octynoate 0–0.3% 0.16%
2.5.5 Patients with Cosmetic Amyl cinnamal* 0–0.2% 0.13%
Dermatitis Anise alcohol 0–0.2% 0.1%
In patients suffering from allergic contact derma- Benzyl cinnamate 0–0.2% 0.1%
titis to cosmetics, 30–45% of the reactions are Benzyl benzoate 0–0.1% 0.03%
Limonene (not 0–0.1% 0.03%
caused by fragrances (Adams and Maibach
oxidized)
1985; De Groot et al. 1988).
HICC hydroxyisohexyl 3-cyclohexene carboxaldehyde
*
Present in the fragrance mix I
**
Present in the fragrance mix II
a
2.6 Clinical Picture of Allergic Not adjusted for sample size
Contact Dermatitis from
Fragrances dermatitis is rather scant and a good description is
lacking. It can be expected, however, that the neck,
In general, fragrance allergy (as diagnosed by pos- skin behind the ear and axillae are often implicated,
itive patch tests) occurs predominantly in women given that they are exposed to products with high
with facial and hand eczema. They will typically concentrations of fragrances (perfume, deodorant).
give a history of a previous rash from a perfume Indeed, the fragrances used in deodorants are an
(fine fragrance) or scented deodorant (Johansen important, if not the most important, cause of induc-
2003). Literature on the clinical picture of perfume tion and elicitation of fragrance allergy (Johansen
2003; Heisterberg et al. 2011a). Also, the sensitive most frequent sources of sensitization to and aller-
skin of the face and the eyelids should be particu- gic contact dermatitis caused by fragrance ingre-
larly susceptible to developing allergic contact der- dients in women, whereas after shave products
matitis to fragrances in skin care products, and deodorants are most often responsible in
decorative cosmetics and cleansing preparations, men. Thereafter, eczema may appear or
and from airborne contact dermatitis. Micro- beworsened by contact with other fragranced
traumata from shaving facilitates contact allergy to products, such as cosmetics, toiletries, household
aftershave fragrances. products, industrial substances, and flavourings
Most fragrance allergic reactions are erythem- (Uter et al. 2013a).
atous, more acute lesions with vesicles, oozing
and papules may sometimes be observed.
Some cases resemble nummular eczema, 2.8 Other Fragrance Allergens
seborrhoeic dermatitis, sycosis barbae, or lupus
erythematosus. Pustular allergic contact dermati- In Table 6, published fragrance allergens are
tis has rarely been described (Verma et al. 2015). tabulated. Over 140 fragrances (including
Lesions in the skin folds may be mistaken for chemicals in tea tree oil and Evernia prunastri
atopic dermatitis. Dermatitis due to perfumes or extract and Evernia furfuracea extract that are
toilet water tends to be ‘streaky’. Hand eczema is not specifically used for fragrance purposes)
common in fragrance-sensitive patients and there have been reported as sensitizers. It should
is a possible but not certain association between be noted, however, that for a substantial number
the dermatitis and fragrance sensitization. Patients of them, only positive patch tests were observed
may first have irritant dermatitis or atopic derma- in routine testing or testing in groups of
titis, which is later complicated by contact allergy selected patients, without establishing their
to products used for treatment or prevention (hand clinical relevance. Recently, many fragrance
creams and lotions) of hand dermatitis, or to other chemicals have been classified as ‘established
perfumed products in the household, hobby, or contact allergen in humans’, other as ‘fragrance
work environment. Dyshidrotic eruptions are substance with positive human data, but not
ascribed to ingestion of spices. Atopic dermatitis sufficient for categorization as established contact
located at other body sites, perianal dermatitis and allergen in humans’ (indicated by resp.f and g in
vulvar dermatitis may also be complicated by Table 6) (Uter et al. 2013a). Since the previous
fragrance allergy. Fragrances present in topical edition of this book (2012), no new fragrance
pharmaceutical preparations such as corticoste- allergens appear to have been identified. Patch
roids, anti-inflammatory drugs, wound healing, test concentrations for these fragrances can be
antiseptic-disinfectant, and antihaemorrhoid prep- found in ▶ Chap. 202, “Patch Test Concentrations
arations, can cause iatrogenic allergic contact and Vehicles for Testing Contact Allergens” and
dermatitis. in Table 4 for commercially available fragrance
Fragrance sensitization may lead to continuous test materials.
or periodic dermatitis, sick leave, and impaired
quality of life, especially in recently diagnosed
young women (Heisterberg et al. 2014). 2.9 Occupational Allergic Contact
Dermatitis to Fragrances
2.7 Products Causing Contact It may be expected that fragrances will cause
Allergy to and Allergic Contact dermatological problems for workers in the cos-
Dermatitis from Fragrances metics industry (cosmetic chemists, workers han-
dling the raw materials and the final products,
Around 80% of the positive patch test reactions to salespeople), beauticians, hairdressers and aroma-
FM I and FM II are clinically relevant (Bennike therapists (see Sect. 11). In a German study, mas-
et al. 2017a). Perfumes and deodorants are the sage therapists and physiotherapists had the
590 A. C. de Groot
Table 6 Fragrances reported as having caused contact Table 6 (continued)

allergy (De Groot and Frosch 1997; De Groot 2000,
Dimethylbenzyl carbinyl acetate (DMBCA)f
2012; Uter et al. 2013a)a
Dimethyl citraconate
Abietic acidd 3,7-Dimethyl-7-methoxyoctan-2-ol (Osyrol ®)g
Acetylcedrene (Vertofix®)f Dimethyltetrahydrobenzaldehyde (isomer mixture)g
5-Acetyl-1,1,2,3,3,6-hexamethylindan (Phantolide ®) Ebanol (3-methyl-5-(2,2,3-trimethyl-
6-Acetyl-1,1,2,4,4,7-hexamethyltetralin (Fixolide ®) 3-cyclopenten-1-yl)-4-penten-2-ol)f
Alantolactonec,d Ethyl anisate
Ambrettolide g Ethylene dodecanedioateg
Amyl cinnnamal (α-amylcinnamic aldehyde)d,e,f Ethylhexyl salicylate
Amyl cinnamate Ethylvanilling
Amylcinnamyl alcohole,f Eucalyptol (1,8-cineole, cajeputol)
Amyl salicylatef Eugenolc,d,e,f
Anetholef Evernia furfuracea extract (treemoss absolute)e
Anise alcohold,e,f Evernia prunastri extract (oakmoss absolute)c,d,e
Anisylidene acetone Evernic acid (in oakmoss absolute)c
Aromadendrene (in tea tree oil) Farnesole,f
Ascaridole (in tea tree oil) Fumarprotocetraric acid (in oakmoss absolute)
Atranorin (in oakmoss absolute)c Galbanum resin (Ferula galbaniflua gum)
Benzaldehyded,f Geranial
Benzyl acetate Geraniolb,d,e,f
Benzyl alcoholb,d,e,f Heliotropine (piperonal)g
Benzyl benzoated,e,f Hexadecanolactone (hexadecanolide)f
Benzyl cinnamatee,f Ω-6-Hexadecenlactone
Benzylidene acetone Hexamethylindanopyran (Galaxolide ®)f
Benzyl salicylateb,e,f cis-3-Hexenyl salicylate
Butylphenyl methylpropional (Lilial ®)e,f Hexyl cinnamal (α-Hexylcinnamic aldehyde)e,f
Camphorf Hexyl salicylate
Carvacrol (isothymol)g Hydroabietyl alcohol (Abitol ®, dihydroabietyl alcohol)
Carvoned,f Hydroxycitronellalb,c,d,e,f
β-Caryophyllenef Hydroxycitronellolg
Cedrol methyl ether (cedramber) Hydroxyisohexyl 3-cyclohexene carboxaldehyde
Cinnamal (cinnamic aldehyde, cinnamaldehyde)c,d,e,f (Lyral ®)e,f
Cinnamyl alcohol (cinnamic alcohol)b,d,e,f Ionone (irisone)
Cinnamyl benzoate Isoamyl salicylateg
Cinnamyl cinnamated Isobornyl cyclohexanol (synthetic sandalwood)b
Citrale,f Isoeugenole,f
Citronellal trans-Isoeugenol
Citronellole,f Isoeugenyl acetate
Coumarinc,d,e,f Isoeugenyl benzoate
Cuminaldehyde g Isoeugenyl benzyl ether (benzyl isoeugenol)
Cyclohexyl acetateg Isoeugenyl methyl ether (methyl isoeugenol)
Cyclopentadecanone g Isoeugenyl phenylacetate
Damascenonef Isolongifolene ketoneg
Damasconef α-Isomethyl ionone (γ-methylionone)d,e,f
Dehydroisoeugenol Isopulegol
Diethyl maleate Ledene (viridoflorene) in tea tree oil
Diffractaic acid (in oakmoss absolute) Ligustral ((methyl-(2,4(3,5)-dimethyl-3-cyclohexen-1-yl)-
Dihydrocoumarin methylene anthranilate)
Dihydro pentamethylindanone (Cashmeran ®) Limonene d-, dl- (dipentene)e,f
(continued) (continued)
Table 6 (continued) Table 6 (continued)

Linalool (oxidized)e,f Terpinen-4-ol (in tea tree oil)
Linalyl acetate (oxidized)f α-Terpineolf
Menthold,f Terpinolene (in tea tree oil)f
o-Methoxycinnamic aldehyde Tetramethyl acetyloctahydronaphthalenes
Methoxycitronellalb,g (1-(1,2,3,4,5,6,7,8-Octahydro-2,3,8,8-tetramethyl-2-
Methyl p-anisateg naphthalenyl)ethanone, Iso-E Super ®)f
Methyl anthranilatec Thymol
α-Methyl-1,3-benzodioxole-5-propanal (Helional ®) 1,2,4-Trihydroxymenthane (in tea tree oil)
Methyl cinnnamateg Trimethylbenzenepropanol (Majantol ®)f
6-Methylcoumarinf 2,4,6-Trimethyl-4-phenyl-1,3-dioxane (Floropal ®)
Methyldihydrojasmonate (Hedione ®)g Usnic acid (in oakmoss absolute)
Methyleugenol Vanillind,f
Methylionanthemeg Verdyl acetate (tricyclodecen-4-yl 8-acetate, Cyclacet ®)
a
6-methyl-α-ionone (α-irone)g For additional references see De Groot and Frosch 1997,
Methyl octine carbonateg De Groot 2000, 2012
b
Has caused pigmented cosmetic/contact dermatitis
Methyl 2-octynoate (methyl heptine carbonate)e,f c
Has caused phototoxicity/photoallergy
Methyl salicylated,f d
Has caused immediate contact reactions
Musk ambretteb,c e
Presence mandatory labelled in the EU on cosmetics and
Musk ketone detergent products, if present at >10 parts per million
Musk moskene (moskene)c (ppm) (0.001%) in leave-on products and >100 ppm
(0.01%) in rinse-off products
Musk tibetene f
Established contact allergen in humans (Uter et al. 2013a)
Musk xylenec g
Fragrance substance with positive human data, but not
Myrcene (in tea tree oil)g sufficient for categorization as ‘established contact allergen
Neral in humans’ (Uter et al. 2013a)
Nerol (cis-3,7-dimethyl-2,6-octadien-1-ol)g
Nerolidolg
Nopyl acetateg highest occupational risk of fragrance contact
α-Phellandrene (in tea tree oil) allergy (Uter et al. 2001). Housewives, health
Phenethyl alcohol (phenylethyl alcohol)g personnel and cleaning personnel may also be
Phenylacetaldehyde (hyacynthin)g
endangered by frequent contact with soap,
3-Phenyl-1-propanolg
cleansers, dishwashing liquids and other
Phenyl salicylate
fragranced products. In spite of this, surprisingly
Physodic/physodalic acid (in oakmoss absolute)
little information on occupational allergic contact
α-Pinenef
β-Pinenef
dermatitis from fragrances can be found in litera-
Propylidene phthalidef ture. This may be because in the majority of
Rhodinol (mixture of 1-citronellol and geraniol)g people at risk, a definite relationship between
Sabinene (in tea tree oil) dermatitis and fragrances is hard to prove. In
Salicylaldehydef many occupations (hairdressers, beauticians,
Sandalore (5-(-2,2,3-trimethyl-3-cyclopentenyl)-3- housewives, health personnel, cleaning person-
methylpentan-2-ol) nel), irritant factors may also be relevant in the
Sandela (isobornyl cyclohexanol +3-trans-isocamphyl aetiology of dermatitis and sometimes other aller-
cyclohexanol)
gens are considered of paramount importance. In
Santalolb,f
addition, non-occupational exposure to fragrances
Sclareolf
occurs in virtually everybody. Although there
Stictic acid (in oakmoss absolute)c
should be individual cases of allergic contact der-
Styryl acetate (in publication ‘styrol acetate’, unknown
compound) matitis from fragrances in hairdressers, frequen-
α-Terpinene (in tea tree oil) cies of positive patch tests are usually no higher
(continued) than in the general patch test population.
592 A. C. de Groot
In an early study, all workers in a factory and an insecticide (Freeman 1990), oakmoss
became sensitised to cinnamal (Bonnevie 1948). absolute in permanent waving solution in a hair-
In Germany, 26 female workers in a perfume dresser (Kanerva et al. 1999), d-limonene in a
factory were investigated of who six had derma- hand cleanser in a mechanic, and cinnamal in a
titis of the hands, forearms and the face. All man making air freshener with perfumes
26 were tested with four perfumes from the fac- (Nethercott et al. 1983).
tory and 30 of their ingredients, both individual An Uber taxidriver developed airborne allergic
fragrance compounds and essential oils. The six contact dermatitis from fragrance released from a
patients with eczema had many positive reactions. diffuser (Perper et al. 2017). Occupational limo-
Twelve others were also sensitized to fragrances, nene allergy was observed in 14 workers who
but never developed allergic contact dermatitis used limonene-containing machine-cleaning
from working in the factory. The high prevalence detergents and hand cleansers, surface cleaners
of fragrance allergy (18/26, 69%) in this popula- or dishwashing liquids. In three cases, the occu-
tion was the result of poor work hygiene and pational limonene allergy resulted from work-
permanent direct and airborne skin contact. The related use of limonene-containing leave-on cos-
degree of automation was very low, even the metic products (Pesonen et al. 2014). Over a
bottle-filling machines had to be operated by period of 2 years, five beauticians working in the
hand (Schubert 2006). same high-end luxury health spa in the United
Fifteen out of 35 coalminers had positive patch Kingdom developed occupational allergic contact
test reactions to one or more fragrances. The high dermatitis of the hands from citral in a range of
frequency was attributed to the use of a highly essential oils and spa products they used on their
perfumed body lotion provided at the pit-head clients (De Mozzi and Johnston 2014).
bath, and to the facilitation of contact sensitisation On the basis of these data, it is concluded that
due to the frequent occurrence of irritant dermati- fragrances may play a role in some cases of occu-
tis from working in the coalmines (Goodfield and pational contact dermatitis, but in no single profes-
Saihan 1988). sion are they a major cause of occupational allergic
There have been single case reports of occupa- contact dermatitis, and rarely are they the sole
tional allergic contact dermatitis from oakmoss aetiological factor. However, fragrances may play
absolute in aftershave lotion in a geriatric nurse an important role in aggravating hand eczema of
(Dahlquist and Fregert 1981), pure methyl heptine other origin (atopic hand eczema, irritant dermati-
carbonate (methyl 2-octynoate) in a laboratory tis, allergic contact dermatitis) by contact with hand
technician (English and Rycroft 1988), oakmoss cleansers, barrier creams, moisturising prepara-
absolute in a coolant oil in an engineer (Owen tions, etc. In addition, flavours and spices may be
et al. 2000), from pure phenylacetaldehyde in a involved in occupational contact dermatitis in
perfume factory worker (Sanchez-Politta et al. bakers, cooks, caterers, and others working in the
2007), from cinnamal in odour-masking powder food industry (Kanerva et al. 1996). Only limonene
in a car engineer (Decapite and Anderson 2004), (Pesonen et al. 2014) and citral (De Mozzi and
from eugenol in restorative material in a dental Johnston 2014) have caused a considerable number
nurse (Kanerva et al. 1998), from d,l-limonene of occupational sensitizations.
(dipentene) in a solvent in a laboratory technician
(Wakelin et al. 1998), dipentene and pine oil in
waxpolish in a car mechanic (Martins et al. 1995), 3 Essential Oils
dipentene in honing oil in three honing machinists
(Rycroft 1980), oxidised d-limonene in fruits, fla- 3.1 Definition and Applications
vours, vegetables and cleaning products (Karlberg
and Dooms-Goossens 1997), d-limonene in hand An essential oil is defined by the International
cleanser in a painter/decorator (Topham and Organization for Standardization (ISO) as a ‘prod-
Wakelin 2003), fragrances in room-fresheners uct obtained from a natural raw material of plant
Table 7 Examples of essential oil applications (De Groot generally termed terpenoids. The oxidation prod-
and Schmidt 2016c) ucts are the most important, creating subgroups
Flavor industry: flavors for the food industry like alcohols, aldehydes, phenols, ethers and
Food industry: soft drinks, foods, alcoholic beverages, ketones. The (approximate) number of chemicals
spices, herbs, tea, food preservation identified by chemical analysis in specific essen-
Fragrance industry: perfumes, fragrances for other
tial oils varies considerably, but usually ranges
products
Cosmetics industry
from 100 to 250. However, some oils have
Household products: detergents, softeners, room scents, been found to contain >400 components: rose-
candles, incense mary oil (n = 505), geranium oil (n = 500),
Tobacco industry: cigarettes lavender oil (n = 450), vetiver oil (n = 445),
Medicinal use: folk medicine, traditional medicine, rose oil (n = 440), sweet basil oil (n = 435) and
phytotherapy, balneotherapy, aromatherapy laurel leaf oil (n = 425). In a literature review of
Pharmaceutical industry: masking agent the chemical composition of essential oils,
Animal food approximately 4350 chemicals were found in the
91 essential oils and two jasmine absolutes
selected because of having caused contact allergy
origin, by steam distillation (which includes (De Groot and Schmidt 2016a).
hydrodistillation), by mechanical processes from Many chemicals are present in a large number
the pericarp (peel) of citrus fruits, or by dry distil- of different oils: 90 have been identified in over
lation, after separation of the aqueous phase - if 40% of the essential oils, 23 of these are present in
any - by physical processes’. Steam-distillation is >80% of all oils, and 6 may be components of
the usual production method for most commercial >90% of all oils: β-caryophyllene (98%), limo-
oils. Citrus oils (bergamot, grapefruit, lemon, nene (97%), α-pinene (94%), α-terpineol (94%),
mandarin, tangerine, sweet orange, bitter orange) δ-cadinene (91%), and α-humulene (91%).
are so-called cold-pressed essential oils: they In many essential oils, there are two to five
are obtained by mechanical processes from the components which together constitute over
peels of the fruit of a citrus (De Groot and 50–60% of the oil. In some oils, however, there is
Schmidt 2016c). one dominant ingredient. In Table 8, the quantita-
Essential oils have a wide field of app- tively most important components in the essential
lications; examples are shown in Table 7. The oils, for which patch test materials are commer-
largest buyers of essential oils are the flavor cially available, are tabulated. In case of oils with
and fragrance industries. Essential oils are also various chemotypes, the major constituents from
increasingly employed to promote health any chemotype are mentioned. Chemicals which
and combat diseases, e.g., in forms of tradit- are important constituents of >10 oils of the
ional and folk medicine, phytotherapy and 79 which have caused contact allergy are limonene
aromatherapy. (n = 38), linalool (n = 33), α-pinene (n = 33),
β-pinene (n = 20), β-caryophyllene (n = 19),
myrcene (n = 17), 1,8-cineole (n = 17), sabinene
3.2 Chemistry of Essential Oils (n = 16), geraniol (n = 12), α-terpineol (n = 12),
p-cymene (n = 11), linalyl acetate (n = 11) and
Essential oils are multi-component mixtures. The γ-terpinene (n = 11).
largest group of chemicals found in essential oils The composition of essential oils can vary con-
consists of terpenes, most importantly the mono- siderably from country to country, from producer
terpenes and the sesquiterpenes. Volatility and the to producer, and even from year to year for the
typical odor of essential oils are created through same producer and crop. Factors that may influ-
both groups. Chemical modification of terpenes ence the oils’ chemical composition include plant
and sesquiterpenes, e.g., by rearranging carbon parameters (e.g., species, cultivated or wild plants),
skeletons or by oxidation, produces compounds environmental parameters (e.g., origin of plant,
594 A. C. de Groot
Table 8 The quantitatively most important components in essential oils for which commercial patch test preparations are
available (Adapted from De Groot and Schmidt 2016d)
Essential oil Most important constituents
Bergamot oil Limonene, linalyl acetate, linalool, γ-terpinene, β-pinene, β-bisabolene, geranial
Cananga oil β-Caryophyllene, α-humulene, germacrene D, δ-cadinene, (E,E)-α-farnesene
Cedarwood oil, Atlasa,b β-Himachalene, himachalol, (E)-α-atlantone, α-himachalene, γ-himachalene
Cedarwood oil, Chinab Thujopsadiene, α-cedrene, β-funebrene, cedrol, β-cedrene, cuparene, widdrol
Cinnamon bark oil, Sri (E)-Cinnamal, eugenol, β-caryophyllene, β-phellandrene, linalool
Lankac
Cinnamon leaf oil, Sri Eugenol, benzyl benzoate, eugenyl acetate, (E)-cinnamyl acetate, (E)-cinnamal, linalool
Lankaa,c
Clove oil Eugenol, β-caryophyllene, eugenyl acetate, α-humulene, caryophyllene oxide
Eucalyptus citriodora Citronellal, citronellyl acetate, isopulegol, citronellol, neoisopulegol
oila,d
Eucalyptus globulus 1,8-Cineole, α-pinene, limonene, aromadendrene, p-cymene, globulol
oild
Geranium oila Citronellol, geraniol, citronellyl formate, linalool, isomenthone, guaia-6,9-diene
Laurel leaf oila 1,8-Cineole,linalool, α-terpinyl acetate, methyl eugenol, α-pinene
Lavender oila Linalyl acetate, linalool, (Z)-β-ocimene, lavandulyl acetate, terpinen-4-ol
Lemon oil Limonene, β-pinene, γ-terpinene, α-pinene, sabinene, geranial, neral
Lemongrass oil, East Geranial, neral, geraniol, geranyl acetate, limonene, β-caryophyllene
Indiana,e
Lemongrass oil, West Geranial, neral, geraniol, β-caryophyllene, nerol, myrcene, limonene, linalool
Indiana,e
Neroli oil Linalool, linalyl acetate, limonene, β-pinene, (E)-β-ocimene, α-terpineol
Orange oil, bitterf Limonene, myrcene, β-pinene, linalyl acetate, α-pinene, linalool
Orange oil, sweetf Limonene, myrcene, α-pinene, sabinene, linalool, n-decanal, n-octanal, geranial
Patchouli oil Patchouli alcohol, α-bulnesene, α-guaiene, β-caryophyllene, β-patchoulene
Peppermint oila Menthol, menthone, isomenthone, menthyl acetate, menthofuran, neomenthol
Rosemary oila 1,8-Cineole, α-pinene, camphor, camphene, borneol, β-pinene, limonene
Rose oil Citronellol, geraniol, nonadecane, nerol, ethanol, heneicosane, n-heptadecane
Sandalwood oil (Z )-α-Santalol, (Z )-β-santalol, (Z )-trans-α-bergamotol, epi-β-santalol, β-santalene,
(Z )-lanceol, (E,E)-farnesol, (Z )-nuciferol, α-santalene
Tea tree oila Terpinen-4-ol, γ-terpinene, 1,8-cineole, α-terpinene, α-terpineol, p-cymene
Turpentine oil α-Pinene, β-pinene, limonene, β-caryophyllene, camphene, p-cymene
Ylang-ylang oil Linalool, germacrene D, benzyl acetate, p-cresyl methyl ether, (E,E)-α-farnesene, geranyl
acetate, methyl benzoate, β-caryophyllene
a
Chemical composition depends on the chemotype
b
Unknown which type of cedarwood oil is used in commercial patch test materials
c
Unknown which type of cinnamon oil is used in commercial patch test materials
d
Unknown which type of eucalyptus oil is used in commercial patch test materials
e
Unknown which type of lemongrass oil is used in commercial patch test materials
f
Unknown which type of orange oil is used in commercial patch test materials
climate, soil conditions, fertilization), harvest and condition and storage time of essential oils, age of
post-harvest / pre-distillation parameters (e.g., sea- essential oil, aging by exposure to oxygen and
son of harvest, pretreatment of biomass, storage ultraviolet light, analytical parameters) (De Groot
conditions of source plant material), production and Schmidt 2016c). Full qualitative and quantita-
parameters (e.g., mode of production, distillation tive compositional data of all essential oils that
parameters, commercial oil or laboratory- have caused contact allergy/allergic contact derma-
produced), and other parameters (e.g., storage titis can be found in De Groot and Schmidt 2016a.
3.3 Contact Allergy to Essential Oils observed. These are, in order of descending maxi-
mum values, laurel oil 6.9% (old data, the test
Nearly 80 essential oils have caused contact material probably was not an essential oil but a
allergy (as demonstrated by positive patch test vegetable oil), turpentine oil 4.2%, orange oil
reactions) or allergic contact dermatitis. These 3.2%, oxidized lavender oil 2.8% (Hagvall and
are listed alphabetically in Table 9, showing their Bråred-Christensson 2016), tea tree oil 2.7%,
common names, botanical sources, INCI names, ylang-ylang oil 2.6%, citronella oil 2.5%, sandal-
results of routine testing and references for occu- wood oil 2.4%, clove oil 2.1% and costus root oil
pational allergic contact dermatitis (De Groot and 2.1% (historical allergen). Thus, it appears that
Schmidt 2016a, b). About half of these essential contact allergy to essential oils as a group is not
oils have been tested in groups of consecutive very frequent. Nevertheless, in the general German
patients suspected of contact dermatitis. In the adult population, 2.5% of 1141 test subjects reacted
USA, four essential oils (tea tree oil, lavender to oil of turpentine, 4.3% of the women and 0.7% of
oil, peppermint oil, ylang-ylang oil) are currently the men (Schäfer et al. 2001). In addition, the
present in the screening series of the North Amer- prevalence of contact allergy to essential oils may
ican Contact Dermatitis Group (NACDG). Test- well increase when oxidized samples of essential
ing in groups of selected patients has been oils are used for patch testing, as has been shown
performed with 51 essential oils, usually in for tea tree oil and lavender oil (Hagvall and
patients suspected of fragrance allergy, of cos- Bråred-Christensson 2016).
metic dermatitis, or patients who previously had Currently, the highest observed prevalences
a positive reaction to the fragrance mix I or to one of positive patch test reactions – depending
of the other indicators of fragrance allergy such as on the country and which oils are patch tested –
Myroxylon pereirae resin (balsam of Peru). Case are observed with lavender oil, tea tree oil,
reports of allergic contact dermatitis were found ylang-ylang oil and sandalwood oil. The latter
for 66 oils. Contact allergy to 13 oils was men- observation is surprizing, because the price of
tioned in one publication only; more extensive sandalwood oil is so high that it is virtually only
literature is available for oils of cananga, clove, used in fine fragrances.
eucalyptus, geranium, lavender, lemon, lemon-
grass, peppermint, rose, sandalwood, spearmint,
turpentine, tea tree and ylang-ylang (De Groot and 3.5 Clinical Relevance of Positive
Schmidt 2016a). For reviews of peppermint, lav- Patch Test Reactions
ender and lemongrass oil see De Groot and to Essential Oils
Schmidt (2016g); tea tree oil was fully reviewed
by De Groot and Schmidt (2016f) and a review of Determining the clinical relevance of positive
sandalwood and ylang-ylang oil can be found in patch test reactions to essential oils appears to be
De Groot and Schmidt (2017). Older literature on difficult. In >80% of all studies, in which oils
allergy to essential oils has been reviewed by De were tested in consecutive dermatitis patients, no
Groot and Frosch (1997). information on relevance was provided. Percent-
ages for ‘definite’ + ‘probable’ relevance in vari-
ous NACDG (North American Contact
3.4 Frequency of Contact Allergy Dermatitis Group) studies were as follows: laven-
to Essentials Oils der oil 30–69%, tea tree oil 20–56%, peppermint
oil 36–39%, and ylang-ylang oil 0–27%. Rates for
Of the 40 essential oils that have been tested in ‘definite’ relevance were usually <10–15% and
consecutive patients (number of studies per oil sometimes zero. It may thus be concluded that
ranging from 1 to 19), 11 have had maximum reliable data on the relevance of positive patch
rates of positive patch test reactions between 1% test reactions to essential oils as reported in liter-
and 1.5% and in nine, rates of over 2% have been ature are largely lacking or inadequate.
596 A. C. de Groot
Table 9 List of essential oils which have caused contact allergy with their botanical sources, INCI names, results of
routine testing and references for occupational allergic contact dermatitis (Adapted from De Groot and Schmidt 2016a, b)
Routine Occupational
Common testing ACD refs. (below
name Botanical source INCI name (EU) (% pos.) table)
Angelica fruit Angelica archangelica L. Angelica archangelica seed 1 1
oil oil
Angelica root Angelica archangelica L. Angelica archangelica root
oil oil
Aniseed oil Pimpinella anisum L. Pimpinella anisum fruit oil 2
Basil oil, sweet Ocimum basilicum L. Ocimum basilicum herb oil 1,3
Bay oil Pimenta racemosa (Mill.) Pimenta acris leaf oil
J.W. Moore
Bergamot oil Citrus bergamia (Risso et Poit.) Citrus aurantium bergamia 0.2–1.5 1,4,5
peel oil
Black cumin Nigella sativa L. Nigella sativa seed extracta
oil
Black pepper Piper nigrum L. Piper nigrum fruit oil 1
oil
Cajeput oil Melaleuca cajuputi Powell Melaleuca leucadendron 1,3
cajaputi oil
Calamus oil Acorus calamus L. Acorus calamus root oil
Cananga oil Cananga odorata (Lam.) Hook Cananga odorata 0.5–1.2 6,7
f. et Thomson, forma macrophylla macrophylla flower
extractb
Cardamom oil Elettaria cardamomum (L.) Maton Elettaria cardamomum 8
seed oil
Carrot seed oil Daucus carota L. Daucus carota fruit oilb 9
Cassia bark/ Cinnamomum cassia (Nees & Cinnamomum cassia (leaf) 0.7–1
leaf oil T. Nees) J.Presl oil
Cedarwood Cedrus atlantica (Endl.) Cedrus atlantica wood oilb 0.6–1.5c 1
oil, Atlas G. Manetti ex Carrière
Cedarwood Cupressus funebris (Endl.) Cupressus funebris wood 0.6–1.5c
oil, China oil
Cedarwood oil Cedrus deodara (Roxb. ex D.Don) Cedrus deodara wood oil 1.5
Himalaya G.Don
Cedarwood Juniperus virginiana L. Juniperus virginiana wood
oil, Virginia oil
Chamomile Chamomilla recutita (L.) Chamomilla recutita flower 0.5 1,3
oil, German Rauschert oil
Chamomile Chamaemelum nobile (L.) Anthemis nobilis flower oil
oil, Roman
Cinnamon oil Cinnamomum zeylanicum Blume Cinnamomum zeylanicum 1.1
bark/ leaf oil
Citronella oil, Cymbopogon winterianus Jowitt. Cymbopogon winterianus 2.5d 1
Java herb oilb
Citronella oil, Cymbopogon nardus (L.) Rendle Cymbopogon nardus oil
Sri Lanka
Clary sage oil Salvia sclarea L. Salvia sclarea oil 0.5 1,7,9,11
Clove oil Syzygium aromaticum (L.) Merr. & Eugenia caryophyllus 0.3–2.1 4,10
L.M. Perry bud/leaf/ stem oil
Coriander fruit Coriandrum sativum L. Coriandrum sativum fruit 1 1
oil oil
Costus root oil Saussurea costus (Falc.) Lipsch. Costus root oilb 2.1
(continued)
Table 9 (continued)
Cypress oil Cupressus sempervirens L. Cupressus sempervirens 1,3,4
(leaf) oil
Dwarf pine oil Pinus mugo Turra Pinus mugo leaf oil 0.6–0.7
Elemi oil Canarium luzonicum (Blume) Canarium luzonicum gum 1
A. Gray oilb
Eucalyptus Eucalyptus citriodora Hook. Eucalyptus citriodora oil 0.6–1.5e 1e,3e
citriodora oil
Eucalyptus Eucalyptus globulus Labill. Eucalyptus globulus leaf/ 0.6–1.5e 1e,3e, 12
globulus oil twig oil
Galbanum Ferulagummosa Boiss. Ferula galbaniflua resin oil 1
resin oil
Geranium oil Pelargonium x spp. Pelargonium graveolens oil 1.2 1,3,6
Ginger oil Zingiber officinale Roscoe. Zingiber officinale root oil 1
Grapefruit oil Citrus paradisi Macfad. Citrus paradisi peel oil 1
Guaiacwood Bulnesia sarmientoi Lorentz ex Bulnesia sarmientoi wood
oil Griseb. oil
Hinoki oil Chamaecyparis obtusa (Siebold & Chamaecyparis obtusa oil 29
Zucc.) Endl.
Hyssop oil Hyssopus officinalis L. ssp. Hyssopus officinalis leaf 1
officinalis oil
Juniper berry Juniperus communis L. Juniperus communis fruit 0.5 1
oil oil
Laurel leaf oil Laurus nobilis L. Laurus nobilis leaf oil 3.1–6.9f
Lavandin oil Lavandula angustifolia Mill. x Lavandula hybrida (herb) 0.5 1
Lavandula latifolia Medik. oil
Lavender oil Lavandula angustifolia Mill. Lavandula angustifolia oil 0.2–1.2 1,2,4,6,9,13,14,15
Lemon oil Citrus limon (L.) Burm. f. Citrus limon peel oil 0.5–0.9 1,3,16,17
Lemongrass Cymbopogon flexuosus (Nees ex Cymbopogon flexuosus oil 1.3–1.6 1,3,7,9,18g
oil, East Indian Steudel) J.F. Watson
Lemongrass Cymbopogon citratus (DC) Stapf. Cymbopogon citratus leaf 0.6–1.3h 1,3,7,9,18g
oil, West oil
Indian
Litsea cubeba Litsea cubeba (Lour) Pers. Litsea cubeba fruit oil 1.5
oil
Lovage oil Levisticum officinale W.D.J. Koch Levisticum officinale oil 19
Mandarin oil Citrus reticulata Blanco Citrus nobilis peel oil 1
Marjoram oil Origanum majorana L. Origanum majorana flower 1,3
(sweet) oil
Melissa oil Melissa officinalis L. Melissa officinalis leaf oil 1,9
(lemon balm
oil)
Myrrh oil Commiphora myrrha (Nees) Engl. Commiphora myrrha gum 1,3
and related Commiphora species oilb
Neem oil Azadirachta indica A. Juss. Azadirachta indica seed
extracta
Neroli oil Citrus aurantium L. Citrus aurantium amara 0.3 4,9,14,16
flower oil
Niaouli oil Melaleuca quinquenervia (Cav.) Melaleuca quinquenervia 1
S.T. Blake oilb
Nutmeg oil Myristica fragrans Houtt. Myristica fragrans kernel oil
(continued)
598 A. C. de Groot
Table 9 (continued)
Olibanum Boswellia sacra Flueck. Boswellia carterii oil 1,3
(frankincense)
oil
Orange oil, Citrus aurantium L. Citrus aurantium 1.5 3,4,16i
bitter amara (bitter orange)
peel oil
Orange oil, Citrus sinensis (L.) Osbeck Citrus aurantium 0.5 1
sweet dulcis (sweet orange)
peel oil
Palmarosa oil Cymbopogon martini (Roxb.) Cymbopogon martini
Will. Watson motia herb oilb
Patchouli oil Pogostemon cablin (Blanco) Pogostemon cablin leaf oil 0.6–0.9 7,16
Benth.
Peppermint oil Mentha x piperita L. Mentha piperita oil 0.3–1.8 1,3,6,12
Petitgrain Citrus aurantium L. Citrus aurantium amara 0.5 1,16
bigarade oil leaf/twig oil
Pine needle oil Pinus sylvestris L. Pinus sylvestris leaf oil 0.4–2.0 1,21
(Scots pine oil)
Ravensara oil Ravensara aromatica Sonn. Ravensara aromatica leaf 1,9
oil
Rosemary oil Rosmarinus officinalis L. Rosmarinus officinalis leaf 1,4
oil
Rose oil Rosa x damascena Mill. Rosa damascena flower oil 1.6 6,7
Rosewood oil Aniba rosaeodora Ducke, Aniba Aniba rosaeodora 3
parviflora (Meisn.) Mez. (rosewood) wood oil
Sage oil, Salvia officinalis L. Salvia officinalis oil 3j
Dalmatian
Sage oil, Salvia lavandulifolia Vahl Salvia lavandulaefolia leaf 3j
Spanish oil
Sandalwood Santalum album L.; Santalum Santalum album oil; 0.1–2.4 16
oil spicata (R. Br.) A. DC; Santalum Santalum spicata wood
austrocaledonicum Vieill oilb; Santalum
austrocaledonicum wood
oil
Silver fir oil Abies alba Mill. Abies alba leaf oil 1
Spearmint oil Mentha spicata L. Mentha spicata herb oilb 0.8–1.6 1,22
Spike lavender Lavandula latifolia Medik. Lavandula latifolia herb 0.5
oil oilb
Star anise oil Illicium verum Hook. f. Illicium verum fruit/seed >33k
oil
Tangerine oil Citrus tangerina Hort. ex Tan. Citrus tangerina peel oil
Tea tree oil Melaleuca alternifolia (Maiden et Melaleuca alternifolia leaf 0.1–2.5 23
Betche) Cheel; Melaleuca oil
linariifolia Smith; Melaleuca
dissitiflora F. Muell.
Thuja oil Thuja occidentalis L. Thuja occidentalis leaf oil
Thyme oil Thymus vulgaris L.; Thymus zygis Thymus vulgaris flower/ 1
L. (Spanish) leaf oil; Thymus zygis
flower oil
(continued)
Table 9 (continued)
Turmeric Curcuma longa root oil Curcuma longa L.
essential oilm
Turpentine oil Pinus pinaster Aiton (Iberian Turpentine, steam distilled 1.2–4.2l 2,24,25,26l
type); Pinus massoniana Lamb. (Pinus spp.)
(Chinese type)
Valerian oil Valeriana officinalis L. Valeriana officinalis root 1
oil
Vetiver oil Chrysopogon zizanioides (L.) Vetiveria zizanoides root 0.5 1,3
Roberty oil
Ylang-ylang Cananga odorata (Lam.) Hook Cananga odorata flower oil 0.7–2.6 1,6,7,13,14,
oil f. et Thomson, forma genuina 20, 27,28,29
Zdravetz oil Geranium macrorrhizum L. Geranium macrorrhizum 0.5
herb oil
ACD allergic contact dermatitis
1 Dharmagunawardena et al. 2002; 2 Vente and Fuchs 1997; 3 Selvaag et al. 1995; 4 Trattner et al. 2008; 5 Zacher and
Ippen 1984; 6 Boonchai et al. 2007; 7 Cockayne and Gawkrodger 1997; 8 Mobacken and Fregert 1975; 9 Newsham et al.
2011; 10 Sánchez-Pérez and García-Díez 1999; 11 Gutman and Somov 1968; 12 Peltonen et al. 1985; 13 Bleasel et al.
2002; 14 Keane et al. 2000; 15 Brandão 1986; 16 Schubert 2006; 17 Hausen and Kulenkamp 1990; 18 Mendelsohn 1944;
19 Calnan 1969; 20 Romaguera and Vilaplana 2000; 21 Martins et al. 1995; 22 Morris 1954; 23 De Groot and Schmidt
2016f; 24 Laube and Tan 2004; 25 Dooms-Goossens et al. 1977; 26 Conde-Salazar et al. 1982; 27 Rudzki et al. 1993;
28 Kanerva et al. 1995; 29 Kim et al. 2015 (non-occupational)
a
It may be doubtful whether the INCI name found refers to an essential oil
b
Perfuming name, not an INCI name proper
c
Tested with a mixture of cedarwood oil, Morocco (Atlas) and Chinese cedarwood oil
d
Tested with ‘citronella oil’ (botanical source unspecified)
e
Tested with ‘eucalyptus oil’ (botanical source unspecified)
f
Data from over 50 years ago; the test substances was probably the vegetable oil, not the essential oil
g
All cases of occupational contact allergy were to ‘lemongrass oil’ (botanical source unspecified)
h
Routine testing with ‘lemongrass oil’ (botanical source unspecified)
i
All data relate to ‘orange oil’ (not specified for bitter or sweet orange oil)
j
Tested with ‘sage oil’ (botanical source unspecified)
k
Routine testing with star anise oil 1% and 2% pet; these concentrations were irritant and resulted in active sensitization
l
Tested with ‘turpentine oil’ (botanical source unspecified)
m
Has probably caused erythema-multiforme-like allergic contact dermatitis, but patch tests were not performed (Huber
et al. 2016)
n
False-positive reactions due to excited skin syndrome cannot be excluded
Insufficient knowledge of the chemical com- contact allergy to limonene has resulted in
position of essential oils and difficulties in non-relevant positive patch tests to tea tree oil
ascertaining whether oils or their ingredients (Pesonen et al. 2014).
are present in materials with which the patients In cases where relevance was established, the
have contact, may partly be responsible. In addi- most important categories of products responsible
tion, a previously acquired contact allergy to a for allergic contact dermatitis were pure essential
fragrance chemical per se may result in a positive oils (notably tea tree oil but also others (Grey et al.
patch test to an essential oil containing it. Thus, 2016)), massage products (mostly occupational),
previous sensitization to geraniol from any cosmetic products (Brás et al. 2015), perfumes
source may result in non-relevant positive patch (Vilaplana and Romaguera 2002), toothpastes
test reactions to rose oil and geranium oil, both and other oral preparations, and pharmaceutical
of which contain high concentrations of products (Storan et al. 2016). Miscellaneous caus-
geraniol (Juarez et al. 2008). Previously acquired ative products were immersion oil, mud bath,
600 A. C. de Groot
aromatherapy lamps, aromatherapy diffuser essential oils is increasingly recognized

(Hagen et al. 2016) and wax polish (De Groot (Boonchai et al. 2007; Dharmagunawardena
and Schmidt 2016e). et al. 2002; Keane et al. 2000; Rademaker
1994; Sánchez-Pérez and García-Díez 1999;
Selvaag et al. 1995; Trattner et al. 2008). The
3.6 Clinical Picture of Allergic patients are usually women who present with
Contact Dermatitis from dermatitis of the hands and sometimes of the
Essential Oils forearms. In a number of them, dermatitis
spreads to other parts of the body and may
There are no descriptions of the clinical picture of become generalized. A 12-month prevalence of
allergic contact dermatitis from essential oils in hand dermatitis in massage therapists was found
larger groups of patients. As the products, in to be 15% by self-reported criteria and 22% by a
which the oils may be present, vary considerably, symptom-based method. Risk factors were hav-
as do the sites of application and the goals of ing a history of atopic dermatitis and having
applying the oils to the skin, the presentation of frequently used aromatherapy products in oils,
patients with allergic contact dermatitis from creams and lotions (Crawford et al. 2004). Aller-
essential oils may take various forms. In the case gic contact dermatitis from essential oils has also
of undiluted oils (notably tea tree oil) and phar- been documented in the cosmetics and fragrance
maceutical products, dermatitis will appear at the industries (Kanerva et al. 1995; Schubert 2006),
site of application and usually stays limited to the in bar workers, citrus fruit pickers, hairdressers
primary site, but spreading of dermatitis is not (lavender oil in shampoo (Brandão 1986)) and
infrequent and even generalisation occurs occa- beauticians (Crawford et al. 2004). Occupational
sionally. Contact allergy to essential oils in tooth- allergic contact dermatitis from oil of cinnamon
pastes, especially spearmint, peppermint and has been reported in bakers, candy makers,
cinnamon oils, may lead to symptoms of the oral cooks, grocers, confectioners and housewives
mucosa, the lips and the perioral skin including (Sánchez-Pérez and García-Díez 1999). All
perioral dermatitis, cheilitis, burning/sore mouth, reports of occupational allergic contact dermati-
stomatitis, swelling of the tongue, lips and gingi- tis from essential oils are indicated in the right
val mucosa and ulceration of the mouth column of Table 9.
(Magnusson and Wilkinson 1975). Rare cases of
pigmented contact dermatitis, airborne allergic
contact dermatitis, systemic contact dermatitis 3.8 The Allergens in Essential Oils
(Mertens et al. 2017) and erythema multiforme-
like reactions (Huber et al. 2016; Uzuncakmak With the exception of tea tree oil and turpentine
et al. 2015) from contact allergy to essential oils oil, large-scale patch testing with components of
have been reported (De Groot and Schmidt essential oils in allergic patients in order to deter-
2016e). mine the major sensitizers has not been
performed. Tea tree oil, stored in open bottles
or in a bottle opened for several times, suffers an
3.7 Occupational Allergic Contact aging process resulting in air- and photo-
Dermatitis oxidation leading to degradation products (per-
oxides, epoxides and endoperoxides), which are
Aromatherapists, when utilizing essential oils strong sensitizers. The most important sensi-
for massaging, often have unprotected bare tizers in tea tree oil appear to be terpinolene,
hands, which results in frequent skin contact ascaridole, α-terpinene and its oxidation
with the oils. Thus, occupational allergic contact products, 1,2,4-trihydroxymenthane, α-phellan-
dermatitis from essential oils in aromatherapists drene, d-limonene and myrcene (De Groot and
and others massaging with products containing Schmidt 2016a, f). In turpentine oil, the allergens
are δ3-carene hydroperoxides (in oils from Scan- to such oils have not yet been tested with oxidized
dinavia [probably hardly used anymore] and limonene, which is the allergenic form of limo-
Indonesia), α-pinene, oxidized limonene, nene (Karlberg et al. 2013).
β-pinene, α-terpineol, and rarely α-phellandrene
(Cachao et al. 1986).
For some other oils, the major allergens can 3.9 Patch Testing with Essential Oils
tentatively be identified on the basis of their gen-
eral composition and co-reactions to important Essential oils should be patch tested in any indi-
ingredients in patch testing as documented in vidual suspected of contact allergy to these oils on
literature, e.g., clove oil and eugenol, bay oil the basis of the patient’s history and the clinical
and eugenol, lemongrass oil and citral (= geranial picture. Suspicion is high in cases of hand derma-
+ neral), geranium oil and geraniol, rose oil titis in aromatherapists, masseurs et cetera, in
and geraniol, cinnamon oil and cinnamal, pepper- patients working in the fragrance industry, the
mint oil and menthol, spearmint oil and food industry and in individuals who have applied
carvone and, recently, lavender oil and linalool essential oils to their skin, e.g., for therapeutic
and linalyl acetate (all oxidized) (Hagvall and purposes (notably tea tree oil). In addition, in
Bråred-Christensson 2016). In citrus peel oils any patient with symptoms of the oral mucosa,
(bergamot, grapefruit, lemon, orange, mandarin, lips (cheilitis) and the perioral skin, contact
tangerine), limonene is by far the most important allergy to essential oils in toothpastes or other
constituent (70–98%), but has thus far not been oral preparations should be considered. Several
identified as main allergen in patients reacting to essential oils are available as commercial patch
citrus oils. The reason may be that patients allergic test substances (Table 10). For screening
Table 10 Essential oils commercially available for patch testing

Patch test allergen Suppliers
SPEurope Chemo SPCanada
Bergamot oil 2% pet.
Cananga oil 2% pet.
Cedarwood oil 10% pet. 10% pet.
Cinnamon oil 0.5% pet.
Clove oil 2% pet.
Eucalyptus oil 2% pet. 2% pet.
Geranium oil 2% pet.
Laurel oil 2% pet. 2% pet.
Lavender oil 2% pet.
Lemongrass oil 2% pet. 2% pet.
Lemon oil 2% pet. 2% pet.
Neroli oil 2% pet. 2% and 5% pet.
Orange oil 2% pet. 2% pet.
Patchouli oil 10% pet.
Peppermint oil 2% pet. 2% pet. 2% pet.
Rose oil 0.5% pet.
Rosemary oil 0.5% pet.
Sandalwood oil 10% pet. 2% pet. 10% pet.
Tea tree oil (oxidized) 5% pet. 5% pet.
Turpentine oil 10% pet. 10% pet.
Ylang-ylang oil 10% pet. 10% pet. 10% pet.
SPEurope: SmartPractice Europe, www.smartpracticeeurope.com; Chemo: Chemotechnique Diagnostics, www.
chemotechnique.se; SPCanada: Smartpractice Canada, www.smartpracticecanada.com
602 A. C. de Groot
purposes, a series of these commercial allergens is Audrain H, Kenward C, Lovell CR et al (2014) Allergy to
very useful. However, when patients have a his- oxidized limonene and linalool is frequent in the
UK. Br J Dermatol 171:292–297
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Colophony: Rosin in Unmodified and
Modified Form 41
Ann-Therese Karlberg and Lina Hagvall
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
3 Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
4 Chemical Composition of Unmodified Rosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
5 Chemical Modifications of Rosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
5.1 Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
5.2 Diels-Alder Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
5.3 Hydrogenated, Dehydrogenated, and Disproportionated Rosin . . . . . . . . . . . . . . . . . . 612
5.4 Formaldehyde-Modified Rosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
5.5 Resinates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
6 Usage and Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
7 Analysis of Content of Unmodified Rosin in Technical Products . . . . . . . . . . . . 614
8 Allergenic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
9 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
9.1 Screening and Patch Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
9.2 Exposure from Products in Close Contact with the Skin . . . . . . . . . . . . . . . . . . . . . . . . . 618
9.3 Occupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
10 Other Health Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Abstract
Colophony (rosin) is the non-volatile fraction of
A.-T. Karlberg (*) the oleoresins from coniferous trees, mainly
Dermatochemistry and Skin Allergy, Department of
Chemistry and Molecular Biology, University of pine trees. The composition varies depending
Gothenburg, Gothenburg, Sweden on the source but also on the way it is produced.
e-mail: karlberg@chem.gu.se There are three types of rosin based on the way
L. Hagvall of recovery: gum rosin, wood rosin, and tall oil
Department of Dermatology, Sahlgrenska Academy, rosin. Rosin is present in unmodified and mod-
University of Gothenburg, Gothenburg, Sweden ified form in many products with various usages
e-mail: lina.hagvall@gu.se

https://doi.org/10.1007/978-3-319-68617-2_41
608 A.-T. Karlberg and L. Hagvall
and is ubiquitous in our daily life. The main • Rosin is present in unmodified and modified
usages are printing ink, adhesives, and sealants, form in many products with various usages and
as well as paper size. Colophony (rosin) is a is ubiquitous in our daily life. Due to this,
common cause of contact allergy and allergic contact with rosin or rosin derivatives in
contact dermatitis (ACD) based on its wide- commercial products is difficult to avoid.
spread usage and the skin sensitizing capacity. • Main usages are printing ink, adhesives, and
The main allergenic components are oxi- sealants as well as paper size.
dized resin acids of the abietadiene-type • Rosin/colophony has a harmonized classification
which are formed on air exposure. 15- as a skin sensitizer in category 1. This means that
Hydroperoxyabietic acid was the first oxida- products containing rosin at a concentration of at
tion product identified as a contact allergen in least 0.1% should be labeled with the statement
gum rosin and is still considered to be the EUH208, “Contains rosin; colophony. May pro-
major sensitizer in colophony. Various aller- duce an allergic reaction,” and a safety data sheet
genic compounds are also created in chemical is required. Products containing at least 1% rosin
modification processes performed to obtain must be classified and labeled as H317: May
improved technical rosin products. One of cause an allergic skin reaction.
those is maleopimaric acid which is a strong • The allergenicity of modified rosins can be
contact allergen present in commonly used caused by new allergenic derivatives, specifi-
modified rosins. Studies on the prevalence of cally maleopimaric acid but also due to
ACD caused by modified rosins and the major unmodified rosin still present after modification.
allergens should be performed in dermatitis • More investigations with regard to the pres-
patients and in the population. ence of various modified rosins in different
Colophony (rosin) has a harmonised classifi- products are needed.
cation as a skin sensitizer in category 1. This • Studies on the prevalence of ACD in dermatitis
means that products containing rosin at a con- patients and in the population caused by mod-
centration of at least 0.1% should be labelled ified rosins should be performed.
with the statement EUH208 — “Contains rosin;
colophony. May produce an allergic reaction”
and a safety data sheet is required. Products 2 Introduction
containing at least 1% rosin must be classified
and labelled as “H317: May cause an allergic Colophony (rosin) obtained from pine trees has
skin reaction”. been used since ancient times due to its technical
(tackifying) and medicinal (antimicrobial) effects.
Keywords Also the skin-sensitizing effects of rosin are well
Allergic contact dermatitis · Colophonium · known since a long time, and it is still one of the
Colophony · Contact allergy · Diels-Alder most common causes of contact allergy in the
adducts · Esterified rosin · Gum rosin · Western society. As most natural products, rosin
Maleopimaric acid · Modified rosin · has a complex chemical composition. A majority
Oxidation products · Rosin · Rosin of rosin is modified in various ways to improve
derivatives · Rosin products · Skin the technical properties. However, the modifica-
sensitization · Tall oil rosin tions are only performed until desirable technical
properties are obtained. This means that in most
cases unmodified rosin is still present in the final
1 Core Messages product. New sensitizers are created in the modi-
fication processes; thus, technical products can
• Colophony (rosin) is a common cause of con- contain allergens from unmodified rosin together
tact allergy and allergic contact dermatitis with new allergens from modification. Contact
(ACD). allergy to these allergens is not detected in
41 Colophony: Rosin in Unmodified and Modified Form 609
standardized screening using unmodified rosin of 4 Chemical Composition

the gum rosin type for patch testing. of Unmodified Rosin
Although there are variations in the chemical

3 Production composition between the different types of rosin,
the major components are the same. The compo-
Colophony (rosin) is the nonvolatile fraction of the sition is complex including about 90% resin acids
fluid oleoresins from coniferous trees mainly pine and 10% neutral components. The acids are
trees. As it is a natural product, the composition monocarboxylic diterpenoid acids of which the
varies depending on the source but also on the way most abundant have abietane- or pimarane-type
it is produced. There are three types of rosin based on structures. Tall oil rosin contains less abietane-
the way of recovery: gum rosin, wood rosin, and tall type acids with conjugated double bonds and
oil rosin. Gum rosin is obtained from various species more dehydroabietic acid compared to gum
of standing pine trees. The trees are tapped for oleo- rosin. This is due to oxidation-dehydration of the
resin, which is then processed by evaporating the abietadiene-type acids in the pine wood during
volatile mono- and sesquiterpenoid components, i.e., pulping and tall oil processing. The tall oil distil-
turpentine, leaving the gum rosin as the residue. lation process at high temperatures also results
Wood rosin is extracted with solvent from pine in some resin acid artifacts which are not found
stumps. Tall oil rosin is obtained as one of the in the other types of rosin (Holmbom 1978). The
major fractions by distillation of crude tall oil, a neutral compounds in rosin are mainly
coproduct of the sulfate (kraft) pulping process of diterpenoid alcohols and aldehydes and also
coniferous trees. Today, the major types of rosin are hydrocarbons. Tall oil rosin also contains small
gum rosin and tall oil rosin. In 2008, the total rosin amounts of fatty acids and alcohols (Holmbom
production was estimated to be 1,190,000 mt of et al. 1974; Soltes and Zinkel 1989; Zinkel
which 763,000 tons were gum rosin; 415,000 tons 1975). The major resin acid is abietic acid.
tall oil rosin; and 12,000 tons wood rosin. Seventy- Dehydroabietic acid and the less stable acids of
five percent of gum rosin is produced in China. Other the abietadiene-type (levopimaric acid, palustric
big producers of gum rosin are Brazil, Indonesia, and acid, and neoabietic acid) are present in varying
India, while small amounts of gum rosin are pro- concentrations depending on production and stor-
duced in Mexico, Argentina, Nepal, Russia, and age. Pimaric acid is of the pimarane-type and
Portugal. The major producers of tall oil rosin are isopimaric acid and sandaracopimaric acid of the
the United States and the Nordic countries. isopimarane-type (Table 1) (Fig. 1).
In technical literature, the term “colophony” Unmodified rosin contains varying amounts of
corresponds to gum rosin. In dermatological liter- oxidized material mainly due to the oxidation of
ature, also wood rosin and tall oil rosin are included abietic acid which is known to oxidize at exposure
in the term colophony as the resins contain the to air. The oxidation of abietic acid has been
same major chemical components and allergens, shown to proceed via a free radical chain reaction.
and most often no declaration of the source is found Hydrogens in benzylic, allylic, and tertiary posi-
for technical products. In American literature, the tions are preferably abstracted as this yields
term “rosin” is more frequently used. In the follow- particularly stable radicals. For abietic acid, the
ing, “rosin” will be used as the general term includ- carbon radical in the tertiary position in the iso-
ing the three major types. Gum rosin under the propyl group is especially stable as it also is allylic
name of “colophonium” from Index of Cosmetic to the two conjugated double bonds (Fig. 1).
Ingredients (INCI) is used in the baseline series for Hydroperoxides are formed as primary oxidation
diagnosis of contact allergy in dermatitis patients. It products, and the first oxidation product identified
should be observed that an important part of the was 15-hydroperoxyabietic acid (Karlberg et al.
rosin on the market is chemically modified in order 1988a). Also peroxides, epoxides, ketones, and
to improve its technical properties. alcohols of abietic acid and dehydroabietic acid
Table 1 Typical composition of resin acids in Chinese gum rosin, Portuguese gum rosin, and Swedish tall oil rosin
Resin acids present in the acid fraction (%)
Chinese Portuguese Swedish
Resin acids gum rosin gum rosin tall oil rosin
Abietic acid 56 48 43
Levopimaric acida – – –
Palustric acid 14 15 8
Neoabietic acid 12 15 3
Dehydroabietic acid 6 5 28
Pimaric acid 9 9 4
Isopimaric acid 1 5 5
Sandaracopimaric acid 2 2 2
Other free resin acids 0 1 7
a
Levopimaric acid is the most unstable of the abietadiene acids and is often not detected by conventional analysis
Fig. 1 Structures of the major resin acids identified in temperature all four compounds can isomerize into the
rosin. Abietic, levopimaric, palustric, and neoabietic acid any of the others
are all of the abietadiene-type and dependent on
have been identified. The major oxidation prod- sites: the carboxylic acid group and the conjugated
ucts were identified both in gum rosin and tall oil double bonds. The rosin derivatives all result from
rosin (Karlberg 1991). Oxidation products identi- chemical reactions on one or both of these sites. The
fied as contact allergens are shown in Fig. 2. reactions on the carboxylic group that are of com-
mercial importance are esterifications (ester gums)
and salt formations. Most important modifications
5 Chemical Modifications regarding reactions on the conjugated double bonds
of Rosin include hydrogenation, disproportionation, Diels-
Alder-type reactions, dimerization/polymerization,
Rosin is modified to a large extent. The major and reactions with formaldehyde (polymerization)
component abietic acid and its isomers are the (Gafvert 1994; Soltes and Zinkel 1989). Different
main targets for the modifications and derivatiza- modification processes are often combined. Gener-
tions of rosin which are performed to improve its ally, the resins obtained are characterized by non-
technical properties (Illing et al. 2009; Soltes and specific and approximate methods such as color
Zinkel 1989). Abietic acid contains two reactive grade, acid number, saponification number, etc.
Fig. 2 Major oxidation products in rosin identified as contact allergens
It should be noted that in most cases the modifica- detail and evaluated with regard to sensitizing
tion is interrupted when certain technical properties capacity (Gafvert et al. 1994a; Shao et al. 1993)
are achieved. This means that also non-modified (Fig. 3).
rosin could be present in the final products (Gafvert
et al. 1996).
More than 200 derivatives of rosin (named 5.2 Diels-Alder Derivatives
modified rosin resins) were reviewed by a task
group within the Hydrocarbon Resins, Rosin Diels-Alder addition is one of the most common
Resins and Pine Chemicals Producers Association modifications of rosin. In this reaction, an α,β-
(HARRPA) of which 80 were found to be com- unsaturated carbonyl compound, referred to as a
mercially significant (Illing et al. 2009). These dienophile, reacts with a conjugated diene such as
80 derivatives were allocated into different group- the ones found in the abietadiene-type acids.
ings. The groupings fit well with the modifications Maleic anhydride or fumaric acid is the dienophile
of the active sites of abietic acid and its isomers and levopimaric acid the conjugated diene in the
described below. commercial processes. Abietic acid is the major
acid in unmodified rosin since it is the more stable,
but the equilibrium is changed by heating in
5.1 Esters the modification process. Maleopimaric acid is
formed in the reaction with maleic anhydride,
Esterification of the carboxylic acid group with while fumaropimaric acid is formed in the reac-
polyalcohols is most often performed with glyc- tion with fumaric acid (Gafvert et al. 1995;
erol or pentaerythritol. The esters produced in Karlberg et al. 1990). However, minor amounts
this reaction are referred to as ester gums. Ester- of maleopimaric acid are formed also in the latter
ification with glycerol was introduced at the end process (Fig. 3). From a skin-sensitizing perspec-
of the nineteenth century as one of the first com- tive, this is very important as maleopimaric acid in
mercially modifications used (Soltes and Zinkel contrast to fumaropimaric acid is a strong sensi-
1989). Esterification with polyalcohols can give tizer not cross-reacting with the sensitizers in
a mixture of esters when the resin acids react unmodified rosin (Gafvert 1994; Gafvert et al.
with 1–3 (glycerol) or 1–5 (pentaerythritol) alco- 1996; Illing et al. 2009). Maleopimaric acid is an
hol groups. The esterification process between anhydride and thus very reactive which can
abietic acid and glycerol has been studied in explain its sensitizing capacity. Fumaropimaric
Fig. 3 Schemes of important modifications of rosin (using (strong allergen) and fumaropimaric acid (weak allergen)
the major component abietic acid as model) which change by Diels-Alder reactions with maleic anhydride and
their technical and skin-sensitizing properties. (a) Esterifi- fumaric acid, respectively. (c) Hydrogenation of abietic
cation of abietic acid with glycerol forming monoabietate acid which reduces the sensitizing capacity of the acid
(weak allergen). (b) Formation of maleopimaric acid
acid on the other hand is a tricarboxylic acid and, one or both of the easily autoxidized conjugated
as acids are rather unreactive, they are also known double bonds could be reduced giving di- or tetra-
to be weak allergens. abietic acid (Fig. 3). Dehydrogenation is the
removal of two hydrogen atoms from the
abietadiene-type acids and rearrangement of the
5.3 Hydrogenated, double bonds to form dehydroabietic acid. This
Dehydrogenated, leads to a reduction of the abietadiene-type acids
and Disproportionated Rosin to the more stable dehydroabietic acid (Fig. 1).
The disproportionation process can be described
Hydrogenation, dehydrogenation, and dispropor- as a dehydrogenation-hydrogenation transfer
tionation are reactions that involve the double reaction which gives mainly dehydroabietic acid
bonds and are performed to stabilize rosin and but also a mixture of di- and tetraabietic acids
prevent from autoxidation. By hydrogenation (Soltes and Zinkel 1989).
5.4 Formaldehyde-Modified Rosin Different modifications are important in the var-

ious industries. The paper industry uses large
Formaldehyde modifications involve several dif- amounts of rosin for paper size, that is, to give
ferent reactions performed under various condi- the paper a smooth and hydrophobic surface. For
tions to form addition products. This type of this purpose mainly Diels-Alder adducts are used
reactions does not necessarily make the but also formaldehyde-modified rosin. Also sodium
abietadiene-type acids less prone to autoxidation salt is used in the paper industry, while ammonium
as the conjugated system of double bonds is still salt is used in detergents due to their properties as
present (Soltes and Zinkel 1989). amphiphiles, containing both a hydrophilic and a
lipophilic region (Soltes and Zinkel 1989).
Disproportionated rosin is present as polymer-
5.5 Resinates ization emulsifiers in the production of synthetic
rubber and also as insulating materials in the elec-
Salts formed by reacting the resin acids with metal tronic industry. Adhesives are primarily com-
salts are called resinates. These salts can be pre- posed of a polymeric component and a
pared in mainly two different ways. In the precipi- tackifying resin. Rosin used in tackifying resins
tation method, a solution of heavy metal salt is are mainly disproportionated, hydrogenated, or
added to a soluble sodium resinate. This will pro- polymerized, as well as their esters with glycerol
duce a water-insoluble heavy metal resinate. In the or pentaerythritol. The rosin derivatives are
fusion method, rosin is fused with a metal hydrox- important components both in pressure-sensitive
ide or oxide. Hydroxides, oxides, and various metal adhesives and hot-melt adhesives. The rosin
compounds react with the carboxyl group of the derivatives are used in large amounts also in
resin acids to form soaps and resinates. The alkali paints, coatings, and road markers.
metals (e.g., sodium and potassium) form water- Many of the modified rosin products are not
soluble salts, while the salts of the alkaline earth possible to connect to rosin by the name. Thus,
metals (e.g., magnesium and calcium) are soluble in trying to find statistics of the usage of rosin in
organic solvents. The reactive conjugated system of different industries and products is difficult. The
double bonds is still present also in the resinates, world consumption in 2008 of rosin in unmodified
but the effect could vary depending on the solubil- and modified form allocated to market application
ity (Soltes and Zinkel 1989). is seen in Fig. 4.
Rosin/colophony (CAS numbers 8050-09-7
(preferred name rosin), 8052-10-6 (preferred
6 Usage and Legislation name tall oil rosin), 73138-82-6 (preferred
names resin acids and rosin acids)) has a harmo-
In the early seventeenth century, extracting resin nized classification (included in CLP Annex VI,
from living pine trees became the first widespread legally binding) as a skin sensitizer in category
industry in America. The business was more 1. This means that products containing rosin at a
famous under the name “naval stores” since the concentration of at least 0.1% should be labeled
product was used by sailors to seal leaking hulls. with the statement EUH208, “Contains rosin;
Rosin has three main properties: it has good tack- colophony. May produce an allergic reaction,”
ifying qualities, it can be used as an emulsifier, and and a safety data sheet is required. Products
it has acid properties without causing corrosion. containing at least 1% rosin must be classified
The technical properties are modified using chem- and labeled as “H317: May cause an allergic
ical reactions as described above. In many cases, skin reaction” (REGULATION (EC) No 1272/
modifications are undertaken on both reactive sites 2008 OF THE EUROPEAN PARLIAMENT
(carboxylic acid and double bonds) in different AND OF THE COUNCIL of 16 December 2008
proportions to get the desired technical properties on classification, labelling and packaging of sub-
(Illing et al. 2009; Soltes and Zinkel 1989). stances and mixtures, amending and repealing
Other Rosin
Adhesives & Sealants
Users
9%
Emulsifiers
10% 24%
Paper Size
18%
28%
3%
2%
4%
2%
Other Esters
& Resinates
Printing Ink
Chewing
Gum Rubber Compounds
Coatings
Fig. 4 World consumption in 2008 of rosin in unmodified and modified form allocated to market application (Turner
2010)
Directives 67/548/EEC and 1999/45/EC, and components and calculations from their percent-
amending Regulation (EC) No 1907/2006). age in rosin. As the content of resin acids varies
Rosin/colophony is also used in cosmetics and depending on the source, the manufacturing,
thus listed on the INCI list (Index of Cosmetic the handling, and the storage, it is not possible
Ingredients) under the name “Colophonium” to determine the exact concentration of rosin in
(EINECS/ELINCS 232-475-7) in the Cosmetics a product. A thorough review with regard to
Regulation but without any restrictions for its analytical methods used for rosin was published
application. The areas of usage mentioned are by the Danish Ministry of the Environment
binding, depilatory, film forming, and viscosity (Nilsson et al. 2009). Two major types of analyses
controlling (http://ec.europa.eu/growth/tools-data for rosin components are described in literature.
bases/cosing/). Traditionally in the pulp industry, the major resin
acids are quantified using gas chromatography
with a flame ionization detector (GC/FID). Later
7 Analysis of Content on, methods based on liquid chromatography
of Unmodified Rosin (LC) using UV, fluorescence, and mass spectrom-
in Technical Products etry have been developed, most often for the ana-
lyses of specific products (Nilsson et al. 2009).
The content of rosin in commercial products as In all the described methods, the quantification
demanded by the regulation (see above) is not is based on content of the non-oxidized resin
possible to quantify with a simple chemical anal- acids. Based on this, a low level of abietic acid
ysis. Rosin is a natural product consisting of indicates a low level of rosin; however, it is impor-
a mixture of hundreds of components. Quantify- tant to check that a low level is not caused by
ing a mixture used as an ingredient of another oxidative degradation resulting in highly aller-
mixture cannot be achieved by any analytical genic compounds such as 15-hydroperoxyabietic
means. To overcome this impossibility, the quan- acid. To avoid such a misinterpretation, a new
tification must be based on an approximation from LC/UV method was developed that, besides the
the quantification of specific tracers, i.e., the major two major acids of unmodified rosin, abietic acid
and dehydroabietic acid, uses a stable oxidation The chemical modifications as described above
product, 7-oxodehydroabietic acid, as a tracer for change the reactivity and thus also the allergenic
oxidative decomposition (Nilsson et al. 2008). activity of rosin. Modification including hydroge-
The necessity of methods and rules for quantifi- nation of the double bonds will reduce the sensi-
cation of specific rosin components as tracers for tizing capacity (Gafvert et al. 1994a; Karlberg
content of rosin in products high enough to be et al. 1988c). Esterifications with polyalcohols
declared according to the EU legislation was dem- can also reduce the sensitizing capacity depending
onstrated in a paper on metal working fluids on how far the process is driven. Studies of ester-
(Henriks-Eckerman et al. 2008). ification of abietic acid with glycerol showed
that mono-, di-, and triabietates can be formed.
Of these, monoabietate (Fig. 3) was found to be
8 Allergenic Activity a sensitizer in guinea pigs, while triabietate was a
non-sensitizer (Gafvert et al. 1994a; Shao et al.
Unmodified rosin is known to cause contact 1993). The Diels-Alder reaction using maleic
allergy. The main allergenic components are anhydride or fumaric acid results in maleopimaric
oxidized resin acids of the abietadiene-type acid which is an anhydride with reactive sites
which are formed on air exposure (Fig. 2). that differ from those in non-modified rosin
15-Hydroperoxyabietic acid was the first oxida- (Fig. 3). Maleopimaric acid is a strong sensitizer,
tion product identified as a contact allergen and both maleated and fumarated rosins are
in unmodified gum rosin and is still considered sensitizers in animal experiments (Gafvert et al.
to be the major sensitizer (Karlberg et al. 1988a). 1995). A sensitizing capacity of maleated or
Later, several articles regarding isolation and fumarated rosins is observed also after esterifica-
identification of oxidized resin acids as tion (Illing et al. 2009). It must be observed
contact allergens were published (Gafvert et al. that most often unmodified rosin is still present
1992, 1994b; Hausen and Hessling 1990; Hausen in a product after modifications have been
et al. 1990; Hausen and Loll 1993; Karlberg et al. performed (Gafvert et al. 1996). This has been
1988b; Khan and Saeed 1994; Sadhra et al. 1996; shown even after double modifications, e.g., anal-
Shao et al. 1995). In the pioneer work of rosin ysis of an esterified and maleated rosin showed
allergy, the allergenic resin acids were isolated as a content of both unmodified resin acids and
their methyl esters. In a later study, a synthesized maleopimaric acid in addition to the maleated
15-hydroperoxyabietic acid was tested in individ- rosin ester which was used in an adhesive for
uals with known contact allergy to gum rosin shoe linings (Lyon et al. 1999).
(Karlberg et al. 2007). The study showed that
a similar proportion of individuals (46%) reacted
to the acid compared with the percentage (57%) 9 Allergic Contact Dermatitis
of reactions to its methyl ester used in previous
investigations. Corresponding oxidation of the 9.1 Screening and Patch Testing
neutral components can also yield allergenic
compounds, and patch test studies with neutrals Gum rosin in petrolatum at a concentration of
have revealed additional cases of rosin allergy 20% is used for patch testing under the INCI
(Karlberg et al. 1986; Sadhra and Foulds 1995). name colophonium (Karlberg and Liden 1988).
When ranking the sensitizing capacity of the In the True Test, a mixture of eight different
oxidation products in gum rosin according to types of gum rosin is applied in a gel at a concen-
the original classification by Magnusson and tration 850 μg/cm2.
Kligman based on guinea pig studies, most of The baseline series including colophonium
the compounds were classified as extreme aller- (gum rosin) is also used in screening studies of
gens with a ranking grade of V (81–100% sensi- contact allergy to the most common allergens in
tized animals) (Karlberg and Gafvert 1996). cohorts from the general population in different
countries. A 10-year prevalence (1992–2002) of two occasions. Furthermore, this study showed
contact allergy to gum rosin in the population a clear decrease in the prevalence in the ages
in Germany based on the positive reactions to <40 years compared to that seen in the older
the baseline series in 78,067 dermatitis patients ages for men (2.0% compared with 3.4%) and
was estimated to 1.4–0.6% (Schnuch et al. 2002). also for women (2.0% compared with 5.4%).
Using the same setup, a prevalence of 0.84–0.62% Colophonium allergy was found in 0.5–2.0% of
of rosin allergy was estimated in the Danish pop- European children with dermatitis 1–16 years old,
ulation (Thyssen et al. 2007). A later study have with increasing prevalence in adolescents (Belloni
shown a prevalence of 0.9% based on patch test- Fortina et al. 2015). As the use of rosin-containing
ing of 3119 individuals in five European countries products for treatment of leg ulcers has been
(Diepgen et al. 2016). In a cohort study of 2285 an important source for contact allergy to gum
unselected 16-year-olds in Sweden, 0.45% had rosin, it might be one of the explanations behind
contact allergy to colophonium (Lagrelius et al. the higher prevalence of allergy in the older group
2016). Similar results have been seen in a Danish (Lindberg et al. 2007). Data from countries out-
cohort of adolescents, and when 442 individuals side of Europe further indicates that colophonium
were retested at 29 years old, prevalence of con- is still an important sensitizer worldwide, with
tact allergy to colophonium had increased to 2.0% 13% of colophonium positive patients in a small
(Mortz et al. 2013). study of 330 dermatitis patients in South Korea
It should be observed that the frequency of (Yu et al. 2017).
contact allergy to colophonium as demonstrated Individuals in whom contact allergy to
via patch testing with the baseline series is still colophonium had been diagnosed at an occupa-
high and within the same range throughout the tional clinic were followed up after 9–13 years.
years. Moreover, thorough research has shown At least 30% of the 83 persons investigated had
that screening with modified rosins can detect current hand eczema on the follow-up examina-
additional cases of contact allergy but no attempts tion. Among those in whom the dermatitis
to implement this in the clinical routine work have had started on the hands, proportionally more
been reported in literature. individuals with current hand eczema were
Clinical aspects of rosin allergy have observed than among those in whom the onset
been extensively reviewed by Färm (1997). had been on other parts of the body. At the time
Colophonium is among the most common causes of the investigation, 72% of the participants were
of contact allergy with a relative frequency of still patch test positive to colophonium, and more
positive reactions varying from 2% to 7% when than half had additional positive reactions to other
patch testing consecutive dermatitis patients with allergens (Farm 1996).
the baseline series (Farm 1997; Schnuch et al. Various types of rosin are used interchange-
2002; Uter et al. 2010). A dominance of positive ably; it is mainly the price that is decisive. When
reactions in women is observed. Results from patch testing with various gum rosins and with tall
testing with the baseline series in about 25,000 oil rosin, fewer positive reactions were found to
consecutive patients in ten European test centers the tall oil rosin, but most persons reacted to both
during the years 1996–2000 were published in gum rosin and tall oil rosin (Hausen and Loll
2005 (Bruynzeel et al. 2005). A relative frequency 1993; Karlberg et al. 1986; Karlberg and Gafvert
of positive reactions to colophonium ranging from 1996; Karlberg and Liden 1985). The slightly
2.2% to 5.2% with a mean of 4.0% (3.2% men and lower allergenic activity of tall oil rosin could
4.5% female) was found. In a Swedish study be due to a difference in composition but as the
(Lindberg et al. 2007), a certain decrease in the allergenic activity is mainly due to oxidation
prevalence of reactions to colophonium was products, the handling and storage times always
observed when comparing data from 1992 with affect the allergenic properties (Karlberg 1988;
those from 2000. More than 3000 consecutive Sadhra et al. 1998). The major oxidation products
patients were tested in different clinics at these are identified also in tall oil rosin (Karlberg 1991);
thus, it is acceptable to use gum rosin in a well- At present, patch test preparations of the individ-
defined form as the first screening material. ual sensitizers are not commercially available, and
In general, the baseline series for patch testing 15-HPA is unstable and cumbersome to synthe-
consists of pure and identified substances, except size (Karlberg et al. 2007).
for some complex natural products among which Cross-reactions between colophonium,
colophonium is one. As stated above, the main Balsam of Peru (Myroxylon pereirae), oil of tur-
allergens are found among the oxidation products pentine, wood tar, and spruce resin were described
formed at autoxidation of the resin acids of by Hjorth in 1961 (Hjorth 1961). Today, concom-
abietadiene-type, while the pure acids have a very itant reactions to gum rosin, Balsam of Peru,
low allergenic activity (Karlberg 1988). The patch and/or fragrances are frequently seen when testing
test preparations of colophonium should be as well with the baseline series in consecutive patients.
defined as possible. It is important that the content Simultaneous reactions are often observed for
of oxidation products is kept at a constant and patch test reactions to colophonium and oxidized
rather high level in the test preparations as they fragrance compounds, i.e., oxidized limonene
are the main allergens. Investigations have shown and linalool in consecutive dermatitis patients
that there is a considerable decrease in the content (Brared Christensson et al. 2016; Karlberg and
of abietadiene-type acids in the patch test prepara- Dooms-Goossens 1997; Matura et al. 2003,
tions (21% in the first 6 months after preparation) 2005). Besides concomitant sensitization, this
which was considered to be due to further oxidation could theoretically be caused by the allergenic
followed by formation of less allergenic secondary hydroperoxides forming nonspecific antigens. As
oxidation products in the preparation process hydroperoxides and peroxides are oxidizing
(grinding and heating) as well as at storage; an agents, they may oxidize functional groups in
additional decrease of 6% was seen between the proteins and thereby form nonspecific agents.
6 and 12 months of storage (Sadhra et al. 1998). Thus, cross-reactions between hydroperoxides
Different rosin components and fractions of with significantly different structures would have
unmodified rosin have been suggested for more been observed. However, cross-reactivity studies
effective patch test diagnosis (Hausen and Loll in animals (Christensson et al. 2006) as well as
1993; Sadhra and Foulds 1995). However, the patch test studies show that hydroperoxides have a
problems with the rosin sensitizers have not been specific reactivity (Christensson et al. 2014).
taken into consideration. Testing with the identi- Patients with positive patch test reactions to
fied allergens will not detect as many cases as colophonium in the baseline series were retested
testing with gum rosin itself. Simultaneous testing with 15-hydroperoxyabietic acid and also with
with the major allergen, 15-HPA (the hydroperox- limonene- and linalool-hydroperoxides. Only
ide of abietic acid) and colophonium showed 1 of the 29 tested individuals reacted to more
that 50–70% of those reacting to colophonium than 1 hydroperoxides (Christensson et al. 2008).
reacted to the isolated allergen as free acid or Patch testing with modified rosins and aller-
methylated (Karlberg et al. 2007; Karlberg and gens formed by modifications will detect addi-
Gafvert 1996). In gum rosin, oxidation products tional cases of contact allergy (Gafvert et al.
are formed continuously due to autoxidation, 1996; Hausen and Mohnert 1989). In an interna-
while pure, isolated, and unstable oxidation prod- tional patch test study, positive reactions were
ucts are degraded. In some cases, testing with a observed to the modified rosin components
major allergen in a newly prepared patch test maleopimaric acid and glyceryl-1-monoabietate
preparation could detect additional cases of (Gafvert et al. 1996). Of the patients who reacted
allergy as the concentration of the allergen in the to modified rosin components, some did not react
mixture might be too low in the screening of the to colophonium in the baseline series. This was
actual individual. It could therefore be of interest expected as no cross-reactivity between the mod-
to test with some of the individual sensitizers in ified rosin components and the allergens in gum
addition to the baseline testing in these patients. rosin (colophonium) is observed. Reactions to
both colophonium and the allergens formed after Medical adhesives are still causing ACD to
modification could be caused by concomitant sen- colophonium. Case reports from Europe and
sitization as unmodified rosin is still present in the Asia describe ACD from colophonium in
modified material (Gafvert 1994; Gafvert et al. adhesive tapes and adhesives in electrodes
1996). It is desirable that at least the potent aller- (Christoffers et al. 2014; Deswysen et al. 2013;
gen maleopimaric acid present in commonly used Suhng et al. 2011). Although colophonium is
modified rosins could be used as a screening rarely used in electrode adhesives, it can still be
material, but it is still not commercially available. present as a contaminant from soldering of the
An alternative is to test with well-defined wiring of the electrode (Deswysen et al. 2013).
maleated rosin derivatives with and without ester- Adhesive tapes often contain modified rosin;
ification (Illing et al. 2009). however colophonium can be present in the mod-
ified rosin. Furthermore, protective sprays used to
protect the wound from adhesives in wound dress-
9.2 Exposure from Products ings can contain colophonium and cause ACD
in Close Contact with the Skin (Han et al. 2014).
Epilating waxes and tissues used for removal
Several case reports deal with the clinical prob- of hair on the lower legs have caused an epidemic
lems caused by rosin in products that are in of allergic contact dermatitis due to their content
close contact with the skin. Intolerance to adhe- of modified rosin (Goossens et al. 2002). In many
sive plasters has been discussed since the begin- cases, a severe systemic eruption led to hospital-
ning of the 1920s (Karlberg 1988). Efforts have ization and administration of systemic corticoste-
been made over the years to make adhesives roids. Primary sensitization occurred in one
non-allergenic using acrylate polymers. However, third of the patients. The majority of patients
rosin is needed to get a maximum of adhesion with positive reactions to the modified rosin
effect, and therefore it is still used, most often in the products did not react to colophonium in
as ester gums. Chemical analysis shows a the baseline series. This is in accordance with
content of the major resin acids in these types of previous findings when screening with allergens
products (Ehrin and Karlberg 1990). In leg ulcer from modified rosin (Gafvert et al. 1996). As
patients, a high incidence of contact allergy to specific allergens have been identified in
colophonium is observed. A French multicenter glycerol-modified rosin, this is not surprising.
study in patients with chronic leg ulcers revealed However, chemical analyses show that the modi-
contact allergy to gum rosin in 7.6% of the tested fications are not performed to completeness in
individuals (Barbaud et al. 2009). A clear corre- epilating waxes but leaving unmodified rosin
lation was found between rosin allergy and to ensure the stickiness of the product (Nilsson
reactions to a rosin-containing dressing tested et al. 2008).
simultaneously. Although the rosin used in these Glycerol-esterified rosin is used as a skin con-
products most often is esterified gum rosin ditioner and surfactant-emulsifying agent in eye
which might be further derivatized, the amount makeup, hair coloring preparations, blushers,
of unmodified rosin still present is high enough foundations, and lipsticks (Goossens et al.
to cause allergic contact dermatitis from gum 2002). Allergic contact dermatitis from rosin in
rosin. Contact allergy to the modified rosins was unmodified or modified form in various types of
also demonstrated, although no reactions to cosmetics has been reported during the years
colophonium in the baseline series were seen (Farm 1997). Also the adhesive of Indian bindi
(Pereira et al. 2007; Salim and Shaw 2001). has been reported to cause ACD due to rosin
Reduction of the allergenic effect of rosin in adhe- derivatives (Koh et al. 1995).
sives and bandages used for treatment of ulcers by Rosin in adhesives for shoe linings is an impor-
addition of zinc oxide could not be confirmed in a tant cause of contact allergy. Esterified gum rosins
specific investigation (Gafvert and Farm 1995). alone or in combination with Diels-Alder
derivatization are used, and thus ACD can be a wooden toilet seat revealed the presence
caused by strong allergens formed by modifica- of abietic acid, dehydroabietic acid, and
tion, especially maleopimaric acid, but can also be 7-oxodehydroabietic acid in the wooden toilet
due to unmodified rosin still present in the adhe- seat (Raison-Peyron et al. 2013). The patient’s
sive (Gafvert 1994; Gafvert et al. 1996). A case ACD was completely resolved after changing to
report describes ACD on the feet caused by rosin a plastic toilet seat.
in shoe linings in a 5-year-old girl. Although the
used adhesive was both maleated and esterified
rosin, it contained enough unmodified rosin to 9.3 Occupational Exposure
cause dermatitis which healed when the girl
was wearing unlined shoes. The content of Individuals exposed to unmodified rosin in pine
unmodified rosin and maleopimaric acid in the wood, sawdust, and wood wool may develop
adhesive was confirmed with chemical analysis hand dermatitis and dermatitis due to airborne
(Lyon et al. 1999). In an Indian study, patients exposure (Burry 1976; Daly and Stevenson
with footwear dermatitis were tested with 1984; Meding et al. 1996; Watsky 1997). Despite
the Indian Standard Battery for screening of a significant production of gum rosin, no reports
contact allergy. Contact allergy to colophonium of occupational allergic contact dermatitis in gum
was detected in 11.6% of the tested patients rosin extractors are found in literature except for a
(Chowdhuri and Ghosh 2007). In cases of ACD report from Brazil (Scherrer and Junqueira 2010).
caused by the adhesive in shoe linings, it is In this case report, a female rosin extractor pre-
recommended that individuals allergic to rosin sented eczematous lesions on her hands, forearms,
should wear either unlined shoes or leather-lined neck, face, and legs. No protection was used.
shoes with the lining stitched, not glued in place, She reacted to the gum rosin obtained and to
and no heel or toe supports. In comparison with its colophonium in the patch test baseline series.
use and close contact with the skin, contact allergy Her eczema improved when she left her job. In
to modified and unmodified rosin in shoes is very Brazil, the gum rosin industry employs 15,000
little investigated. workers (Data from the Resin Association in
Pharmaceutical uses of oils and pitch from Brazil (ARESB)). The conclusions from the
pine trees were noted by physicians 2000 years authors are that cases in gum rosin extractors
ago (Zinkel 1975), but nowadays they are mainly very seldom are reported and diagnosed (Scherrer
used in folk medicine. However, gum rosin is still and Junqueira 2010). The prevalence of contact
used in dental materials, e.g., in periodontal dress- allergy to gum rosin and tall oil rosin among the
ings, cavity varnishes, and fluoridizing dental employees in a factory for production of tall oil
varnishes. Some reports of stomatitis and lichen rosin was found to be in accordance with that of
planus in the mouth from dental materials dermatitis patients and, thus, higher than in the
containing rosin have been published (Sharma general population (Farm et al. 1994). However,
2006). A case report from Japan reveals ACD the clinical symptoms were rare. A healthy worker
from a rosin-containing ointment sold as naturo- effect cannot be excluded among people working
pathic drug (Tsuruta et al. 2011). with extraction and production of rosin. In the
Exposure to rosin components in paper products local areas, it is well known that you might get
has mainly been a matter of occupational exposure, skin problems from working with rosin and you
but rosin components have also been identified in either continue to work or, if possible, leave for
diapers and sanitary pads (Kanerva et al. 2001; another job without involving a dermatologist.
Karlberg and Magnusson 1996). Occasional cases Skin problems among performing artists have
are still reported (Wujanto and Wakelin 2012). been reported through the years (Farm et al. 1995;
Exposure to rosin can also occur from Helm et al. 1993). Artists are often extensively
extended exposure to wood itself as well as exposed to cosmetics in their occupation. Theat-
varnish. An unusual case of ACD caused by rical cosmetics do not differ essentially from
corresponding products for everyday usage, apart Other types of industries have also moved
from higher pigment content. The frequency of to Asia, and reports of ACD followed. Patch testing
cosmetics intolerance and contact allergy to revealed that colophonium is a common cause
colophonium in the baseline series was investi- of contact allergy in textile workers, both workers
gated among artists in an opera house (Farm et al. and managers. Workers showed predominantly
1995). Contact allergy to gum rosin was not caus- hand dermatitis, whereas managers showed
ing frequent problems among the artists. Only one predominantly head and neck dermatitis, perhaps
individual among the dancers in the opera house indicating an airborne exposure (Chen et al. 2017).
had ACD caused by gum rosin. The dancers use The content of rosin in paper and paper prod-
rosin on the floor, on their shoes, and even on the ucts has been investigated. It was found that paper
female dresses, as an anti-slipping agent. Also in of mechanical pulp from coniferous wood, com-
this case, a healthy worker effect could be distin- monly used in newsprint paper, contains more com-
guished as it takes many years of training before ponents from unmodified rosin than paper based on
you become a professional dancer. However, chemical pulp (Ehrin and Karlberg 1990; Karlberg
rosin allergy among the dancers’ masseurs was et al. 1995). As the extractive material containing
observed (Farm et al. 1995). the rosin components is not separated from the
The most prevalent skin disorders of instrumen- mechanical pulp, a higher response was seen to
tal musicians, particularly among string instrumen- unprinted paper of mechanical pulps than to paper
talists, include contact allergy to gum rosin. Several based on chemical pulps in persons with known
reviews on occupational diseases include this prob- contact allergy to gum rosin (Karlberg et al. 1995).
lem (Crepy 2015; Gambichler et al. 2004). It is well When patch testing patients who suspected that
known that gum rosin is used by string players to their dermatitis was caused by contact with paper,
wax the strings in order to increase the attrition only those with positive patch test reactions to
between the bow and the strings. The use of rosin colophonium or maleopimaric acid reacted to the
by percussionists to tighten their grip of the sticks is paper extracts (maleopimaric acid is the main com-
less well known and not discussed in the dermato- ponent in maleated rosin used for paper size). The
logical literature. It could be concluded that presence of rosin in paper can contribute to hand
although a member of an orchestra does not use dermatitis in sensitized subjects, and the use of
rosin himself, the air exposure caused by other cotton gloves when in contact with paper might
members is significant. The use of rosin in ballet alleviate the dermatitis (Karlberg and Liden
will increase the airborne exposure in the opera 1992). In a study on the prevalence of hand derma-
orchestra (Farm et al. 1995). It should be remem- titis and contact allergy in Sweden, it was found
bered that instrumental rosin could cause ACD not that rosin allergy was overrepresented among
only in professional instrumentalists but also in women in administrative work (Meding and
musicians of all ages and ability (Gambichler Swanbeck 1990). However, this group showed a
et al. 2004). low prevalence of hand eczema. Cases of rosin
Rosin in soldering fluxes for electronic assem- allergy among workers in a paper mill are rare
blies is a well-known cause of ACD (Liden 1984; (Meding et al. 1993). Compared with office work,
Widstrom 1983). As the allergens can be airborne, the handling of paper in a paper mill is not as
facial dermatitis is not uncommon in addition to intensive as very little work is performed manually.
hand eczema. In the late 1980s, the production of Metalworking machinists are exposed to
electronic equipment was moved from Europe diverse skin irritants and sensitizers. Rosin com-
to Asia and so did the reports on occupational ponents in metalworking fluids are a common
problems (Koh et al. 2001). Chemical analysis of cause of ACD which has been reported through-
a soldering flux revealed a content of abietic acid out the years (Fregert 1979; Grattan et al. 1989;
corresponding to 20% gum rosin in the product Matos et al. 1988). More recent publications dem-
(Ehrin and Karlberg 1990). onstrate that rosin from metalworking fluids still
causes contact allergy in the machinists using Burry JN (1976) Contact dermatitis from radiata pine.
them (Geier 2004; Suuronen et al. 2007). The Contact Dermatitis 2(5):262–263
Chen YX, Gao BA, Cheng HY, Li LF (2017) Survey of
source of rosin components in metalworking occupational allergic contact dermatitis and patch test
fluids originates mainly from distilled tall oil among clothing employees in Beijing. Biomed Res Int
which contains typically10–30% tall oil rosin. 2017:3102358. https://doi.org/10.1155/2017/3102358
Chemical analyses detect rosin components in Chowdhuri S, Ghosh S (2007) Epidemio-allergological
study in 155 cases of footwear dermatitis. Indian J
the fluids in amounts high enough to demand a Dermatol Venereol Leprol 73(5):319–322
declaration of the content of rosin according to the Christensson JB, Matura M, Backtorp C, Borje A, Nilsson JL,
EU legislation (See above) (Ehrin and Karlberg Karlberg AT (2006) Hydroperoxides form specific anti-
1990; Henriks-Eckerman et al. 2008). gens in contact allergy. Contact Dermatitis 55(4):230–237
Christensson JB, Johansson S, Hagvall L, Jonsson C,
Borje A, Karlberg AT (2008) Limonene hydroperoxide
analogues differ in allergenic activity. Contact
10 Other Health Effects Dermatitis 59(6):344–352. https://doi.org/10.1111/
j.1600-0536.2008.01442.x
Christensson JB, Hellsen S, Borje A, Karlberg AT (2014)
The potential of rosin fumes to induce occupational Limonene hydroperoxide analogues show specific
asthma has been recognized since the 1970s and is patch test reactions. Contact Dermatitis
primarily found in employees soldering conductive 70(5):291–299. https://doi.org/10.1111/cod.12195
connections in the electrical or electronic industry. Christoffers WA, Coenraads PJ, Schuttelaar ML (2014)
Bullous allergic reaction caused by colophonium in
This work caused about 5% of all new cases of medical adhesives. Contact Dermatitis 70(4):256–257.
occupational asthma according to the UK Surveil- https://doi.org/10.1111/cod.12170
lance of Work-related Occupational Disease in Crepy MN (2015) Skin diseases in musicians. Eur J Dermatol
1994. The respiratory symptoms have been consid- 25(5):375–383. https://doi.org/10.1684/ejd.2015.2559
Daly BM, Stevenson CJ (1984) Contact dermatitis to wood
ered to be due to hypersensitivity. However, spe- wool. Contact Dermatitis 11(2):123
cific IgE antibodies were detected in serum from Deswysen AC, Zimerson E, Goossens A, Bruze M,
rosin-exposed workers with a likely diagnosis of Baeck M (2013) Allergic contact dermatitis caused by
occupational asthma (Elms et al. 2005). self-adhesive electrocardiography electrodes in an
infant. Contact Dermatitis 69(6):379–381. https://doi.
org/10.1111/cod.12137
Diepgen TL, Ofenloch RF, Bruze M, Bertuccio P,
Cazzaniga S, Coenraads PJ, Elsner P, Goncalo M,
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Industrial Enzymes
42
David A. Basketter and Monika Raulf
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
3 Regulatory Classification of Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
4 Predictive Assays for Enzyme Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
5 Immunologic Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
6 Skin Irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
Keywords • The primary risk that they present to

Enzymes · Respiratory allergy · Contact human health is sensitization of the respira-
urticaria · Risk management tory tract.
• Proteolytic enzymes can give risk to skin
irritation.
1 Core Messages • All enzymes have the potential to cause immu-
nologic contact urticaria, although this is not
• A wide range of enzymes is used in many common.
industrial environments.
2 Introduction
D. A. Basketter (*) Enzymes are proteins that are used as
DABMEB Consultancy Ltd., Sharnbrook,
Bedfordshire, UK
biocatalysts, and they are able to participate in
e-mail: dabmebconsultancyltd@me.com multiple, repeated processes. Therefore they are
efficient ingredients in a variety of industries,
M. Raulf
Institute for Prevention an Occupational Medicine of including cleaning, food processing, animal
German Social Accident Insurance, Institute of the Ruhr- feed, textile, paper, and pharmaceuticals (Bern-
Universität Bochum, Bochum, Germany stein and Sarlo 2006). The major focus for many
e-mail: raulf@ipa-dguv.de

https://doi.org/10.1007/978-3-319-68617-2_42
626 D. A. Basketter and M. Raulf
years has been proteolytic enzymes deployed in

fabric washing products (e.g., Peters et al. 2001).
In the 1940s, they are introduced commercially
in Europe as part of an application for soaking
and washing soiled linen. These enzymes are
very largely of bacterial or fungal origin but
also from plants (such as papain or pepsin) and
are thus foreign to the human immune system.
As a consequence, they should all be assumed to
be potential respiratory allergens (Basketter et al.
2012). This property translated into a fairly dra-
matic outbreak of respiratory symptoms in deter- In addition, proteolytic enzymes are likely to
gent workers after inhalation exposure to be irritant to skin and will be labeled “Causes
Bacillus subtilis-derived powdered enzymes (mild) skin irritation” and show the following
(Alcalase and Maxatase ®) (Flindt 1969; Pepys symbol:
et al. 1969; Schweigert et al. 2000). These index
cases were strong indicators that enzymes were
highly allergenic materials and that susceptible
exposed workers were at increased risk of
becoming sensitized (IgE-mediated reaction
with positive skin test results) and developing
asthma (Bernstein and Sarlo 2006). However,
even in this situation, immunologic contact urti-
caria was not reported, only a limited degree of
irritant contact dermatitis (Zachariae et al. 1973).
Since then a number of reports of occupational
contact urticaria have arisen, but it remains
No other hazard classification relevant to
uncommon, perhaps because the often very strict
skin effects is normally applied to enzymes. In
exposure limits related to respiratory sensitiza-
theory, enzymes could be classified as “May
tion risk tend to ensure that skin contact is also
cause sensitization by skin contact” if they
very low. Indeed, when used correctly, the sig-
were to show a sufficient propensity to cause
nificant sensitization risk that enzymes present
immunologic contact urticaria to a significant
can be very successfully managed (Basketter
extent, but the clinical evidence for this is so
et al. 2015).
sparse (see below) that such an action would
not be merited.
3 Regulatory Classification
of Enzymes
4 Predictive Assays for Enzyme
Although it is likely that not all enzymes have Hazards
been reviewed by regulatory authorities, all
those that have in Europe have been judged to Since this is handbook on occupational dermatitis,
be respiratory sensitizers and thus have the anno- it is not appropriate to go into details of predictive
tation “May cause sensitization by inhalation,” tests for respiratory sensitization. However, it
and such wording must therefore appear on the is worth mentioning that for skin irritation,
safety data sheet. Under the new GHS regula- the traditional toxicology test involved 4 h semi-
tions, it should also be indicated by the following occluded application of undiluted test material to
symbol: the shaved skin of three rabbits (Draize et al.
42 Industrial Enzymes 627
1944). It is well recognized that this is a poor Table 1 Enzymes reported to cause immunologic contact
predictor of acute skin irritation potential urticaria
(Basketter et al. 2004; Jirova et al. 2010), and of Enzyme type References
course it clearly provides no more than a minimal α-amylase Tarvainen et al. (1991), Morren et al.
insight concerning the cumulative irritant poten- (1993), Wuthrich (1996), Kanerva
et al. (1997), and Medeiros et al. (2006)
tial of a substance. What is evident from testing of
Cellulase Kanerva and Tarvainen (1990) and
enzymes diluted to product and to in-use concen- Kanerva et al. (1998)
trations is that at these exposure levels, skin irri- Glucoamylase Kanerva and Vanhanen (1999)
tation is essentially undetectable (reviewed in Lactase Laukkanen et al. (2007)
Basketter et al. 2008). Papain Soto-Mera et al. (2000)
However, a key question concerns the possi- Protease Kanerva and Vanhanen (2001)
bility of skin-sensitizing activity of enzymes! The Xylanase Kanerva and Tarvainen (1990)
experience to date is that all bacterial and fungal
enzymes presented to mice and guinea pigs in
the context of standard predictive assays for the “prick” (Smith Pease et al. 2002). Neverthe-
skin sensitization (OECD 1992, 2002) lead to less, where the skin barrier is compromised, the
positive results. However, there is no evidence proteins, including enzymes, can cause an
that delayed hypersensitivity reactions occur in immunologically mediated dermatitis, and
human subjects, either under experimental, occu- this was first identified a quarter of a century
pational, or consumer exposure conditions, and ago as “protein contact dermatitis” (Hjorth
thus the positive predictive test data from animal and Roed-Petersen 1976). The whole subject
models is rightly regarded as an irrelevant conse- of contact urticaria/protein contact dermatitis
quence of a normal immune reaction to a foreign is reviewed in standard textbooks of contact
protein (HERA 2009a, b; Basketter et al. 2008). dermatitis (Amin et al. 2008a, b; Levin and
In addition, animal models to study relative aller- Warshaw 2008; Basketter et al. 2010), and
genic potencies of enzymes in the respiratory tract there is a recent specific review of immunologic
were developed, e.g., a guinea pig intratracheal contact urticaria to proteins (Amaro and
test or a mouse intranasal model (e.g., Robinson Goossens 2008). This last mentioned reference
et al. 1998). Although animals are valuable tools notes that there is some suggestion of a delayed
to assess toxic, irritant, and immunologic effects (Type IV) hypersensitivity component to protein
of enzymes, the direct extrapolation of findings in contact dermatitis (since it is eczematous rather
animals, to humans, must be made with consider- than urticarial) but that this is uncertain and
able caution, because interspecies differences and diagnostic testing is best focused on the presence
variable exposure conditions that occur in the of specific IgE.
workplace exist. A range of enzymes have been reported in the
literature as a cause of immunologic contact urti-
caria and/or protein contact dermatitis. These are
5 Immunologic Contact Urticaria summarized with references in Table 1.
Diagnostic testing for possible immunologic
Exposure to enzyme proteins which can generate contact urticaria is well covered elsewhere
an IgE antibody response can, in theory, also (Amin et al. 2008b). In principle, a skin prick
produce immunologic contact urticaria. After test or serum-specific IgE immunoassays (e.g.,
all, this is the basis of the skin prick test for radioallergosorbent test (RAST) or enzyme-
diagnosis of IgE allergy, with the cutaneous allergo-sorbent test (EAST) or fluorescence-
weal and flare representing the urticarial enzyme-immunoassay (FEIA)) will give a fairly
response to local mast cell degranulation reliable indication of whether an individual
(Pepys 1972). However, it is well known that has become sensitized to a particular enzyme,
proteins struggle to pass the skin barrier, hence but caution must be exercised. The presence
628 D. A. Basketter and M. Raulf
of sensitization does not mean that urticaria and 7 Summary

dermatitis must follow. Consider the detergent
enzyme industry: despite stringent exposure con- Enzymes are a potential cause of immunologic con-
trols, such that airborne enzyme is in the very low tact urticaria and, at least for proteolytic enzymes,
ng/m3 region, there is still approaching a 10% also of skin irritation. The extent to which either of
prevalence of sensitization (Nicholson et al. these types of skin reaction occurs is likely to be
2001; Sarlo 2003; Basketter et al. 2010, 2015). extremely low where airborne exposure is properly
Where factories have not been in control, this controlled to minimize the risk of respiratory sensi-
level is even higher, such that asthma symptoms tization. Higher concentration contact, particularly
begin to appear (Cullinan et al. 2000). However, on damaged skin, is more likely to produce immu-
occupational skin disease due to enzymes in these nologic contact urticaria/protein contact dermatitis.
factory situations is almost unknown. So the At very high exposure levels, proteolytic enzymes
presence of enzyme-specific IgE will be a require- may well give rise to some degree of skin irritation.
ment for immunologic contact urticaria, but it is
probably far from an inevitable consequence.
Keep in mind too that skin prick testing with References
proteolytic enzymes (especially when using
Amaro C, Goossens A (2008) Immunological occupational
crude non-standardized enzymatic extracts) in contact urticaria and contact dermatitis from proteins:
particular carries an additional risk of false posi- a review. Contact Dermatitis 58:67–75
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(Simesen et al. 1976). Additionally, a significant and contact urticaria syndrome (immediate contact
reactions). In: Zhai H, Wilhelm K-P, Maibach HI
problem in correlating enzyme exposure with sen- (eds) Dermatotoxicology, 7th edn. CRC Press,
sitization has been the lack of (commercially) Boca Raton, pp 525–536
available test reagents for skin prick testing as Amin S, Lauerma A, Maibach HI (2008b) Diagnostic tests
well as for specific IgE determination. in dermatology: patch and photopatch testing and con-
tact urticaria. In: Zhai H, Wilhelm K-P, Maibach HI
(eds) Dermatotoxicology, 7th edn. CRC Press,
Boca Raton, pp 581–586
6 Skin Irritation Basketter DA, York M, McFadden JP et al (2004) Deter-
mination of skin irritation potential in the human 4-h
patch test. Contact Dermatitis 51:1–4
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α-amylase, a flour additive: an important cause of Zachariae H, Thomsen K, Rasmussen OG (1973) Occupa-
protein contact dermatitis in bakers. J Am Acad tional enzyme dermatitis. Results of patch testing with
Dermatol 29:723–728 Alcalase. Acta Derm Venereol 53:145–148
Nickel
43
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
3 Prevalence, Use, and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
3.1 In Nature and Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
3.2 Plating, Alloys, and Nickel Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
4 Health Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
4.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
4.2 Sensitizing Potency and Cross-Reactivity in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . 634
4.3 Sensitization and Prevalence of Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
4.4 Hand Eczema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
5 Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
5.1 The Dimethylglyoxime Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
5.2 Nickel Release in Artificial Sweat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
5.3 Skin Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
6 Occupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
6.1 Platers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
6.2 Electronics Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
6.3 Metalworkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
6.4 Hairdressers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
6.5 Car Mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
6.6 Construction Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
6.7 Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
6.8 Coins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
6.9 Cleaning, Domestic, and Hospital Wet Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
6.10 Miscellaneous Occupations and Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
7 Systemic Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
8 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
9 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
A. Julander (*) · C. Lidén

Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden
e-mail: anneli.julander@ki.se; carola.liden@ki.se

https://doi.org/10.1007/978-3-319-68617-2_43
632 A. Julander and C. Lidén
9.1 The EU Nickel Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642

9.2 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
9.3 Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
10 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Abstract 1 Core Messages

Nickel is the most frequent cause of contact
allergy, affecting up to 22% of women and 5% • Nickel is the most frequent cause of contact
of men, and hand eczema is reported by allergy, affecting up to 22% of women and 5%
30–40% of nickel-allergic individuals. Cer- of men in the general population. Certain occu-
tain occupational groups are much more pational groups are much more affected.
affected. Occupational skin exposure to • Hand eczema is reported by 30–40% of nickel-
nickel is an important risk factor for hand allergic persons. Occupational exposure to
eczema. Exposure reduction is essential for nickel is an important risk factor for hand
prevention. eczema.
Pure nickel metal, nickel-containing alloys, • Occupational nickel dermatitis usually pre-
coatings, and compounds have different ability sents as hand eczema. Exposure reduction is
to release nickel ions and to cause sensitization essential for the prognosis.
and dermatitis. The dimethylglyoxime test is • Pure nickel metal, nickel-containing alloys,
useful in assessment of nickel exposure and coatings, and compounds have different ability
exposure reduction in the workplace and else- to release nickel ions at skin contact and to
where. Skin exposure to nickel can be quanti- cause sensitization and dermatitis.
fied, and knowledge on exposure levels will • The dimethylglyoxime test for nickel ions is
contribute to improved risk assessment and very useful in assessment of nickel exposure
prevention. and exposure reduction in the workplace and
Nickel release from articles intended for pro- elsewhere.
longed contact with the skin is restricted in the • Skin exposure to nickel can now be quantified.
EU. In an attempt to improve protection, the Knowledge on exposure levels in different
European Chemicals Agency (ECHA) has occupations and in patients will contribute to
defined that “prolonged contact” in relation to improved risk assessment and prevention.
nickel is 10 min or more and has explained that • Nickel release from articles intended to come
the restriction covers articles for workers, pro- into direct and prolonged contact with the skin
fessionals, and consumers. It should be recalled is limited by the EU nickel restriction. Occu-
that also short and repetitive contact contributes pational exposure is now also covered.
significantly to nickel exposure.
Acid wipe sampling · Alloys · Cashiers ·
Coins · Construction workers · Nickel allergy is the most frequent contact allergy
Dimethylglyoxime test · DMG test · Nickel in the industrialized world and an important cause
directive · Exposure reduction · Hairdressers · of hand eczema. Nickel allergy predominantly
Metal workers · Nickel · Nickel release · affects young girls and women sensitized by jew-
Nickel restriction · Platers · Prevention · elry and other personal items, but various other
Exposure assessment · Stainless steel · Tools items do also cause sensitization and dermatitis. A
43 Nickel 633
hundred years ago, however, nickel dermatitis investigated concerning rate of nickel release,
was mainly an occupational disease affecting deposition on the skin, and ability to cause der-
men. Occupational exposure to this metal is still matitis. Some of the most relevant information is
of great importance for sensitization and elicita- summarized below.
tion and for maintaining hand eczema. Skin contact with homogeneous nickel, other
than with some coins, is not common. Many items
that are electroplated with nickel come into con-
3 Prevalence, Use, and Properties tact with the skin. Bright nickel plate contains
sulfur which facilitates the release of nickel ions.
3.1 In Nature and Production Nickel plate is often covered with a top coat of,
e.g., chromium, silver, gold, tin/nickel, or differ-
Nickel is present in the earth’s crust, occurs ent lacquers which, although reducing formation
naturally in drinking water and in food, and is of nickel ions, may not be adequate to prevent
possibly an essential nutrient for humans. Health contact dermatitis. Top coats often have pores or
problems are however not caused primarily by cracks and they are subject to wear. Nickel used as
the nickel in the natural environment but are an interliner under plating of gold, silver, or chro-
related to industrial activity and manufactured mium and nickel compounds used for various
items. Nickel (Ni) is a transitional metal with surface treatments (e.g., black nickel plating and
the atomic number 28. Ni (0) in metal nickel cold sealing of aluminum) cause nickel release
and its alloys and Ni (II) in nickel salts and stable and dermatitis (Lidén 1994a; Lidén et al. 1996).
inorganic compounds are the most prevalent oxi- A broad spectrum of nickel-containing alloys is
dation states. Numerous nickel salts and sulfides produced. Common examples are stainless steels
with different properties and uses are known. (iron/nickel/chromium), copper-nickel, and nickel-
Nickel ions are formed when metallic nickel is silver (nickel/copper/zinc). Brass (copper/zinc) and
in contact with, e.g., sweat. red gold (gold/silver/copper) are examples of
Nickel is today the fourth most-used metal nickel-free alloys. Alloys are compounds or solid
after iron, chromium, and lead. During the nine- solutions of more than one element in metallic form
teenth century, white nickel-containing alloys but cannot be considered as mixtures of the metals.
were produced in Europe as substitutes for silver, Resistance to corrosion upon skin contact varies
and around 1870, the use of nickel in steels and widely between different nickel-containing alloys
platings started. Nickel production has increased depending on their composition.
considerably since 1940, and, today, two thirds Most stainless steels have a low rate of nickel
of the production is used in stainless steels. release, and they are unlikely to cause allergic
Nickel is used in numerous alloys and coatings contact dermatitis. Copper-nickel, nickel-silver
and in chemical compounds. It is also used in (nickel/copper/zinc), and nickel-brass (copper/
products for occupational and private use, many zinc/nickel) are examples of nickel-containing
of which may come into contact with the skin alloys with very high rate of nickel release in
(Flint 1998; Lidén 2018; Lidén et al. 2011). sweat. Significant amounts of nickel can be depos-
ited onto the skin by repeated contact of short
duration (seconds) with such materials, explaining
3.2 Plating, Alloys, and Nickel why, e.g., coin handling can cause nickel dermatitis
Release (Erfani et al. 2015; Julander et al. 2013; Lidén and
Carter 2001; Thyssen et al. 2013).
Metallurgical aspects of nickel and the corrosion There is no relationship between the content of
of nickel-containing materials in contact with nickel in an alloy and its ability to cause an aller-
sweat have been reviewed (Flint 1998). Various gic reaction, while there is a close relationship
nickel-containing materials have been between the rate at which ions form from nickel
in contact with sweat and the potential to cause a cross-challenge experiments have been
reaction. This fact may be difficult to understand carried out in guinea pigs (Lidén and Wahlberg
and has caused demands for “nickel-free” items 1994; Wahlberg and Boman 1992; Wahlberg
instead of the generally more relevant demand for and Lidén 2000). It appears that the reactivity
“low nickel release.” to nickel and palladium is due to cross-
reactivity, while cross-reactivity is not probable
for nickel and cobalt or nickel and chromium
4 Health Effects (chromate).
4.1 Toxicology
The major health effect of nickel and its 4.3 Sensitization and Prevalence
compounds is contact allergy and allergic of Allergy
contact dermatitis as a result of skin exposure
to nickel ions, Ni (II). Inhalation exposure to Sensitization to nickel is caused by soluble
soluble nickel and nickel oxides/sulfides has nickel deposited onto the skin, often skin contact
caused nasal and pulmonary cancer in workers with solid items that release nickel ions. The
in nickel refineries. Exposure to nickel or nickel major causes of sensitization and elicitation
compounds via routes other than inhalation vary depending on fashion, materials, and
has not been shown to increase the cancer risk other factors which influence exposure. Cheap
in humans. The overall evaluation by IARC is jewelry and piercing are often focused,
that nickel compounds are carcinogenic to but nickel allergy is also common among people
humans (Group 1) and that metallic nickel and without piercings. Precious metal jewelry,
alloys are possibly carcinogenic to humans watches, spectacle frames, buckets, zips, elec-
(Group 2B) (International Agency for Research tronic equipment, and toys are other important
on Cancer and 2017). Inhalation of nickel causes. The role of occupational exposure in
compounds may induce asthma. Nickel-induced sensitization and elicitation of nickel dermatitis
asthma, however, is rare. Nickel and numerous is discussed below.
nickel compounds are classified according to The prevalence of nickel allergy varies
the CLP as hazardous to health (classifications between genders, age groups, countries, and
include Skin Sens. 1 H317, Resp. Sens. over time (Ahlström et al. 2017; Lidén 2018). A
1 H334, and Carc. 1A H351i) and to the envi- recent epidemiological study by patch testing of
ronment (European Chemicals Agency and the general population in Europe has shown that
2017). up to 22% of women and 5% of men are allergic to
nickel (Diepgen et al. 2016). See further Table 1.
Nickel allergy increased significantly between
4.2 Sensitizing Potency and Cross- the 1960s and the 1990s (Thyssen et al. 2007).
Reactivity in Animals Nickel allergy has generally been more frequent
in younger women compared to older women,
Nickel is a moderate or weak sensitizer, but a decrease in nickel allergy is now being
according to predictive studies in guinea indicated among younger females in Denmark
pigs (guinea pig maximization test, GPMT) and some other EU countries, in both the popula-
and in mice (local lymph node assay, tion and among dermatitis patients. This is
LLNA, and other test methods) (Basketter et al. probably a result of the EU nickel restriction
1994; Wahlberg 1989; Vennegaard et al. (Table 2) and, in Denmark, also the preceding
2014). To better understand the simultaneous Danish regulation (Ahlström et al. 2017; Fall
patch test reactivity to metals and possible et al. 2015; Garg et al. 2013). The prevalence
cross-reactivity often recorded in humans, of nickel allergy in patch-tested dermatitis
43 Nickel 635
Table 1 Prevalence of nickel allergy in the general population and in dermatitis patients. Examples of recent studies to
illustrate differences between genders and countries or regions
Nickel allergy
Total Men Women
Study population, period (no. tested) (%) (%) (%) References
General population
Denmark, 2006–2008 (n = 3460) 5.9 1.0 9.9 Thyssen et al.
(2009b)
5 European countries, 2008–2011 (n = 3119) 14.5 5.2 22.2 Diepgen et al.
Germany (n = 1024) 13.9 – – (2016)
Italy (n = 546) 16.4 – –
Portugal (n = 531) 18.5 – –
Sweden (n = 518) 8.3 – –
The Netherlands (n = 500) 15.8 – –
Sweden, 2011–2013 (n = 2236)a 7.5 4.9 9.8 Lagrelius et al. 2016
Thailand (n = 1397)b 27.8 3.9 33.8 White et al. (2007)
Dermatitis patients
4 European countries, 1985–2010 (n = 180,390) Garg et al. (2013)
Denmark, 1985–2010 (n = 19,828) 12.3 3.1 17.4
Germany, 1995–2010 (n = 104,933) 13.6 5.1 18.9
Italy, 1997–2010 (n = 20,231) 25.0 10.8 31.9
UK, 2002–2010 (n = 35,398) 17.7 6.2 23.4
12 European countries (ESSCA), 2009–2012 19.7 – – Uter et al. (2016)
(n = 56,761)
North America, 2013–2014 (n = 4850) 20.1 – – DeKoven et al.
(2017)
Sweden, 2008–2010 (n = 3112) 17.6 7.0 26.7 Fall et al. (2015)
– Results not divided by gender
a
Adolescents
b
Test period not reported
patients varies widely. A selection of publications Most people, in daily life and in many jobs,
from different parts of the world and different time have repeated contact with coins, electronic
periods is listed in Table 1 showing prevalence equipment, handles, keys, scissors, tools, and
rates of 17–32% in female patients and 3–11% in various other items that may release nickel. Wet
male patients. work and other irritant factors impair the skin
barrier function and facilitate the penetration of
nickel and other allergens into the skin. These
4.4 Hand Eczema factors contribute to the development of hand
eczema.
Nickel-sensitive people run a considerably To what extent atopic dermatitis, filaggrin
increased risk of developing hand eczema gene mutations, and epigenetic regulation
(Lidén et al. 2011). Approximately 30–40% of may affect nickel sensitization and nickel
nickel-sensitive persons report that they ever dermatitis remains to be further elucidated,
have experienced hand eczema versus approxi- as it may be of high clinical relevance
mately 15–20% among non-nickel-sensitive (Friedmann et al. 2015; Martin 2015; Thyssen
controls (Meding et al. 2001; Menné et al. et al. 2014). Dietary intake of nickel has by
1982; Peltonen 1979). Figures from dermatol- some authors been proposed to be of significant
ogy departments on hand eczema in nickel- importance for hand eczema, but this issue is
sensitive patients vary between 20% and 60%. controversial.
Table 2 Summary of the EU nickel restriction, as by 2004, and is from 2009 part of REACH (EC 1907/2006).
2017. The Nickel Directive (94/27/EC) was adopted in The scope was broadened in 2014 by the definition of
1994, entered into full force in 2001, was amended in prolonged contact with the skin
EU nickel restriction and related documents References
Nickel shall not be used European Commission (2009)
(a) In any post assemblies inserted into pierced parts of the body if nickel
release is >0.2 μg/cm2/week
(b) In articles intended to come into direct and prolonged contact with the
skin such as earrings, necklaces, wristwatch cases, watch straps, buttons, zips,
if nickel release is >0.5 μg nickel/cm2/week
(c) In coated articles in point (b), unless the coating is sufficient to ensure
that the nickel release will not exceed 0.5 μg nickel/cm2/week after 2 years of
normal use
CEN standards to show conformity with the restriction European Committee for
EN 1811 (nickel release in artificial sweat)a; EN 12472 (wear and corrosion Standardization (2009), (2015))
test)a
Definition by ECHA of “prolonged contact with the skin” in relation to the European Chemicals Agency (2014),
nickel restriction (2017a)
Potentially more than 10 min on three or more occasions within 2 weeks or
30 min on one or more occasions within 2 weeks
Draft guideline with examples of article types; articles for workers,
professionals, and consumers are covered by the restriction
CEN European Committee for Standardization, ECHA European Chemicals Agency, REACH Regulation on the Regis-
tration, Evaluation, Authorisation and Restriction of Chemicals
a
First version published 1998
occupational hygienists, and occupational

5 Exposure Assessment
health services, and it is recommended to
nickel-allergic patients for identification of
5.1 The Dimethylglyoxime Test
nickel and exposure reduction. The DMG
test has also been used in surveys of nickel
The dimethylglyoxime (DMG) test is a simple spot
release from handheld tools and various
test to visualize the presence of nickel ions (Feigl
consumer articles on the market (Biesterbos
1972). The test is based on DMG in ethanol and
et al. 2010; Kickinger-Lörsch et al. 2015; Lidén
ammonia. A cotton wool-tipped stick moistened by
et al. 1998; Ringborg et al. 2016; Thyssen et al.
one to two drops of the solution is rubbed for up to
2011a).
20 s against the surface to be tested. A pink-red color
indicates presence of nickel ions. In many countries,
the DMG test is commercially available, and alter-
native preparations exist. The DMG test has been 5.2 Nickel Release in Artificial
validated against nickel release in artificial sweat (see Sweat
below). The specificity is high, but the sensitivity is
modest in the range of the limit values of the EU Nickel release may be quantitatively determined by
nickel restriction (0.2 and 0.5 μg/cm2/week) (Thys- immersing items in artificial sweat at 30 C for
sen et al. 2010). The DMG test has been standardized 1 week and analyzing nickel in the solution at the
for use as a screening test in relation to the EU nickel end of the period (European Committee for Stan-
restriction (European Committee for Standardization dardization 2015). Analysis may be carried out
2002; German Institute for Standardization 2017). with inductively coupled plasma (ICP) detection
The DMG test is a very useful tool for screen- or with atomic absorption spectrometry (AAS).
ing purposes. It is used by dermatologists, Nickel release of 0.2 and 0.5 μg/cm2/week,
43 Nickel 637
respectively, are the limits of the EU nickel restric- Immersion of fingers in water has been used for
tion (Table 2). The CEN standard, EN 1811, assessment of exposure to nickel in some occupa-
was developed to meet the needs of controlling tions, showing exposure levels comparable to acid
compliance with the EU nickel restriction. By wipe sampling (Table 3) (Gawkrodger et al.
shorter duration of immersion in artificial sweat, 2012). The DMG test may be used for semiquan-
it has been shown that some alloys have a very titative assessment of nickel on the skin (Julander
high nickel-release rate and thus release substan- et al. 2011). Tape stripping has been used for
tial amounts of nickel within minutes or hours studies of how nickel is adsorbed in the skin
(Erfani et al. 2015; Julander et al. 2013; Lidén (Hostynek et al. 2001).
and Carter 2001). This is important for under-
standing why also brief and repeated skin contact
with coins, tools, and other items may result in 6 Occupational Exposure
sufficient nickel exposure to cause dermatitis,
while the EU nickel restriction covers items Some examples of jobs and exposures with risk of
intended for direct and prolonged contact occupational contact dermatitis due to nickel are
(Table 2). described below and in Table 4. It has been esti-
mated, based on occupational skin disease data in
UK surveillance schemes, that up to 12% of all
5.3 Skin Exposure Assessment cases of occupational skin disease were due in part
to nickel (Shum et al. 2003). Knowledge about
Increasing attention has been given development skin exposure levels in occupations, workplaces,
of methods for skin exposure assessment. and individual cases, and of nickel release from
Methods for sampling by different removal tech- surfaces, is crucial for assessment of risks and
niques (wipe sampling, rinsing, and tape strip- prevention but is largely lacking. Methods for
ping) have been developed and used in studies skin exposure assessment are now available (see
of occupational exposure to nickel (Julander Sect. 5).
et al. 2018).
Acid wipe sampling was developed for assess-
ment of nickel, chromium, and cobalt deposited 6.1 Platers
onto the skin (Lidén et al. 2006). Sampling is
performed by wiping demarked areas with dilute Dermatitis due to nickel exposure was reported
nitric acid (1%) before and after the work session among platers in 1889, and up to 1930, nickel
for exposure, and analysis is performed with dermatitis was a frequent male occupational dis-
ICP-MS or other suitable equipment. The method ease in the plating industry (Blaschko 1889;
has very high sampling efficiency and recovery Schwartz et al. 1957). Since then, improved
(>90%), and the mass per area unit (e.g. μg/cm2) industrial hygiene and technical development
may be calculated. Acid wipe sampling has been have decreased the risk. Much of the work may
used to assess skin exposure to nickel in work- today be automated, but handling of hot nickel salt
place studies, in experimental studies, and in solutions and heavy contamination of the work
patients with nickel allergy and work-related environment, skin, working clothes, and protec-
hand eczema (Jensen et al. 2011; Julander et al. tive gloves are still prevalent. While this consti-
2010, 2013; Lidén et al. 2008a, b). Substantial tutes a significant risk of sensitization, reports of
amounts of nickel have been shown to be depos- nickel sensitivity in the electroplating industry
ited onto the hands of, e.g., cashiers, locksmiths, since 1960 have been sparse.
and metal workers, but not of office staff An outbreak of occupational dermatitis in
(Table 3). A simplified method for self-sampling an electroforming plant in the UK was due to
by a swab has recently been published (Erfani heavy nickel exposure (Wall and Calnan 1980).
et al. 2017). Almost half the workers were allergic to nickel
Table 3 Amount of nickel deposited on hands in different occupations and in nickel dermatitis patients. Assessed by
sampling after 1–2 h of regular work
Sampling Skin surface dose of nickel (μg/cm2)a
Group method and range or SD References
Carpenters (n = 4) AWS 0.25 (range 0.09–0.38) Lidén et al.
(2008a)
Cashiers (n = 7) AWS 0.27 (range 0.09–0.59) Lidén et al.
(2008a)
Cashiers (n = 7) FI 0.15 (SD 0.092) Gawkrodger
et al. (2012)
Electroplaters (n = 5) FI 1.82 (SD 1.230) Gawkrodger
et al. (2012)
Locksmiths (n = 3) AWS 0.82 (range 0.73–0.97) Lidén et al.
(2008a)
Metalworkers
Tools sharpening (n = 8) AWS 0.04 (range 0.02–0.14) Julander et al.
(2010)
Components, various tasks (n = 8) AWS 0.54 (range 0.24–3.2) Julander et al.
(2010)
Thermal application (n = 8) AWS 0.62 (range 0.03–15) Julander et al.
(2010)
Office staff (n = 4) AWS 0.02 (range 0.01–0.03) Lidén et al.
(2008a)
Office staff (n = 5) FI 0.06 (SD 0.021) Gawkrodger
et al. (2012)
Nickel-allergic patients with work-related AWS 0.13 (range 0.05–0.29) Jensen et al.
hand eczema (n = 6) (2011)
AWS acid wipe sampling, FI finger immersion, range minimum – maximum, SD standard deviation
a
Generally mean value on index finger and possibly additional surfaces; see original publications for details
(Table 4). Improvement in industrial hygiene led occupational dermatology patients were from the
to an immediate decrease in the incidence of electronics industry, and one third of the patients
dermatitis. were patch test positive to nickel (Table 4)
A work site survey was carried out in all (Tan et al. 1997). Sources of contact included
38 Finnish electroplating plants (Kanerva et al. nickel-plated earthing straps, nickel-plated tools,
1997). Nickel allergy was found at the same fre- and coolants.
quency as in Finnish dermatitis patients (Table 4).
Seventy percent of those with nickel allergy
reported past or present hand eczema. Sensitized 6.3 Metalworkers
workers were often able to continue their work in
the electroplating industry. Metalworkers are often heavily exposed to
cutting fluids and cutting oils, and they are
at high risk of developing irritant and allergic
6.2 Electronics Industry contact dermatitis due to additives in the fluids
(biocides, antioxidants, fragrances, tall oil rosin)
Workers in the electronics industry are exposed to and to nickel and other sensitizing metals in
skin irritants and contact allergens, among them the materials and equipment they are handling.
nickel, colophony (rosin) in soldering flux, rubber The role of contamination of recirculating
chemicals, epoxy, and acrylates (Koh et al. 1990; fluids by metals, including nickel, has been
Shiao et al. 2004). In Singapore, 24% of discussed and may be of some importance. Skin
43 Nickel 639
Table 4 Prevalence of nickel allergy in selected occupational groups according to epidemiological and workplace
(non-patient) studies and among dermatitis patients, examples
Nickel allergy
Total Men Women
Study population (%)a (%) (%) References
Workers (non-patients)
Car mechanics, Sweden (n = 105 with self-reported – 7.6 – Meding et al. (1994)
hand eczema)
Electroforming plant workers, UK (n = 27) – 48 – Wall and Calnan
(1980)
Electronics workers, Taiwan (n = 183 with self-reported 16 – – Shiao et al. (2004)
hand eczema)
Electroplaters, Finland (n = 103) – 4 15 Kanerva et al. (1997)
Dermatitis patients
Cleaners, Germany (n = 803) – – 28.2 Liskowsky et al.
(2011)
Construction workers, Spain (n = 408) – 10 – Conde-Salazar et al.
(1995)
Construction workers, Germany (n = 322) – 7.5 – Geier and Schnuch
(1998)
Electronics industry workers, Singapore (n = 149, 57% 32.8 – – Tan et al. (1997)
male)
Hairdressers, Spain (n = 300, 93% female) 37.0 – – Valks et al. (2005)
Hairdressers, UK (n = 725, 91% female) 32.1 – – O’Connell et al.
(2010)
Hairdressers, Denmark (n = 399, 96% female) 21.4 – – Schwensen et al.
(2014)
Mechanics/repairers, North America (n = 272, 94% 4.8 – – DeKoven et al.
male) (2017)
a
Results not reported by gender
exposure to metals has been assessed among was focused by Wahlberg (1975), who reported
metalworkers, and the exposure to nickel was 40% nickel allergy among hairdresser patients
high compared to other studied occupations. It with hand eczema. Results from patch testing
varied considerably between departments, of hairdressers have since been published,
tasks, and individuals (Table 3) (Julander et al. some shown in Table 4. The prevalence of
2010). Nickel allergy was significantly associ- nickel allergy has varied considerably but often
ated with metal and mechanical work been higher in hairdressers than in other
among female dermatitis patients in Italy (Rui dermatitis patients or in the general population.
et al. 2010). The highest incidence rate of occupational
skin disease due to nickel was seen in hair-
dressers (23.9/100,000 workers/year) (Shum
6.4 Hairdressers et al. 2003). It has sometimes been suggested
that the high prevalence of nickel allergy
Hairdressers are highly exposed to wet work, among hairdressers is due to other factors
nickel, fragrances, preservatives, hair dyes, than occupational exposure. In an individual
and various specific occupational allergens. case, it must, however, be recognized that
These factors are responsible for the high occupational nickel exposure might be an
prevalence of hand eczema among hair- important factor contributing to or causing the
dressers. Nickel allergy among hairdressers hairdressers’ hand eczema.
6.5 Car Mechanics known to elicit nickel dermatitis in workers

using tools (Table 3) (Jensen et al. 2011; Lidén
Car mechanics have a high prevalence of hand et al. 2008a).
eczema, often related to irritants such as organic No relevant information concerning nickel
solvents and oils. In an epidemiological study of release or composition of the materials in tools
hand eczema, a high prevalence of nickel allergy is available for workers, consumers, or retailers.
was found (Meding et al. 1994). Eight percent of Now, when the EU nickel restriction has been
the car mechanics with self-reported hand eczema sharpened by the definition of prolonged contact,
were patch test positive to nickel (Table 4). Han- many tool types will be covered by the restriction
dling of tools with nickel release was suggested as (Table 2) (see Sects. 9 and 9.1). It seems reason-
a contributing factor. able that existing high-nickel-releasing tools in
workplaces should be phased out, for protection
of the health of workers.
6.6 Construction Workers
Construction workers risk occupational contact 6.8 Coins

dermatitis from exposure to irritants, chromate,
cobalt, rubber, and epoxy. Nickel allergy, how- Hand eczema in nickel-sensitive cashiers is a
ever, is not often discussed in relation to construc- problem in clinical occupational dermatology.
tion work (Coenraads et al. 1984). Nickel allergy Coins may cause or aggravate hand eczema
has been more frequent among dermatitis patients among cashiers, other professionals, and con-
who are construction workers than among many sumers with nickel allergy, owing to the ability
other male dermatitis patients (Table 4). Sources of many coin materials to release nickel and con-
of nickel exposure in plumbers, carpenters, lock- taminate the skin by repeated contact (Thyssen
smiths, or electricians, shown by a positive DMG et al. 2013).
test, include tools, pipes, locks, and other items Copper-nickel is the most frequently used
(Lidén 1994b; Lidén et al. 1998). It has been coin alloy, and other frequent high-nickel-
shown that large amounts of nickel are deposited release coins are nickel-plated steel and nickel-
onto the skin in locksmiths and carpenters brass. Approximately 40% of circulating
performing their normal tasks (Table 3) (Lidén coin denominations worldwide, however, do
et al. 2008a). not release nickel (Hamann et al. 2013).
The Euro coinage consists of six nickel-free
cent coins and two Euro coins made of nickel-
6.7 Tools containing alloys (copper-nickel combined
with nickel-brass). In the UK, new high-nickel-
Handheld tools are used in many occupations. release coins recently were introduced, while
Metal parts may come into repeated contact with all Swedish coinage from 2017 is nickel-free
the skin, often under friction and wet conditions. (Julander et al. 2013).
The Swedish tool market was surveyed to study Nickel ions are readily available on the
the prevalence of unused tools that release nickel, surface of coins, and several μg of nickel
and a similar study was performed in Germany may be transferred daily to hands by intense
(Kickinger-Lörsch et al. 2015; Lidén et al. 1998). handling of high-nickel-releasing coins, as
Twenty-seven percent of 565 handheld tools with shown by controlled exposure and also in
metal parts that come into contact with the skin cashiers performing their normal tasks (Table 3)
were DMG test positive in Sweden and 33% of (Gawkrodger et al. 2012; Julander et al. 2013;
600 in Germany. Such tools may cause nickel Lidén et al. 2008a, b). Provocation studies by
allergy and dermatitis, and it has been shown coin handling have been performed, with differ-
that nickel is deposited onto the skin at levels ent outcome.
43 Nickel 641
6.9 Cleaning, Domestic, lip dermatitis (Gambichler et al. 2004). Tailors and
and Hospital Wet Work dressmakers are exposed to needles and scissors,
some of which release much nickel. Guards, nurs-
Hand eczema is common among people in wet ing personnel, and many office workers often han-
work in hospitals, cleaning and domestic work, dle keys, some of which are special keys that may
especially among nickel-sensitive individuals. be difficult to substitute.
Water and detergents are important skin irritants, It is important to identify the causes of expo-
and nickel release from frequently handled equip- sure and dermatitis and to substitute them with
ment, handles, keys, and tools may contribute to alternatives without nickel release. The DMG test
the hand eczema. Nickel allergy was significantly is of great help in this. It is likewise considered
more frequent in female cleaners with occupa- important to perform skin exposure assessments
tional dermatitis compared with female controls in individual cases, to support conclusions on
without occupational dermatitis; moreover, nickel cause-effect relationships between dermatitis and
allergy was more frequent in females with occu- occupational exposure in nickel allergy.
pational dermatitis independently of occupation
(Table 4) (Liskowsky et al. 2011).
7 Systemic Exposure
6.10 Miscellaneous Occupations The role of nickel in diet, surgical implants, and
and Exposures dental materials remains controversial and is
reviewed elsewhere (Chen and Thyssen 2018;
There are numerous case reports on occupational Veien and Menné 2011).
nickel dermatitis among workers in different
occupations (Fischer 1989; Lidén et al. 2011). In
the individual case, there has often been a con- 8 Diagnosis
vincing relationship between occupational nickel
exposure and dermatitis, sometimes also between Nickel sulfate 5% in petrolatum is the test material in
the exposure and primary sensitization. the European baseline series. Nickel sulfate 2.5% is
It is important to consider that brief and used in North America. The ready-to-use patch test
repeated contact with items, not only contact of system TRUE Test® does also contain a nickel patch.
long duration, may contribute significantly to Patch testing with serial dilution of nickel sul-
nickel exposure (Erfani et al. 2015). It is also fate or with nickel chloride is sometimes used to
important to consider common contacts and not gain more information on the degree of sensitivity
only contact with occupation-specific items and and to discriminate between allergic reactions and
materials. The list of examples may be extensive. irritant ones (Johansen et al. 2015). The propor-
Examples are given below, to display the broad tion of irritant or doubtful patch test reactions to
spectrum of potential hazards, which may not be nickel is low, compared with other metals (Lidén
shown by epidemiological studies. et al. 2016; Warshaw et al. 2010). Open tests to
Coins, handles, keys, mobile phones and other study the elicitation threshold have been carried
electronic equipment, pens, scissors, and other out with nickel sulfate or chloride as single or
tools are just few examples of items that are han- repeated applications (Fischer et al. 2007).
dled frequently in many occupations and that may Patch testing with metal discs of different
cause nickel dermatitis. In restaurants, kitchen, and nickel-containing materials may be used as a sup-
bars, the employees may be exposed to nickel from plement to the analysis of metal release in artificial
coins, cutlery, handles, kitchen utensils, openers, sweat. This will give information about the ability
and water taps. Musicians may be intensely of the materials to cause allergic contact dermatitis
exposed to nickel by parts of string instruments, (Haudrechy et al. 1997; Lidén et al. 1996; Menné
wind and brass instruments, which also may cause et al. 1987).
9 Prevention exposure reduction. People with contact dermati-

tis due to nickel allergy should minimize exposure
9.1 The EU Nickel Restriction to nickel, including personal items and exposure
in the workplace and during leisure. Nickel-
The European Union decided in 1994 on a legisla- sensitive people and occupational health care
tion aiming at the prevention of nickel allergy, the may identify objects in the workplace with
Nickel Directive. It entered into full force in 2001 which skin contact should be avoided and which
and has since been slightly revised (Table 2) (Thys- should possibly be exchanged for other materials.
sen et al. 2011b). It limits nickel release from articles
intended for direct and prolonged contact with the
skin. The aim was to prevent both sensitization and 9.3 Protection
elicitation, initially by focusing certain consumer
articles. Until now, several studies indicate that the Protective gloves and clothing may be heavily
legislation has started to give some positive effects contaminated by soluble nickel salts, especially
by reduction of exposure and disease. New cases of in platers and battery workers. Good occupational
nickel allergy are less frequent among younger hygiene is of great importance in these kinds of
women than before the regulation, and the relation- job, as shown by the history of nickel dermatitis.
ship between nickel allergy and hand eczema has Workers handling metallic items may use protec-
weakened in some countries (Ahlström et al. 2017). tive gloves of fabric, leather, rubber, or plastic, but
It is known that nickel release from certain consumer contamination as well as possible penetration of
articles has decreased on the market in Sweden, nickel ions must not be forgotten. Barrier creams
where it has been followed (Biesterbos et al. 2010). have until now been of limited value in preventing
The need to sharpen the EU nickel restriction, nickel dermatitis. Possibly useful preparations,
for more efficient prevention, is obvious. The with a specific protective effect against nickel,
European Chemicals Agency (ECHA) has there- will be presented in the future.
fore defined what shall be understood by “pro-
longed contact” (Table 2). ECHA has also drafted
a guideline explaining that the restriction covers 10 Prognosis
articles for workers, professionals, and consumers,
with examples of article types, including handheld Many mild cases of nickel dermatitis will clear,
equipment, handles, keys, musical instruments, when exposure to the causative object(s) is avoided
tools, and utensils. Articles in short (less than and by topical treatment. Hand eczema in nickel-
10 min) but repeated contact with the skin, includ- sensitive patients is however considered to have a
ing coins and kitchen utensils, are according to the poor prognosis and may in some cases be resistant
draft guideline outside the scope of the restriction to treatment and persist for years. This may be the
(European Chemicals Agency 2014, 2017a). case when occupational exposure is massive or
Nickel allergy is still the most frequent contact difficult to avoid or combined with wet work
allergy worldwide, causing hand eczema and suf- (Lidén et al. 2011). Recurrent vesicular hand
fering in large parts of the population. Hopefully eczema is frequent in patients with nickel allergy
countries outside the EU will implement similar (Boonstra et al. 2015). Nickel dermatitis has been
legislation for prevention of nickel allergy. the second most common dermatological disease in
Denmark, after irritant contact dermatitis, giving
rise to compensation for occupational skin disease.
9.2 Elimination Studies in Denmark indicate that the prognosis
now is more favorable and that the relationship
The DMG test presents a cheap, simple, and pow- between nickel allergy and hand eczema has
erful tool for prevention of nickel dermatitis by weakened (Thyssen et al. 2009a). In a 20-year
43 Nickel 643
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Chromium
44
John Havens Cary, Howard I. Maibach,
Desmond Burrows, and Jurij J. Hostynek
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
2 Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
3 Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
3.1 Chrome Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
4 Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
4.1 Irritant Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
4.2 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
4.3 Patch Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
5 Incidence of Chromate Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
6 Exposure to Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
6.1 Cement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
6.2 Anticorrosion Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
6.3 Welding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
6.4 Leather . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
6.5 Chrome Plating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
6.6 Galvanizing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
6.7 Pigments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
6.8 Printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
6.9 Stainless Steel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
6.10 Bleaches and Detergents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
J. H. Cary (*)
Louisiana State University School of Medicine, New
Orleans, LA, USA
e-mail: havenscary@gmail.com
H. I. Maibach (*) ·
D. Burrows · J. J. Hostynek
e-mail: Howard.Maibach@ucsf.edu;
howard.maibach@ucsf.edu; jurijj@hotmail.com

https://doi.org/10.1007/978-3-319-68617-2_44
648 J. H. Cary et al.
6.11 Other Sources of Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654

7 Detection of Chromate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
7.1 Spot Test for Detection of Hexavalent Chromium (Chromate) . . . . . . . . . . . . . . . . . 654
7.2 Acid Wipe Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
8 Photosensitivity and Chrome Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
9 Effect of Systemic Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
10 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
11 Change of Occupation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
12 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
12.1 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Keywords 2 Chromium
Chromium allergy · Chromate allergy · Cr
(VI) · Cr(III) Chromium is a metallic element commonly found
in the environment. Cement was one of the earli-
est agents incriminated in the causation of chro-
1 Core Messages mate dermatitis, with a high incidence among
construction workers handling wet cement. Expo-
• Hexavalent chromium (salt) is a form sure to chromium may be occupational or house-
of chromium responsible for sensitization and hold with the skin and mucous membranes both
contact dermatitis in chromate allergy. being affected. The risk of exposure to chromium
• Exposure to chromium is often is high among other industries/professions such
occupational and is commonly seen among as leather tanning, chrome plating, welding,
building workers handling cement, carpentry (handling of chromated metal
leather workers, electroplaters, welders, and products: screws and fittings), painting
painters. (also water coolants), and printing. In susceptible
• Addition of ferrous sulfate has reduced individuals, bleaches and detergents and stainless
the incidence of chromate allergy in the steel utensils containing chromium may also be
Scandinavian countries, since it decreases the potential causes of chromate sensitization.
concentration of hexavalent chromate in cement. Chromium is derived from the Greek word
• Simple office-based tests are helpful in “chroma” meaning “color” due to the brightness
detecting chromium in objects. of many of its salts. Chromium can occur in
• Patch testing with chromate (in chromium- every one of the oxidation states from 2 to
sensitive subjects) to detect the minimum +6, but the ground states 0, +2, +3, and + 6
elicitation threshold (MET) is best are common (Love 1983). The metal chromium
done by using serial dilutions of Cr(III) and in itself does not act as an allergen but does
Cr(VI). so in combination with a protein. Only the triva-
• Chromium can cause lipid peroxida- lent and hexavalent salts are able to act as
tion, nephrotoxicity, and affect the immune haptens and form potentially antigenic bonds
system. with proteins. Chromium is highly resistant
• Reduction or elimination of exposure is the to corrosion in the atmosphere and many aque-
best method for prevention of chromium- ous solutions and is, thus, an unlikely cause of
induced contact allergy. contact allergy.
44 Chromium 649
3 Toxicity 4 Contact Dermatitis
While trivalent chromate is not considered toxic, 4.1 Irritant Contact Dermatitis
hexavalent chromate has significant toxic effects.
In sufficient concentrations, it can cause respira- Irritant dermatitis is seen particularly in individuals
tory symptoms such as bronchitis (Langard 1983) with high chromium exposure in the workplace.
and asthma (Fernandez-Nieto et al. 2006), irritant
dermatitis and chrome ulcers of the skin and
mucous membranes, affect the immune system 4.2 Allergic Contact Dermatitis
(Snyder et al. 1996), and also induce cancer, par-
ticularly of the lung (Bidstrup 1983). Dermatitis occurs more commonly with Cr(VI)
Its effects on the immune system are demon- than Cr(III) chromate. Cr(III) binds very readily
strated by the significantly lower levels of IL-6 in to protein and thus penetrates the skin poorly;
workers exposed to chromium, as compared to the little trivalent chromate gets past the stratum
normal population (Snyder et al. 1996). However, it corneum. On the other hand, Cr(VI) penetrates
was found that exposure to Cr(VI) in early stages easily and deeply into the dermis where it is trans-
can stimulate IL-6 and IL-8 and cause a fall in the formed to Cr(III), which results in the formation
percentage of B-cells (Kuo and Wu 2002). of hapten-protein complex capable of being pro-
cessed as an allergen. Guinea pig sensitization
3.1 Chrome Ulcers with Cr(III) is difficult; however, once sensitized,
they react to patch testing in a similar fashion to
The most common symptoms associated with the those sensitized with Cr(VI) (Polak 1983).
irritant effect of chromates are chrome ulcers/holes
occurring on the skin (cement workers) or nasal
septum (electroplaters and lithographers). The ulcers 4.3 Patch Testing
occur as 2–5 mm punched out lesions that heal with
scarring, when the patient is removed from the The standard test material is potassium dichro-
source. Necrosis of cartilage (but not bone) can mate in petrolatum (0.5%, Europe; 0.25%,
ensue but malignant change does not occur (Wil- USA). At these concentrations, contact allergy
liams 1997). can be elicited despite being close to the concen-
In 1978, there were about 100 reported cases of tration at which irritant reactions occur (Burrows
chrome ulcers occurring in the UK (Burrows 1978). 1987). While patch testing with 0.5% and 0.375%
The ulcer is formed due to the toxic necrotizing potassium dichromate will produce a similar num-
action of chromium on tissue. A recent report dem- ber of irritant reactions, patch testing with lower
onstrated that Cr(VI) causes mitochondrial-depen- percentages will produce fewer irritant reactions
dent apoptosis of the dermal fibroblasts by but may potentially miss some allergic reactions
disrupting their actin cytoskeleton (Rudolf et al. (Burrows et al. 1989). Consequently, 0.25% is
2005), contributing to the formation of an ulcer. In probably a safer percentage in the hands of those
addition, workers prone to ulcer formation seem to lacking experience in patch testing.
have a lower incidence of allergic contact dermatitis A population-based, serial dilutions patch test-
(Walsh 1953). This is probably because the ulcer ing method (Fig. 1) demonstrating the wide range
impairs the ability of the skin to mount an immune in patient/worker sensitivity has been published
response. (Nethercott et al. 1994). This method implements
An active program of reducing chromate con- the delivery of a controlled amount of allergen per
tamination at workplaces can significantly reduce surface area of skin, for determination of the
the incidence of chrome ulcers (Dornan 1981; minimum elicitation threshold (MET). The high
Williams 1997). water solubility of compounds K2Cr2O7 [Cr(VI)]
Serial dilution patch test method for chromate allergy (determination of the minimal elicitation threshold, MET, for Cr(VI) and Cr(III)
Selection of Cr(VI)-sensitive individuals
Patch test
round 1 Cr(VI) concentration = 4.4 µg/cm2 (Highest conc.)
Positive?
Patch test Cr(VI) concentration = 0.018 and 0.088 µg/cm2 (two lowest conc.)
round 2 and
Cr(III) = All concentrations
Negative?
Patch test Cr(VI) concentration = 0.18 and 0.88 µg/cm2

round 3 (two higher concentrations)
Positive? Positive?
At both 0.18 and At both 0.018 and

Threshold 0.88 µg/cm2 At 0.88 µg/cm2 0.088 µg/cm2 At 0.088 µg/cm2
reached
MET = 0.18 MET = 0.88 MET = 0.018 MET = 0.088
Fig. 1 Serial dilution patch test method for determination of minimum elicitation threshold in chromate allergic
individuals (Nethercott et al. 1994)
Table 1 Serial concentrations (μg/cm2) of Cr(III) & not find a significant difference between sensitized
Cr(VI) used individuals with and sensitized individuals without
Cr(III) 0.66 3.3 6.6 33 – allergy using patch testing and other tested experi-
Cr(VI) 0.018 0.088 0.18 0.88 4.4 mental in vitro methods. Further studies should
investigate the potential clinical application of
LTT and other in vitro methods to more accurately
and CrCl3 [Cr(III)] is exploited for their applica-
detect allergy to chromate and other allergens.
tion as T.R.U.E. test patches. The serial dilutions
of Cr(III) and Cr(VI) used are given in Table 1.
4.3.1 In Vitro Methods 5 Incidence of Chromate Allergy

While the standard for ACD testing has long been
patch testing, Lindemann et al. (2008) used cellular The incidence of positive patch tests to chromate
in vitro methods to test for chromium sensitization depends on the subset of workers being studied and
between chromium-sensitized individuals with an illustrates the risk of getting sensitized. In a study of
allergy, chromium-sensitized individuals without healthy volunteers, the patch test positivity to chro-
an allergy, and nonsensitized volunteers. The mium was 0.5% in those without apparent contact
authors found sensitized individuals with a clinical with chromate, as compared to 1.8% in those
allergy to display significantly higher lymphocyte who had contacted chromate (Peltonen and Fraki
transformation test (LTT) responses than sensitized 1983). A similar incidence of 1.7% in chromate-
volunteers without a clinical allergy and non- pigment workers (Decaestecker et al. 1990), and
sensitized volunteers. In contrast, the authors did 2.9% in prefabrication-construction factory workers
44 Chromium 651
(Goh et al. 1986b) with normal skin, has been noted. The prevalence of chromate allergy in Den-
In a review of world literature, the incidence of mark decreased significantly from 3.6% (in
chromate sensitivity in a routine patch testing clinic 1985) to 1% (in 1995) and then increased again
was found to be 7.9% (Nethercott 1982). In a recent to 3.3% in 2007 (Thyssen et al. 2009).
North American multicenter study by Nguyen et al.
(2008) over the period 1970–2002, the incidence of
patch test positivity to dichromate was 8% in 1970, 6 Exposure to Chromium
decreasing to 2% in1992–1994, rising to 5.8% in
1998–2000, and leveling off to 5.0% in 2002. Other Contact exposure is possible with the following
studies found patch test positivity to dichromate to compounds (Burrows and Adams 1990):
be 6.8% of 1159 men and 2.8% of 1823 women
Metals
(Peltonen and Fraki 1983). Of these, 16.1% of the
Analytic standards/reagents
men and 18.1% of the women had a present or past
Anticorrosion agents
history of atopic dermatitis; however, of the 390
Batteries
patients with atopic dermatitis as a primary diagno-
Catalysts (for hydrogenation, oxidation, polymerization)
sis, only 1.3% showed a positive reaction to
Ceramics
dichromate. These high figures of apparent allergy
Cement
to dichromate must be accepted with a certain
Drilling muds
amount of reserve due to the potentially irritant
Chromium lignosulfonates (from sodium dichro-
nature of 0.5% potassium dichromate. Fischer and
mate using lignosulfate waste)
Rystedt (1985) found that only 40% of their positive
Electroplating, anodizing agents
chromium patch tests were relevant.
Engraving
In a skin clinic, the incidence of chromate sensi-
Explosives
tivity is close to 1–2%, and if the figures are higher,
Fire retardant
then some special reason should be sought. The data
Galvanized sheeting
from two British occupational surveillance schemes
Hardeners, resins (aircraft industry)
found 22,184 cases of occupational contact derma-
Leather
titis over a period of 11 years (1993–2004), of which
Magnetic tapes
chromium accounted for 6% of the cases with a
Metallic chromium
male:female ratio of 5:1(Athavale et al. 2007). The
Milk preservatives
Finnish registry of occupational diseases observed a
Paints and varnishes
5.6% incidence of ACD due to chromium over a 7-
Paper
year period (1991–1997). The incidence of chro-
Chrome cake (sodium sulfate/dichromate)
mium allergy per 10,000 working years in different
Photography
occupations has also been elaborated in Table 2
Roofing
(Kanerva et al. 2000).
Stainless steel
Sutures
Table 2 Occupational exposure to chromate per 10,000 Tanning leather
working years Textile mordants and dyes
Occupations Incidence Television screens
Tanners, fellmongers, pelt dressers 12.20 Welding
Cast concrete product workers 6.94 Wood preservatives
Leather goods workers 4.71
Metal plating and coating workers 3.66 Chromium is used in the industry as follows:
Bricklayers 3.44
Reinforcement concreters 2.79
1. Metallurgical industries (85%): primarily
Building workers 1.32
stainless steel. It is added to harden the metal
and provide high-temperature strength and cor- aluminate (spinal refractories) (Tandon and Aarts
rosion resistance. It is also used in combination 1993); (2) slag from iron blast furnaces, which con-
with aluminum, zirconium, and zinc alloys. tains little or no chromate (Goh and Gan 1996), is
2. Chemical applications (8%): predominantly likely to be increasingly used as a clinker substance;
used in leather tanning followed by timber (3) with increased mechanization, cement is being
preservation and in paints, inks, textiles, and decreasingly handled, leading to a reduction in
as pigments in plastics. Zinc and strontium cement dermatitis (see ▶ Chap. 48, “Cement”);
chromates are used as corrosion inhibitors in (4) addition of ferrous sulfate to cement decreases
priming paints. Chromium is used as a catalyst the concentration of hexavalent chromate in cement
in drilling muds, water treatment, electro- (Fregert et al. 1979). This has been substantiated by
plating, passivation treatments of metal, and the findings of significant decreases in the urinary
as a preservative in milk testing. chromium of workers with hand dermatitis after the
3. Refractory bricks (7%): useful in refractory addition of ferrous sulfate in cement (Chou et al.
linings for furnaces and the kilns of the cement 2008), and chromium allergy due to cement from
industry and in molding sands in foundries 12.7% in 1989–94 to 3% in 1995–2007 (Thyssen et
because of its high melting point and relatively al. 2009).
low cost.
6.2 Anticorrosion Agents
6.1 Cement
Chromates are still being exploited as anticorrosion
agents, in water-cooling systems and paints. Their
Cement is the most common and best-recognized
use persists despite their toxicity, as they are very
cause of chromate allergy. Cement contains varying
effective, persistent, relatively inexpensive agents,
amounts of chromate; for instance, it was found that
and moreover, they do not form insoluble com-
the chromate content of water-soluble cement in
plexes as some other anticorrosion agents do.
Australia varied from less than 1 ppm to
124 ppm, with the majority tested showing less
than 10 ppm (Ellis and Freeman 1986). Upon addi- 6.3 Welding
tion of water, cement becomes alkaline (pH, 12)
and is probably a factor in facilitating sensitization Chromium may be present in electro rods used in
to the chromate in cement. This probably explains electric arc welding. During welding, chromium
the rarity of allergic contact dermatitis to chromate is oxidized to hexavalent chrome (present in
in cement-manufacturing workers or in those han- fumes), which causes dermatitis (Fregert and
dling dry, powdered cement. The percentage of Ovrum 1963; Shelley 1964).
patients with cement dermatitis who have positive
patch tests to chromate is probably 80–85%, but 6.4 Leather
some (Conde-Salazar et al. 1995) have found lower
levels (42%; 20% had positive patch tests to The incidence of chromate allergy in footwear
cobalt). Chromate in cement derives from the ingre- dermatitis varies among populations studied, with
dients (clinker), the machinery used in processing recent literature questioning the role of chromate in
(grinders, etc.), and from refractory bricks. Most of footwear dermatitis (Moretto 2015). Trivalent
the chromate that goes into the cement is trivalent, chromate is used in leather good processing;
but a varying proportion of this is changed to hexa- hence, the sensitization potential is low. Neverthe-
valent chromate during manufacture. less, chromate allergy should always be considered
In the future, it is likely that the amount of chro- in shoe dermatitis, and possibly even as a factor in
mate in cement will decrease due to the following hand dermatitis due to wearing of leather gloves.
factors: (1) a number of magnesium chrome refrac- Chromate is used in leather tanning as a water
tories are currently beginning to use magnesium repellant [Cr(III) and fluorinated carboxylic acids]
44 Chromium 653
and a dye. In those performing tanning, the sensiti- 6.7 Pigments

zation risk is increased because of contact with other
irritants, oxidation of small amounts of Cr(III) to Cr Chromates are used as:
(VI) (Hansen et al. 2002), and wetness in the tanning
process. Histocompatibility antigens (HLA-B8 and 1. Dye substances (e.g., lead chromate): used in
DR-3 alleles) have been incriminated in the suscep- an insoluble hexavalent form and, thus, not
tibility of patients to immunotoxicity with Cr(VI) relevant as a skin hazard. Chromium oxide, a
(Mignini et al. 2004). In Denmark, 35% of leather trivalent form, is used in artists’ paints and
products had Cr(VI) content exceeding the detection ceramics.
limits of 3 ppm (Hansen et al. 2002). Thyssen et al. 2. Soluble sodium dichromate: used as a chelat-
(2009) found an increase of 24.1% to 45% during ing agent in the presence of acid to yield an
the periods of 1989–1994 and 1995–2007, respec- insoluble dyestuff, which is particularly used
tively, (p < 0.02) in the prevalence of footwear in wool processing.
dermatitis attributable to chromate allergy. Others 3. Dyestuffs: occasional addition prevents wool
have found no significant change in the exposure from reducing the dye.
source or prevalence of chromate allergy in leather
dermatitis over the period of 1992–2009 in Den-
mark (Carøe et al. 2010). Hedberg et al. (2015) 6.8 Printing
found Cr(VI) to be minimally released from leather
products unless the leather was exposed to very dry Printing was a relatively common source of
environments, UV radiation, and/or oxidizing or allergy to chromate (Burrows 1983); however,
alkaline species. In review of current literature, with the use of acrylates, this has become
Moretto (2015) questions the ability of leather prod- infrequent.
ucts to release sufficient amounts of Cr(VI) to cause
allergic or even irritant reactions. Hansen et al.
(2006) failed to find a correlation between amount 6.9 Stainless Steel
of Cr(VI) or Cr(III) released from leather and reac-
tion to patch test with leather samples. While Most stainless steel contains about 18% chromate,
methods of detecting chromium release from leather but this can be as high as 30%. A thin layer of
may be flawed, perhaps further studies should inves- chromium oxide is formed under conditions of
tigate other potential allergens in leather. acidity and high chloride content. The oxide film
may break down and permit corrosion to occur.
Corrosion products are trivalent, but with an oxi-
6.5 Chrome Plating dizing agent present, hexavalent chromium could
be produced. The literature on leaching of chro-
Chrome plating using chromic acid and sulfuric mium from various cooking utensils has been
acid provides a significant risk for exposure to reviewed (Kanerva 1997). It has been concluded
chromate (Lee and Goh 1988). that chromium is leached only in small amounts,
from stainless steel in contact with marked acidity
and high temperature. It is unlikely that the
6.6 Galvanizing amount leached from stainless steel utensils,
even with acidic food, would exceed 50 μg per
Galvanizing iron with zinc, either by electro- day, the amount considered to be beneficial to
plating or dipping in molten zinc, protects it health. A similar observation was made when
from rusting. Coating with chromate enhances the difference in nickel and chromium content
the protective effect; however, it has been found was studied in 11 habitual menus cooked in dif-
to lead to a significant incidence of chromate ferent grades of stainless steel utensils
dermatitis (Rycroft and Calnan 1977). (Accominotti et al. 1998).
6.10 Bleaches and Detergents We await follow-up studies to ascertain chro-

mate percutaneous penetration in such metal
A large percentage of female patients tested pos- products to verify if these levels elicit ACD in
itive to chromate on routine patch testing without man.
any obvious cause. A case of a person previously Stern et al. (2010) quantified hexavalent chro-
sensitized to dichromate, developing inflamma- mium in house dust between an area with historic
tion of the sweat ducts by dipping the forearm in contamination, Jersey City (JC), and background
a solution containing 25 μg/ml of chromate for locations – revealing a mean Cr(VI) concentration
30 min, has been reported (Nethercott et al. of 3.9 +/ 7.0 μg/g in JC and 4.6 +/ 7.8 μg/g in
1996). Allenby and Goodwin (1983) found one background locations. Thus, it is plausible that
patient who reacted to as little as 1 ppm and house dust is a source of chromium; we await
could not rule out detergents as a factor in chro- further studies to determine whether chromium
mate dermatitis. A study done on various com- from these sources is sufficient to elicit ACD in
monly used detergents in India showed chromate individuals:
levels (by diphenyl carbazide spot test) to be less
than 10 ppm, indicating that chromium may not Magnetic tapes (Krook et al. 1977)
be an important cause of dermatitis Paper pulp manufacture (Pirila and Kilpi 1954;
(Krupashankar et al. 2009). Note that the spot Conner 1972; Fregert et al. 1972)
test may, because of its detection limits, have Cutting fluids (Calnan 1978a)
missed small amounts of chromate. In Israel, it Tire fitters (Burrows 1981)
was found that 90% of detergents and bleaches Milk testers (Huriez et al. 1975; Rogers and Bur-
contained chromium levels higher than 1 ppm, rows 1975)
thus, resulting in a high incidence of chromium Food laboratories (Pedersen 1977)
allergy (Ingber et al. 1998). Therefore, to prevent Machine oils (Oleffe et al. 1971; Einarsson et al.
the development of chromium allergy and to 1975; Calnan 1978b)
decrease the incidence of chromium dermatitis Pigment in soap (Mathias 1982)
in already sensitized individuals, it is now Resin hardeners containing high amounts of chro-
recommended that the chromium content of mate (this is especially seen in aircraft workers)
household products should not normally exceed (Handley and Burrows 1994)
1 ppm (Basketter et al. 2003). Antifreeze (Freeman 1995)
It has been suggested that contact with ashes in
cigarette trays can explain some cases of chromate
allergy in females (Clemmensen et al. 1981). Con- 7 Detection of Chromate
tact of chromate is thought to occur via the ashtray
cleansing cloth, which becomes increasingly con- Chromate is often a hidden allergen; any situation in
taminated throughout the day. which a patient has contact dermatitis and a positive
patch test to chromate, one should always suspect
the possibility of contact with chromate. In these
6.11 Other Sources of Contact cases, spot testing for chromate can be helpful.
Dermatitis
Recently, several studies have unmasked other 7.1 Spot Test for Detection of
potential chromate allergens. Geier et al. (2009) Hexavalent Chromium
released 95 previously patch test chromate patients; (Chromate)
49/95 (52%) tested positive again. Of this latter
population, half reacted to patch test with black Reagents:
chromated rings, suggesting that chromated metal (a) Reagent I: 1,5-diphenylcarbazide (1% wt./vol.
products may be hazardous to such patients. in ethanol)
44 Chromium 655
(b) Concentrated sulfuric acid noted when subsequently irradiated with ultravi-
Investigative procedures: olet light (Manciet et al. 1995).
• Chromate on the surface of a solid object: A
few drops of each reagent are applied on a
cotton swab. The cotton swab is thereafter 9 Effect of Systemic Chromium
rubbed against the surface of the object for
1 min. If chromate is present, a red-violet Chromium is an essential element, especially in
color appears. glucose metabolism. The daily addition of 200 μg
• Chromate in solutions: To a sample of approx- chromium to diet improved the metabolism of
imately 10 ml, a few drops of each reagent is glucose in diabetics. It was found that 63% of
added. If chromate is present, a red-violet color patients with type 2 diabetes mellitus responded
appears. to treatment with chromium compared to 30%
• Chromate in powders insoluble in water with placebo (Wang et al. 2007). This was sub-
(cement): Cement is mixed with 10 ml water stantiated by Ghosh et al. (2002), who stipulated
for some minutes. The mixture is then that the effect of chromium may be due to an
filtered and the filtrate is handled in the same increase in insulin action rather than stimulation
way as described for chromate in solutions. of insulin secretion (Ghosh et al. 2002).
However, a randomized-double blind placebo
Reagent I must be prepared immediately before the controlled study in the Netherlands did not find
investigation. Spot testing is not so accurate or easily any relation between chromium administration
carried out as the dimethylglyoxime test for nickel. and glycemic control (Kleefstra et al. 2007).
There have been several open studies on the
systemic effects of chromate in patients with chro-
7.2 Acid Wipe Sampling mate dermatitis (Schleiff 1968) suggesting an
association. Joensen et al. (1979) found that 11
This technique detects the presence/amount of out of 31 patients experienced a flare with 2.5 mg
nickel, chromium, and cobalt in the skin of workers potassium dichromate. Veien et al. (1994), in a
at their workplace. It is performed by an inductively placebo-controlled oral challenge of 2.5 mg,
coupled plasma mass spectrometer and has a high found a significant number of flares.
sampling efficiency (Liden et al. 2008). Chromium has been found to induce lipid per-
oxidation in humans, the precise mechanism of
which is not known (Bagchi et al. 1995; Kasprzak
8 Photosensitivity and Chrome 1995). Increased concentrations of chromium and
Allergy malondialdehyde (product of lipid peroxidation)
have been observed in chromium-exposed
Photosensitivity has been suggested as a factor in workers. Therefore, malondialdehyde may be
chromate allergy since many patients develop used as a biomarker for occupational chromium
dermatitis on the exposed areas. This might be exposure (Huang et al. 1999).
expected in a substance that is a potential air- Excessive chromium intake or contact has also
borne allergen (El Sayed and Bazex 1994). How- been associated with nephrotoxicity (Zhang and
ever, negligible amounts of chromate were Jin 2006).
found, in the atmosphere of a Singapore cement Depending on the geographical area, the daily
construction factory and a busy city center (Goh human chromium intake varies from 20 μg and
et al. 1986a). Patients have developed a more 85 μg per day, although values up to “130 μg” per
intense reaction when sites were irradiated with day have been reported (Kanerva 1997). In other
short-wavelength ultraviolet light (Wahlberg and studies from the USA, the daily dietary intake of
Wennersten 1977), and recently, both immediate chromium was estimated to be 5 μg and 100 μg
and delayed reactions on patch testing were per day (Kumpulainen et al. 1979; Anderson and
Kozlovsky 1985). The doses used in trials of oral 12 Management

aggravation of chromate dermatitis vastly exceed
the normal human daily consumption (even in 12.1 Prevention
exceptional circumstances), and, therefore, do
not offer any evidence that chromate dermatitis Reduction of exposure is clearly the best method
is aggravated by oral intake. While it is well of prevention. Mechanization in the construction
recognized that nickel and cobalt implants can industry and allergen replacement like change to
aggravate dermatitis, particularly in the vicinity trivalent chromate for plating results in significant
of the implant; this is not a problem with improvement (Burrows and Cooke 1980). A sur-
chromium. vey of the chrome industry reflected the need and
scope for further considerable improvement and
demonstrated efforts to improve hygiene have
10 Prognosis been worthwhile (Dornan 1981). In a study
conducted at an electroplating facility, authors
It is well documented that the prognosis in noted significant neglect of preventive measures;
chromium dermatitis is probably worse than in workers wore internally contaminated gloves,
any other form of dermatitis. A very small per- degloved themselves in a manner which led to
centage was found to be clear after 10–15 years contamination of skin, did not wear personal pro-
(Burrows 1972). This was later confirmed tective equipment, and displayed unsafe habits
(Halbert et al. 1992), and a review of the progno- such as nose picking (Cohen et al. 1974).
sis of occupational hand dermatitis further highli- Hence, employee education regarding high
ghted the finding (Hogan et al. 1990). Outcome standards of personal hygiene accompanied by
studies were performed before current under- the presence of a well-trained individual in iden-
standing of exposure, protection, and therapeu- tifying and reporting any abnormal signs and
tics. In the authors’ experience, most workers symptoms among workers are important steps in
have had a good outcome in the San Francisco preventing morbidity (Williams 1998).
area. Following the lead of several Scandinavian
countries, the EU restricted the amount of chro-
mium in cement to <2 ppm under EU Directive
11 Change of Occupation 2003/53/EC beginning 17 January 2005. In ana-
lyzing health and occupation data in the UK,
Data pertaining to the benefits of change in Stocks et al. (2012) found the difference in inci-
occupation is unclear, but common wisdom dence of allergic contact dermatitis in the period
and clinical experience suggest it to be benefi- before (from 2002–2004) and after (from
cial. In a review of chromate allergy in 122 2005–2009) implementation of the EU Directive
patients followed-up after 6–9 years, it was to decrease in both chromate and nonchromate
found that 62 (52%) continued in the same attributed ACD. However, the greatest decrease
occupation and, of these, 55 (89%) had ongoing in incidence was found to be in the subgroup,
dermatitis and 7 (11%) had completely cleared “ACD attributed to chromate in ‘cement
despite continuing chromate exposure. The workers’” (Stocks et al. 2012).
remaining 58 (48%) had completely changed Replacing Cr(IV) with Cr(III) via addition
their type of work since initial presentation, of ferrous sulfate in cement, a process first
and despite this change, dermatitis persisted discovered by Sigfrid Fregert et al. (1979),
in 40 (69%) workers. The period an individual has been undertaken in several countries
continued in employment (with dermatitis) and led to a significant reduction in chromate
prior to change of occupation appeared a dermatitis in the cement industry (Bock et al.
significant factor in improvement (Halbert 2004). However, this practice is hindered by
et al. 1992). the overall decrease in chromate allergy
44 Chromium 657
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Cobalt
45
Anneli Julander, Jolinde Kettelarij, and Carola Lidén
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
3 Prevalence and Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
4 Health Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
4.1 Sensitizing Capacity and Cross-Reactivity in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
4.2 Sensitization and Prevalence of Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
5 Occupational Exposure and Occupational Contact Dermatitis . . . . . . . . . . . . . . 664
6 Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
6.1 Cobalt Spot Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
6.2 Cobalt Release in Artificial Sweat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
6.3 Skin Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
7 Systemic Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
8 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
9 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Abstract healthcare sector. It is often difficult to evaluate

Cobalt is a frequent cause of contact allergy the clinical relevance of patch test reactivity to
often seen with concomitant contact allergy to cobalt for dermatologists, owing to scarce
nickel or chromate, although solitary cobalt knowledge about sources of skin exposure.
allergy is frequently observed. Cobalt allergy Cobalt has broad applications, especially
is prevalent among workers within hard-metal, within the areas of metal working, hard metal,
construction, and electronics industries and the batteries, and electronics industries. Cobalt is
also frequently used as pigment in many dif-
ferent applications. It has been shown that
A. Julander (*) · J. Kettelarij · C. Lidén cobaltcontaining materials such as hard metals,
Institute of Environmental Medicine, Karolinska Institutet,
alloys and coatings have different abilities to
Stockholm, Sweden
e-mail: anneli.julander@ki.se; jolinde.kettelarij@ki.se; release cobalt ions at skin contact and to cause
carola.liden@ki.se allergic contact dermatitis.
https://doi.org/10.1007/978-3-319-68617-2_45
662 A. Julander et al.
Quantification of cobalt on the skin by acid 2 Introduction

wipe sampling, identification of cobalt release
from items and surfaces with a spot test, and Cobalt (Co) is one of the most frequent causes of
the assessment of cobalt release from materials contact allergy. Cobalt allergy affects women
immersed in artificial sweat will increase the more often than men, but the gender difference
knowledge about sources of cobalt exposure is not as large as is the case with nickel allergy.
and facilitate prevention of cobalt contact The causes of cobalt allergy in dermatitis patients
allergy. do often remain unknown, probably largely due to
scarce knowledge among dermatologists about
Keywords how cobalt is used and how exposure occurs.
Acid wipe sampling · Alloys · Cement ·
Cobalt · Cobalt spot test · Cobalt release ·
Construction workers · Contact dermatitis · 3 Prevalence and Use
Exposure reduction · Hard metal ·
Metalworkers · Occupational exposure · Skin Cobalt is a silvery and magnetic metal. It belongs to
exposure assessment the transition metals together with nickel and chro-
mium. Cobalt is present in the earth’s crust, and it is
mainly a by-product of nickel and copper mining.
1 Core Messages Most mined cobalt is produced in Congo (Kinshasa),
whereas China and Finland are main producers of
• Cobalt is a frequent cause of contact allergy, refined cobalt (USGS 2014). During recent decades,
seen as solitary allergy or together with allergy the price of cobalt has increased, which has resulted
to nickel or chromium. in more efficient refining, and, thus, nickel is not
• Workers in the hard-metal, construction, and contaminated by cobalt to the same extent as for-
electronics industries and healthcare, among merly. Vitamin B12 (cobalamin) contains cobalt,
others, are often allergic to cobalt. which is an essential trace element.
• The clinical relevance of patch test reactivity to Cobalt has been used for more than 4,000 years,
cobalt is often difficult to establish. Scarce initially for coloring of glass and pottery. Nowadays,
knowledge about sources of skin exposure the largest amount of produced cobalt is used in
contributes to the difficulties. rechargeable batteries and stress- and corrosion-
• Cobalt has broad applications. Cobalt-con- resistant superalloys. In addition, cobalt as metal or
taining materials such as hard metal, alloys, chemical compound is used in integrated circuits,
coatings, and cobalt compounds have different tungsten carbides (hard metal), and other cemented
ability to release cobalt ions at skin contact and carbides, as paint dryer, in magnets, dental alloys,
to cause dermatitis. and orthopedic implants, and as a catalyst (Harper
• Quantification of cobalt on the skin by wipe et al. 2012; USGS 2014; Cobalt Institute 2017).
sampling, a spot test for identifying cobalt Current main uses for cobalt are shown in Table 1.
release, and the assessment of cobalt release Cobalt and cobalt compounds are widely used in
from materials immersed in artificial sweat different types of industry where skin exposure
will increase knowledge about sources of occurs and contact allergy to cobalt has been
cobalt exposure and facilitate prevention of described (Rietschel and Fowler 2008; Lidén et al.
cobalt allergy. 2011; Burrows et al. 1999).
• Cobalt and cobalt compounds cause occupa- Hard metal has 90–95% of the hardness of
tional lung disease, and they are classified diamond and is used for the cutting edges of
as possibly carcinogenic and may be tools and drills, for milling, and for many other
harmful to aquatic life. Cobalt metal with industrial applications. Hard metal is a type of
and without tungsten carbide is classified as cemented carbide manufactured by mixing tung-
probably and possibly carcinogenic, sten powder with carbon to produce tungsten car-
respectively. bide, which is then mixed with cobalt as a binder.
45 Cobalt 663
Table 1 Main applications of cobalt, based on Harper 4 Health Effects

et al. (2012), USGS (2014), and Cobalt Institute (2017)
Category Main applications Cobalt is a well-known skin sensitizer. Other
Alloys Superalloys, tungsten carbides (hard known skin effects are skin irritation, urticaria,
metal) and other cemented carbides, granuloma, and photosensitization. Severe health
hard and soft magnets, high-speed
steels effects by inhalation, particularly hard-metal
Catalysts Desulphurization, recyclable plastics pneumoconiosis and occupational asthma by
Colorant Inks and pigments inhalation of hard-metal dust, have attracted
Electronics Integrated circuits, semi-conductors, much concern. Cardiomyopathy has been
magnetic recording described among heavy consumers of cobalt-
Healthcare Prosthetic alloys, vitamin B12, cobalt containing beer. Cobalt and several cobalt com-
metal isotopes pounds are classified according to the CLP as
Rechargeable Cathode in lithium-ion, nickel-
sensitizing by inhalation and skin contact (H334
batteries cadmium, and nickel-metal hydride
batteries and H317) and may cause harmful effects to
aquatic life (H413) (ECHA). The International
Agency for Research on Cancer (IARC) has clas-
The mixture is milled and processed to produce an sified cobalt metal with tungsten carbide as prob-
ultrafine powder, which is pressed, formed, ably carcinogenic (Group 2A), whereas cobalt
sintered, and grinded. The typical cobalt content metal without tungsten carbide and cobalt sulfate
in hard metal is 3–5%. Titanium (Ti) and other and other soluble cobalt (II) salts are possibly
metals are often added. Hard-metal items may carcinogenic to humans (Group 2B) (IARC
also be coated with titanium and aluminum com- 1991, 2006).
pounds (see ▶ Chap. 162, “Grinders and Brazers
of Hard Metal and Stellite”).
There is a wide range of cobalt-containing 4.1 Sensitizing Capacity and Cross-
alloys, mainly for use in industry and health- Reactivity in Animals
care. They have different properties based on
the composition and different fields of The skin sensitizing potential of cobalt chloride
application. Orthopedic implants are often has been evaluated in animal experiments.
made of Co-Cr steels, with 52–62% cobalt. Cobalt chloride is an extreme skin sensitizer
Cobalt-containing dental alloys are much used. (grade V) in the guinea pig maximization test.
Cobalt is also used in jewelry. Examples are Co- Animals induced with cobalt chloride did not
Cr steels used in rings and cobalt-containing react to nickel sulfate or potassium dichromate
gold plating. at challenge – the results speaking in favor of
Many cobalt compounds are used in processes multiple sensitization rather than cross-reactivity
and products of interest in occupational dermatol- (Wahlberg and Lidén 2000; Lidén and Wahlberg
ogy. Cobalt is used as pigment (cobalt blue) which is 1994). Cobalt chloride is a potent skin sensitizer
widely used in pottery and glass production. Cobalt also in the local lymph node assay (LLNA)
compounds are also used as pigment in inks and as (Basketter et al. 1999). It is a skin sensitizer
dryers in paints and in putties. Cobalt naphthenate is as shown by the human maximization test
used in the synthesis of polyester. Household prod- (Kligman 1966).
ucts and cosmetics may contain cobalt, chromium,
and nickel. Based on risk assessment addressing
contact dermatitis, it has been recommended that 4.2 Sensitization and Prevalence of
such products shall not contain more than 1 ppm Allergy
of each of the metals (Basketter et al. 2003). Cement
products and clay used in pottery may contain cobalt Cobalt allergy is typically observed in about
in addition to possible nickel and chromium content 1–4% of adults in the general population
(Tandon and Aarts 1993). (Table 2). Contact allergy to cobalt has been
Table 2 Prevalence of cobalt allergy in dermatitis patients, examples from different parts of the world
Cobalt allergy
Study population, period (no. tested) Total (%) Men (%) Women (%) Reference
General population
5 European countries 2008–2011 (n = 3119) 2.2 1.1 3.0 Diepgen et al.
Germany (n = 1024) 2.3 – – (2016)
Italy (n = 546) 0.9 – –
The Netherlands (n = 500) 3.8 – –
Portugal (n = 531) 2.5 – –
Sweden (n = 518) 1.1 – –
Sweden 2011–2013 (n = 2226)a 1.17 1.05 1.11 Lagrelius et al.
(2016)
Dermatitis patients
12 European countries (ESSCA) 2009–2012 6.6 – – Uter et al. (2016)
(n = 56,826)
Sweden 2008–2010 (n = 3112) 4.5 3.0 7.3 Fall et al. (2015)
North America 2013–2014 (n = 4859) 7.4 – – DeKoven et al.
(2017)
Northern Ethiopia 2010–2011 (n = 480) 4.6 – – Morrone et al.
(2014)
Australia 2001–2010 (n = 5169) 11.0 – – Toholka et al.
(2015)
a
Adolescents; – Results not divided by gender
reported at approximately 4–11% of patch-tested hard-metal workers, metalworkers, dental tech-

dermatitis patients and generally at a higher rate nicians, electronics workers, and healthcare pro-
in women than in men (Table 2). Contact allergy fessionals belong to the occupational groups in
to cobalt is often associated with concomitant which allergic contact dermatitis to cobalt is
contact allergy to nickel or chromate, although well-known. Table 3 displays the frequency of
solitary cobalt allergy is frequently observed contact allergy to cobalt in some occupational
(Hegewald et al. 2005; Uter et al. 2014a; groups.
Lagrelius et al. 2016; Lidén et al. 2016). Cobalt Occupational contact dermatitis from met-
allergy has not decreased in parallel with nickel allic cobalt dust in a factory producing tungsten
allergy that is decreasing in some countries as a carbide was first described in 1945 (Schwartz
result of the EU restriction of nickel release. et al. 1945) and in a pottery factory from
Solitary occupational cobalt allergy is seen exposure to wet clay containing cobalt
mainly in hard-metal workers and in the glass in 1953 (Pirilä 1953). Cobalt is an important
and pottery industries. It is often difficult to occupational contact allergen in construction
identify the source of isolated positive cobalt workers, and it has often been associated
patch tests. with allergy to chromate. Occupational con-
tact dermatitis is frequent in metalworkers
exposed to water-based metalworking
5 Occupational Exposure and fluids, cobalt being an important cause,
Occupational Contact together with other metals, biocides, skin irri-
Dermatitis tants, etc.
There are several publications, including
Cobalt and cobalt compounds are important case reports, on dermatitis related to occupa-
causes of occupational contact dermatitis, partic- tional exposure to cobalt-containing mate-
ularly hand eczema. Construction workers, rials and processes, some of them displayed in
45 Cobalt 665
Table 3 Examples of cobalt allergy in some occupational Table 4 Examples of causes of work-related cobalt der-
groups according to workplace studies and reports on dermatitis (see also Tables 1 and 3)
matitis patients
Cause or tasks Reference
Study population (no. Cobalt Accelerators in polyester resin Aalto-Korte and
patch tested) allergy (%) Reference Suuronen (2016)
Workers (non-patients) Animal feeds Ratcliffe and
Cement workers, Taiwan 7.2 Wang et al. English (1998)
(n = 97) (2011) Cement workers, tile setters, Bock et al. (2003)
Dental technicians, Korea 12.2 Lee et al. terrazzo workers, painters
(n = 49) (2001) Clay in pottery industry Pirilä (1953)
Hard-metal workers, 4.6 Fischer and Cobalt in offset printing Malten (1975)
Sweden (n = 853) Rystedt Cobalt in porcelain dyes Pirilä and Geier
(1983) (1964)
Dermatitis patients Cobalt naphthenate in polyester Cahill and
All occupations, reported 4 Athavale resin Andersen (2010)
cases of occupational et al. (2007) Metal baking sheets Bregnbak et al.
contact dermatitis, UK (2015)
(n = 22,184)
Metal working fluids Geier et al. (2004)
All occupations, reported 9.3 Pesonen
Underground workers Irvine et al. (1994)
cases of occupational et al. (2015)
contact dermatitis,
11 European countries
(ESSCA) (n = 9737)
6 Exposure Assessment
Bricklayers and 25.3
stonemasonsa
Medical doctorsa 11.8 6.1 Cobalt Spot Test
Office clerksa 12.4
Physiotherapistsa 10.4 The cobalt spot test is a simple test for cobalt
Waitersa 16 release (Thyssen et al. 2010; Midander et al.
Blue-collar workers 4.6 and 3.4 Schwensen 2013). It has been shown to detect cobalt release
(n = 1468) and matched et al. (2014) from alloys at levels corresponding to the elicitation
controls (n = 1471), concentration seen in cobalt-allergic patients. A
Denmark
cotton-wool-tipped stick with drops of the yellow
Clothing processing 28.4 Chen et al.
industry workers, China (2017) cobalt test solution is rubbed for up to 30 s against
(n = 74) the surface to be tested. A color change from yellow
Construction workers, 8.6 Uter et al. to orange-red indicates the presence of cobalt ions.
Germany and Austria (2004) The test is based on oxalic acid, nitroso-R salt, and
(n = 1238)
sodium acetate in deionized water. The cobalt spot
Construction industry, 20 Bock et al.
registered cases of (2003)
test can be prepared in the laboratory and is com-
occupational skin disease, mercially available. It has been applied in research
Germany (n = 335) and in the clinical setting and workplaces to iden-
Electronics workers 9.8 and 2.2 Shiao et al. tify sources of sensitization and elicitation of cobalt
(n = 183) and reference (2004) dermatitis, as the dimethylglyoxime test for nickel
workers (n = 185),
Taiwan does (see ▶ Chap. 43, “Nickel”).
Hospital nursing staff, 28.6 Lee et al.
Korea (n = 70) (2013)
a
6.2 Cobalt Release in Artificial
Number patch tested not specified
Sweat
Table 4. The wide applications of cobalt as Cobalt release may be quantitatively deter-
metal, in alloys and hard metal and in com- mined by immersing items and materials in
pounds (Table 1), should be considered. artificial sweat and analyzing cobalt in the
solution, according to the European standard EN short and repetitive contact with items that
1811 (Julander et al. 2009) (see ▶ Chap. 43, release cobalt was shown to result in deposition
“Nickel”). The standard was developed to meet and accumulation of cobalt on the skin (Midander
the needs of controlling compliance with the EU et al. 2014).
Nickel Directive. It has been shown that some
materials release substantial amounts of cobalt.
A broad selection of discs made of cobalt- 7 Systemic Exposure
containing hard metal was immersed in artificial
sweat for 1 min to 1 week (Julander et al. 2009). Skin exposure contributes significantly to the
The amount of released cobalt varied signifi- uptake of cobalt in hard-metal workers, although
cantly from different hard-metal compositions. airborne exposure has a larger impact on sys-
Considerable amounts of cobalt have also been temic uptake, measured as cobalt concentration
shown to be released from dental tools and in the urine or blood (Scansetti et al. 1994;
alloys, laptop computers, and single jewelry Linnainmaa and Kiilunen 1997; Klasson et al.
items (Uter et al. 2014b; Kettelarij et al. 2014; 2017). Suspended cobalt powder and cobalt
Midander et al. 2016). nanoparticles were able to permeate intact and
damaged skin in several in vitro static Franz
diffusion cell experiments (Larese Filon et al.
6.3 Skin Exposure Assessment 2004, 2009, 2013).
The role of cobalt uptake from diet, surgical
Increasing attention has been given to the devel- implants, and dental materials remains controver-
opment of methods for skin exposure assessment sial and is reviewed elsewhere (see relevant chap-
(Gruvberger et al. 2011; Julander et al. 2018). ters in Contact Dermatitis 5th edn 2011 and Chen
Acid wipe sampling was developed for the assess- and Thyssen (2018)).
ment of nickel, chromium, and cobalt deposited
onto the skin (Lidén et al. 2006). Sampling is
performed by wiping demarked areas with dilute 8 Diagnosis
nitric acid (1%) before (cleaning the skin) and
after a normal work session. After extraction of Cobalt chloride 1% in petrolatum is the test mate-
the wipes, analysis is performed with ICP-MS or rial in the European baseline series. Sometimes it
other suitable equipment. The method has very has been suggested that 1% is too high, causing
high sampling efficiency and recovery (>90%), irritant or false-positive reactions, and the rele-
and the mass per area unit (e.g., μg/cm2) may be vance of patch test reactions to cobalt has been
calculated. questioned. Cobalt chloride 0.5% has been used in
Acid wipe sampling has been used to assess Sweden since the 1980s, but cobalt chloride 1% in
skin exposure to metals in cashiers, locksmiths, petrolatum has been shown to be more suitable,
carpenters, (hard-)metal workers, secretaries, and owing to a larger proportion of missed cases with
dental technicians (Lidén et al. 2008; Julander et al. 0.5% (Lidén et al. 2016). The ready-to-use patch
2010; Kettelarij et al. 2016; Klasson et al. 2017). test system TRUE Test (Mekos) also contains a
Cobalt was detected in most samples, and the larg- cobalt chloride patch.
est amounts of cobalt (up to 100 μg/cm2/h) Patch testing with a serial dilution of cobalt
were deposited onto the hands in hard-metal chloride is sometimes used to gain more informa-
workers. Skin and surface contamination by tion on the degree of sensitivity and to discrimi-
cobalt, chromium, and nickel were assessed in nate between allergic reactions and irritant ones
the production of cemented tungsten carbides by (Lidén et al. 2011). The concentration of cobalt
another wipe sampling technique (Day et al. chloride required to elicit a positive patch test
2009). All sampled skin and work surfaces were reaction in 10% of cobalt-allergic individuals
contaminated with cobalt and other metals. Even (ED10) was found to be between 30.8 and
45 Cobalt 667
259 ppm, or 0.0663 and 1.95 μg cobalt/cm2 sampling (Lidén et al. 2006; Julander et al. 2010)
(Fischer et al. 2016). may be important tools for primary and secondary
Patch testing with metal discs of cobalt- prevention of cobalt allergy in workplaces.
containing materials may be used as a supplement
to the analysis of metal release in artificial sweat.
This will give important information about the References
ability of materials to cause allergic contact der-
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were tested simultaneously with cobalt chloride allergy to components of polyester resin systems. Con-
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containing hard metals and dental alloys in cobalt- Dermatol 157(3):518–522
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Gold
46
Marléne Isaksson
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
3 Physical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
4 Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
5 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
6 Contact Allergy to Gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
7 Patch Test Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
8 Patch-Test Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
9 In Vitro Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
10 Allergic Contact Dermatitis from Gold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
11 Stent Implantation and Gold Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
12 Allergic Contact Stomatitis and Glossitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
13 Occupational Exposure and Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . 679
14 Occupational Exposure and Irritancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
15 Chrysotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
16 When Should Gold Be Patch Tested? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
17 Treatment and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
Abstract
M. Isaksson (*) Gold was considered to be an inert material not
Department of Occupational and Environmental being able to give contact allergy or allergic
Dermatology, Department of Clinical Sciences Malmö contact dermatitis. However, gold allergy is
Lund University, Skåne University Hospital, Malmö,
Sweden
common among dental patients as well as der-
e-mail: marlene.isaksson@med.lu.se; matitis patients. The relevance, however, is
Marlene.isaksson@skane.se

https://doi.org/10.1007/978-3-319-68617-2_46
672 M. Isaksson
usually uncertain except in dental patients and copper, nickel, and lead. The world gold produc-
in stented patients having received a gold stent. tion increased steadily from 2005 up to an esti-
Gold should be tested in dental cases and in mated 3.1 thousand metric tons in 2016.
cases of eyelid and/or facial dermatitis or when
jewelry allergy is suspected. Testing should
also be considered when there is dermatitis of 3 Physical Properties
the ears, hands, or neck. Gold should also be
tested in potential occupational exposure. The purity of gold is measured in carat, one carat
being a 24th part and where the carat number
Keywords indicates the proportion of gold in an alloy.
Gold allergy · Dental gold · Patch testing · Hence, 24 carat is absolute pure gold. High carat
Patch test readings · Gold sodium thiosulfate · gold easily produces black dermografism, which
Gold jewelry · Stent material · Oral lichenoid is the most common cause of skin discoloration
lesions · Gold trichloride · Gold sodium from metal jewelry. It refers to thin deposits of
thiomalate · Chrysotherapy · Facial dermatitis · metallic powder, which is always black because
Eyelid dermatitis these fine particles do not reflect light, and they
are produced by friction of a metallic object on
skin that is contaminated by powders or abrasives.
1 Core Messages Dusty environments or fabrics may contaminate
the skin with abrasive particles (Rapson 1985).
• Patch testing to gold is best performed with Pure gold is very soft but malleable and ductile.
gold sodium thiosulfate 2.0% petrolatum. If To increase its strength, alloys with other metals
negative and a strong suspicion that gold such as silver, copper, nickel, palladium, and zinc
allergy is present, 5.0% petrolatum can are common. The color of gold is influenced by
be used. the alloy addition, where silver gives a greenish-
• Reading of patch tests to gold is necessary both yellow, copper a red and nickel a light-yellow cast
on day 3 or 4 and on day 7, not to miss contact to white gold.
allergy. Sometimes allergic reactions show up As pure gold is malleable, it can be rolled or
even later, up to 3 weeks after patch testing. beaten to a thickness of less than 1 μm. From
• The frequency of gold allergy in dermatitis 1 gram of gold, a thread of 2–3 km in length can
patients is high, around 10–15%. be made. Gold has good electrical conductivity
• The clinical relevance of gold allergy in der- and, through its durability, a low and stabile con-
matitis patients is rather low. tact resistance is achieved. It has a high reflective
• Gold allergy is correlated to dental gold. power, especially within the infrared spectrum,
• The more dental gold, the higher the blood which makes surfaces covered by gold good for
level of gold. heat reflectors. Thin gold foils that reflect heat
radiation and yet are able to let visible light
through can be used in windowpanes of trains
2 Introduction and airplanes. If these panes are electrically
heated, mist and rime can be avoided (Cavelier
Gold, Aurum in Latin, is the only metal except and Foussereau 1995).
copper that is markedly colored. It is abundant in
low concentrations almost all over the earth’s
crust, in seawater, above all in metallic form and 4 Chemical Properties
also as goldtellurid. Gold is found as grains in the
bottom of rivers in California, Australia, Alaska, Gold is resistant to corrosion as it does not com-
and Russia, while in South Africa gold ore is won bine with oxygen or other substances in the atmo-
from mines with auriferous leaders. Gold is also sphere, even at elevated temperatures. Gold
won as a by-product from the production of occurs in oxidation states 0, +I and +III, the latter
46 Gold 673
being most stable, and the equilibrium between 6. In gilding in which two techniques principally
these states can be altered easily (Brown et al. occur: methods free of water and wet methods.
1982). All halogens attack gold, and so do halo- The former is when gold leaf is placed on
gen acids mixed with nitric acid or other oxidizers. objects that are covered with varnish or when
Aqua regia (kingly water), a mixture of hydro- gold is applied on glass through vacuum
chloric and nitric acids, and cyanide solutions methods by means of a pigmented lacquer or
attack gold. Gold can also dissolve in water solu- a solution of a gold salt. The object is then
tions that contain thiol-substituted amino acids heated to a temperature near the glass-softening
(cysteine, glutathione) and can be absorbed level. Wet methods imply electrolytic gilding,
through animal skin (Brown et al. 1982). and this method has been in use since the
middle of the nineteenth century. Pretreatment
of the base metal (if made of copper alloys)
5 Applications with electrolytically won nickel to stop the
copper and other alloy metals from diffusing
Gold is or has been found in a variety of into the gold surface is a prerequisite. Some-
applications: times the nickel surface needs to be activated in
an acid bath to increase the attachment of the
1. In jewelry, either as an alloy, as gold plating, gold. In electrolytic gilding, different baths are
or as rolled gold (Cronin 1980). In alloys of used: acid cyanide baths are used for decorative
18-carat and 22-carat gold, copper and silver purposes as well as within the industry; neutral
are added; in 14-carat gold, copper, nickel, baths were formerly used as alloy baths but,
and zinc are added. White gold is hardened by nowadays, to get very pure coatings in the
the addition of palladium and nickel and can electronics industry; alkaline baths are used
also contain copper and zinc. In plating, a for decorative purposes to get different colors;
base metal such as copper is electrolytically gold baths free of cyanide are used for decora-
covered with nickel, and then gold of varying tive purposes and when thick coatings are
thickness is added. Rolled gold can be applied wanted; and current-free gold baths are used
to a metal base by mechanical pressure. in the manufacture of electronics. Gold potas-
2. As gold leaf, used for lettering, decoration of sium cyanide (potassium dicyanoaurate) (KAu
books and the like. (CN)2) is used in the acid, neutral, alkaline, and
3. In dentistry, as alloys with silver, copper, current-free baths; whereas gold sodium sulfite
palladium, platinum, and zinc to make (NaAuSO3) and gold chloride (AuCl3) are used
crowns, bridges, etc. in the cyanide-free baths (Asthner 1990). Gild-
4. As a colloidal solution of a gold salt in stannic ing through electroplating is common in the
acid (purple of Cassius), to make ruby glass manufacture of alloys for electrical contacts,
and to color enamel and porcelain. Gold when bonding transistors and diodes to wires
hydroxide, gold oxide, potassium and sodium is needed and in printed circuit boards in the
gold trichloride are also used in this decora- manufacture of electronics (Adams 1990).
tive application. The gold salt is painted on 7. As an anti-rheumatic drug since the 1920s
the object and, when heated, the gold salt is (chrysotherapy) (Forestier 1929). Myocrisin
reduced to metallic gold. [gold sodium (I)thiomalate][GSTM], intended
5. As gold salts, such as gold trichloride, and for intramuscular injections, and Auranofin
complex gold salts, such as sodium tetra- [2,3,4,6-tetra-O-acetyl-1-thio-ß-D-
chloroaurate dihydrate (Cronin 1980), for glucopyranosato-5-triethylphosphine gold (I)],
toning and stabilizing silver images in pho- to be given orally, have been used.
tography, Gold chloride in neutron-activated 8. As a topical gold salt (Auranofin) in the treat-
form has been used in the intensifying of very ment of psoriasis (Helm et al. 1995; Marks
weak images formed in some modern photo- et al. 1995).
graphic applications. 9. As a deposit of wealth (gold bars).
674 M. Isaksson
10. In the medical profession, as Hulka clips for gold allergy is more frequent in women (Fowler
the ligation of the Fallopian tube in steriliza- 1988; Nonaka et al. 2003). This predominance
tion procedures (Trathen and Stanley 1985), probably reflects increased contact with jewelry
as a gold ball inserted into the capsule after rather than increased susceptibility (Elgart and
enucleation of an eye (Forster and Dickey Higdon 1971; Chen and Lampel 2015). Even chil-
1949), as a weight in the upper eyelid in dren react allergically to gold. Figures from 6% to.
paralysis of the orbicularis oculi muscle to be 10% are published (Admani and Jacob 2014).
able to close the eye (Björkner et al. 2008), In dental patients with gold restorations, the
and as a radioactive isotope in the form of frequency of gold allergy is even higher with
colloidal gold or seeds used either therapeuti- figures ranging from 12.4% to GSTS (Räsänen
cally or diagnostically (Merck Index 1983). et al. 1996). One study found 34% of patients
Formerly in gold-plated stents and metallic with gold dental restorations to have positive
implants, used in patients with stenosis of the patch test reactions to gold as compared with
cardiac vessels (Ekqvist et al. 2007). 11% of those without such dental restorations
11. In alcoholic beverages (Russel et al. 1999). (Schaffran et al. 1999).
12. In homeopathic medications (Malinauskiene In a study of 134 patch tested dental patients,
et al. 2013). gold allergy was noted in 14% (Khamaysi et al.
13. As metallic gold in make-up, such as lipstick, 2006). Another recent study of 44 patients with
mascara, eye shadow (Fisher 1967), and in oral disease and who were patch tested to a dental
some leave-on products. screening series showed 70.5% to have positive
reactions to at least one allergen 25% were allergic
to gold (Kim et al. 2015). Oral diseases included
6 Contact Allergy to Gold oral lichen planus (54.5%), cheilitis (27.3%), burn-
ing mouth syndrome (9.1%), and others (9.1%).
In the past contact allergy to metallic gold and A multicenter study of patch test reactions with
gold salts was considered rare (Cronin 1980), but dental screening series from Finland revealed a
since the beginning of the 1990s when gold contact allergy frequency of 7.7% for gold
sodium thiosulfate (GSTS). (Kanerva et al. 2001).
[Na3 Au(S2 O3)2] was added to many baseline In patients with endovascular coronary gold-
series, several reports on a high frequency of plated stents, 37–45.5% gold allergy was found
contact allergy among dermatitis patients have (Svedman et al. 2005; Ekqvist et al. 2007).
been published. Hypersensitivity to gold may be seen together
Figures ranging from 0.78% to 13.0% are pre- with contact allergy to other metals such as mer-
sented (Björkner et al. 1994; McKenna et al. cury, nickel, and palladium (Koch and Bahmer
1995; Sabroe et al. 1996; Fleming et al. 1997b; 1995; Heise et al. 1997). Other investigators
Silva et al. 1997; Leow et al. 1998; Nonaka et al. found no positive statistical correlation with
2003). other allergens in a baseline series (Björkner
In Malmö the department of Occupational and et al. 1994; Sabroe et al. 1996).
Environmental Dermatology patch tested gold as
GSTS within the extended baseline series since
1991. Data from 13,106 dermatitis patients, patch 7 Patch Test Materials
tested to gold between the years 1995–2014, have
shown a frequency of 14%. The contact allergy Formerly, several gold salts as well as elemental
frequency increased with age, was more common gold in the form of gold leaf have been utilized in
among women, and was correlated to atopy and patch testing in gold allergy but, as many gold
facial dermatitis. There was also a trend of a slight salts are acidic (Cronin 1980), irritant reactions
decline in frequency of gold allergy (to be have followed. Gold trichloride often causes irri-
published). Other authors also have seen that tant, false-positive, and persistent reactions
46 Gold 675
(Fowler 1990). The test solution, which is and to assess whether a measurable systemic
HAuCl3, is a solution of gold chloride in hydro- uptake was possible. With an acid wipe sampling
chloric acid since it is insoluble in water. Hence, it technique used in nine individuals not allergic to
is a strong primary irritant that causes damage to gold, release of gold was detected in seven and a
the horny layer and can elicit a lympho-monocytic higher amount of metal was found on the skin
reaction with pseudo-lymphomatous features when the provocation time was prolonged up
(Monti et al. 1983). This has been noted by others until a week. No increase in systemic gold was,
(Bowyer 1967; Comaish 1969) and, clinically, it however, detected (to be published).
consists of a papular, non-eczematous reaction GSTS at 0.5% petrolatum has been
sometimes persisting for weeks to months (Fow- recommended as a reliable patch-test allergen for
ler 1987). Gold chloride was shown to be a potent gold allergy (Fowler 1987; Koch et al. 1997) and
sensitizer in the human maximization test in addition also at 2.0% and 5.0% petrolatum
(Kligman 1966). Also, gold sodium thiomalate (Bruze & Björkner 1996) (Fig. 1). Positive reac-
(GSTM) has been used in concentrations from tions to this salt represent true contact allergy
0.5% to 2.0% in petrolatum (Fox et al. 1961; rather than an irritant contact reaction (Björkner
Bowyer 1967; Elgart 1972; Fowler 1987; et al. 1994). This gold salt has been used when
Björkner et al. 1994). There are no reports of high prevalence figures of contact allergy have
persistent or severe reactions to this salt (Fowler been reported. Epicutaneous and intracutaneous
1987). Sometimes these low concentrations may
give false-negative reactions and, when a high
concentration (11.5% aqueous) was tested on
12 gold-allergic individuals, all reacted to
GSTM. No irritant patch-test reactions were
noted, and controls reacted to the salt neither
epicutaneously nor intracutaneously (Bruze et al.
1995a).
Several studies have shown that potassium
dicyanoaurate often has caused false-negative
reactions. The patch-test concentrations have
then been low and probably too low to elicit a
positive reaction. In one study, this salt gave con-
cordant positive reactions compared with GSTS
when the same volumes of solutions of GSTS and
potassium dicyanoaurate at equimolar concentra-
tions were used (Björkner et al. 1994). Gold leaf is
unsatisfactory due to the often-negative patch-test
result (Fox et al. 1961; Bowyer 1967; Comaish
1969), and it is presumed to be due to the insolu-
bility of metallic gold (Fowler 1987). Rarely have
gold leaf (Forster and Dickey 1949; Cowan 1960),
gold rings (Cowan 1960), gold earrings (Cowan
1960), or a gold ball (Forster and Dickey 1949)
given positive patch-test responses when tested
as is.
In a recent study at the department of Occupa-
tional and Environmental Dermatology in Malmö,
Fig. 1 Results of serial dilution test with GSTS with
it was attempted to measure metal release from strong allergic test reaction to 5.0% in petrolatum and a
gold objects worn in close contact with the skin weak allergic test reaction to 0.5% petrolatum
676 M. Isaksson
test reactions to GSTS are long-lasting (Bruze release was allergen specific (Möller et al. 1999).
et al. 1995b) and may persist for several months. Gold induced a mixed Th1- and Th2-type cyto-
Intracutaneous positive tests to this salt have a kine response in vitro in subjects with contact
tendency to change from thin infiltrates to deep allergy to gold (Minang et al. 2006).
nodules (Bruze et al. 1995b).
10 Allergic Contact Dermatitis

8 Patch-Test Readings from Gold
Delayed readings at 96 h and 7 days (168 h) are There are several sporadic cases of allergic con-
essential when patch testing with GSTS tact dermatitis from both metallic gold and gold
epicutaneously. Even readings after 1 week some- salts reported in the literature. Elemental gold
times seem to be insufficient and should be found in jewelry, such as earrings, rings, and
supplemented by a reading after 3 weeks necklaces, seems to make up the majority of
according to some (Bruze et al. 1995b). If intra- causes (Fowler 1987; Wiesner and Pambor
cutaneously injected GSTS was used, all test reac- 1998) (Fig. 2). It was shown that gold
tions appeared within the first week after testing, (0) dissolved in various aqueous amino acid solu-
making only a D7 reading useful, albeit intracuta- tions exposed to dioxygen, suggesting that gold
neous testing might lead to persistent nodules jewelry in close skin contact could slowly solubi-
(Bruze et al. 1995b). lize to gold complexes in sweat and be absorbed
through the skin (Brown et al. 1982), thus leading
to an allergic contact dermatitis from gold. The
9 In Vitro Testing process of dissolution of metallic gold is facili-
tated by the presence of other metals in the alloy or
A lymphocyte blast transformation test was posi- in the neighborhood (Brown et al. 1982; Holland
tive in a patient patch test allergic to GSTS 1980). The dermatitis under rings is often more
(Silvennoinen-Kassinen and Niinimäki 1984; severe in summer due to warm (Gaul 1954),
Aro et al. 1993) and GSTM (Kobayashi et al. humid (Elgart and Higdon 1971) weather or if
1992). In vitro blast transformation test was the ring is broad and tight (Comaish 1969). One
suggested to be of significant value in the diagno- patient stated that in cold weather he could wear
sis of gold contact dermatitis (Silvennoinen- gold jewelry for 4 days without problems, but in
Kassinen and Niinimäki 1984) and gold allergy warm weather it took only 2 days for the derma-
(Aro et al. 1993) and might be useful in the titis to appear (Fox et al. 1961). Gold allergy may
diagnosis of drug reactions due to systemic present solely as eyelid dermatitis (Bruze et al.
gold therapy used in rheumatic diseases (Silve-
nnoinen-Kassinen and Niinimäki 1984). A
positive lymphocyte transformation test in
12 of 13 arthritic patients with skin reactions to
systemic gold therapy was reported (Räsänen
et al. 1999). Several cytokines, such as IL-1 recep-
tor antagonist and TNF-α in particular, were
detected in the elicitation phase of gold allergy
in sensitized patients and also in the flare-up reac-
tion after systemic provocation (Möller et al.
1998). The TNF-α and the IL-1 receptor antago-
nist were released in blood when GSTM was
given by intramuscular injection to patients with Fig. 2 Allergic contact dermatitis from a gold necklace in
contact allergy to gold (Larsson et al. 1997). The a gold-allergic individual
46 Gold 677
1995a) and two women with eyelid dermatitis and eyelid to be able to close the eye. They all got an
contact allergy to gold cleared when avoiding inflammatory reaction due to gold allergy, and
gold jewelry (Fowler 1988). It was thought that when the implant was removed, the dermatitis
the allergen was being transferred from the hands resolved completely (Björkner et al. 2008).
to the eyelids. In a recent publication, six female Some authors propose that a personal and family
patients presented with isolated bilateral peri- history of gold allergy should be looked for before
orbital dermatitis. The average duration was 16.8 upper eyelid gold weight implantation. Patch test-
months prior to referral. Patch testing showed ing should be performed for patients where there
strong contact allergy to gold. When totally is doubt about whether gold has been the specific
discontinuing contact with gold jewelry, the aller- cause of previous allergic reactions, for patients
gic periorbital dermatitis completely resolved who have undergone previous dental restoration
(McDaniel and Couch 2017). It has been specu- involving gold, or if there is a positive family
lated that cosmetic powders that contain micro- history of gold allergy (Doyle et al. 2005).
abrasives such as titanium dioxide may abrade Gold rings, but also earrings, are believed to
jewelry and act as carriers to the face. Titanium sensitize, and several cases are reported where the
dioxide in cosmetics and physical blocker sun- piercing of ears (Comaish 1969; Fisher 1974a;
screens may adsorb gold particles from jewelry Armstrong et al. 1997), followed by wearing of
worn on hands or wrists but that this jewelry gold earrings, often studs, has resulted in an
occasionally come into contact with the facial eczema on the earlobes not long after (Elgart and
skin and in this way could lead to an allergic Higdon 1971; Petros and MacMillan 1973;
contact dermatitis such as facial or eyelid eczema Iwatsuki et al. 1982), and, at patch testing, allergic
despite not giving it on the primary site, i.e., hands reactions to various gold salts were noted (Elgart
or wrists. The same could apply to eyeglass and Higdon 1971; Petros and MacMillan 1973;
frames plated with gold (Nedorost and Wagman Iwatsuki et al. 1982; Nakada et al. 1997). Subse-
2005). In a North American Contact Dermatitis quent development of persistent papular elements
Group analysis, 445 (8.7%) of 5106 patients had on earlobes but without superficial eczematous
positive patch tests to gold, being the most com- changes have been seen, where the microscopic
mon allergen to induce eyelid allergen contact specimen showed dense dermal infiltration of
dermatitis, despite its general absence in eye cos- lymphocytes and plasma cells (Petros and Mac-
metics. The authors propose a trial of avoidance of Millan 1973; Fisher 1974c; Iwatsuki et al. 1982;
gold jewelry or titanium dioxide, even when Kobayashi et al. 1992; Fleming et al. 1997a). A
patients do not have dermatitis at the site of pri- lymphomatoid contact reaction to gold earrings
mary contact (Danesh and Murase 2015). due to persistent gold exposure has been
An orbital implant – a 14-carat gold ball – gave suspected, and gold has actually been identified
an eczematous reaction on the eyelids of a patient in a skin specimen taken from a dermatitic earlobe
4 years after its insertion (Forster and Dickey in a gold allergic woman that had not used gold
1949). In a study, 60 female patients with pierced studs for 4 months (Suzuki 1998) and also beneath
ears, test-positive to GSTS, wore earrings coated gold rings (Brown et al. 1982). Histological exam-
with gold or titanium nitride for 8 weeks. Around ination of earlobe nodules in another such patient
17 of the 60 female patients got a skin reaction, with persistent nodules demonstrated a sarcoidal-
either on the earlobes or distant, 12 of whom had type granulomatous reaction (Armstrong et al.
received gold-plated earrings compared to five 1997). After ear piercing and after the channel is
with titanium. The difference was statistically sig- epithelialized, any earrings may be inserted
nificant and the conclusion was that exposure to (Fisher 1974a, 1987).
gold jewelry can be clinically relevant in persons There is even a report on contact allergic der-
hypersensitive to gold (Ahnlide et al. 2000). Four matitis to gold in a tattoo (Tammaro et al. 2011).
patients with paralysis of the orbicularis oculi There is also a case of systemic allergic contact
muscle had a gold weight implanted in the upper dermatitis from gold in a homeopathic
678 M. Isaksson
medication, Aurocard, used for 4 months and said that there was a statistically significant correlation
to be good for “heart strengthening.” Aurocard between the intensity of the gold test reactions and
contained 5 g/mL elemental gold confirmed by the level of gold in blood, concluding that gold
atomic absorption spectrometry. The 76-year-old was released from the gold-plated stent and that
woman showed general malaise with a subfebrile patients with such a stent had a fivefold higher
temperature, intensely pruritic eruptions, and gold blood level than those with a nickel stent
itching of the perianal area. Patch testing showed (Ekqvist et al. 2008).
a very strong allergic reaction to GTST2% pet. Restenosis is the recurrence of stenosis at the
The patient was told to stop the Aurocard and after site of a previously successful intervention. The
2 days she reported that her perianal itching was factors predisposing to in-stent restenosis are still
gone and after 4 weeks she was completely clear largely unknown. Studies have reported higher
of her eczema. Not using Aurocard, 5 months restenosis rates with gold-plated stents than with
later, she was still clear of skin lesions stainless steel stents of the same configuration
(Malinauskiene et al. 2013). (Park et al. 2002) but contact allergy was not
evaluated. In the aforementioned retrospective
study comprising 484 patients treated with percu-
11 Stent Implantation and Gold taneous coronary interventions and stented, the
Allergy frequency of gold allergy was 39% in the gold-
stented group. A correlation between contact
Percutaneous coronary interventions are used to allergy to gold, gold-stent, and restenosis was
treat atherosclerotic coronary artery disease. The found with a threefold increased risk for restenosis
risk of restenosis has been shown to be greatly if the patient was gold allergic and stented with a
reduced by intravascular stenting. Among metal- gold-plated stent (Svedman et al. 2009).
lic implants, stents, some brands have been coated In vitro experiments have shown gold metal
with gold. A pilot study showed a high prevalence release from gold-plated metal coronary artery
of contact allergy to gold in patients given gold- stents when immersed in an extraction media
plated stents (Svedman et al. 2005). In a retro- made from artificial sweat and cysteine solution
spective study 484 patients, treated with coronary (Svedman et al. 2013). A great amount of gold
stent implantation, were patch tested to metals was released (Svedman et al. 2014). Given the
used in the stents, to investigate the contact allergy high rate of in-stent restenosis, the use of gold
rate, especially to gold and nickel. Results showed stents has been largely abandoned (Chen and
that the frequency of contact allergy to gold was Lampel 2015), and in recent years competing
higher in the stented patients compared to controls materials have gained favor.
irrespective of stent material. The authors
suggested that an induction of gold allergy was
possible through a gold-plated stent implanted in 12 Allergic Contact Stomatitis
the coronary vessel. They also found a statistically and Glossitis
significant correlation between the gold-plated
stents and contact allergy to gold in a multivariate Dental appliances, such as crowns (Wiesenfeld
analysis considering other risk factors for gold et al. 1984), bridges, and dentures (Fregert et al.
allergy, such as dental gold, old age, and ear 1979), have also been implicated in allergic con-
piercing (Ekqvist et al. 2007). tact stomatitis and glossitis. The first case of aller-
Nearly 460 patients treated with stenting gic contact stomatitis to metallic gold was
underwent patch testing with gold and nickel, reported in 1971, when a patient got irritation
and information on gold and nickel exposure and and superficial ulceration of the gingival mucosa
blood samples were collected. Blood samples of adjacent to a gold crown and where there already
200 patients were randomly selected to be ana- was a history of sensitivity to gold jewelry, such as
lyzed for gold and nickel in blood. Results showed earrings, rings, and a wristwatch. Patch testing
46 Gold 679
with GSTM and gold trichloride (0.5% aqueous) surfaces in dental gold alloys in examined patients
confirmed the contact allergy to gold (Elgart and and contact allergy to gold. However, no statisti-
Higdon 1971). After that, several cases were cal relationship to oral lesions was found (Ahlgren
published in which gold crowns have given sore- et al. 2002). Patients with dental gold restorations
ness and erosions of the tongue (Fisher 1974b), had a statistically significantly higher blood level
mucosal erosions (Klaschka 1975; Wiesenfeld of gold than patients without gold restorations.
et al. 1984), oral burning or stinging sensations There was also a positive correlation between
(Young 1974; Fregert et al. 1979; Aro et al. 1993), the blood level of gold and the number of dental
and where gold sensitizing was considered to be gold surfaces, implying that gold is released from
due to earrings (Fisher 1974b) and a signet ring dental restorations and taken up into the circula-
(Wiesenfeld et al. 1984). After removal of the tion (Ahnlide et al. 2002).
incriminating gold, the patient has usually recov- An increased frequency of patch test positivity
ered fully (Elgart and Higdon 1971; Fisher 1974b; to gold was found in patients with oral lichenoid
Wiesenfeld et al. 1984). Primarily gold stomatitis lesions compared to dermatitis patients without
seems rare, and only a few cases have been oral problems (Ahlgren et al. 2012). Others have
reported (Schöpf et al. 1970; Young 1974; Fregert not found an association between oral gold and
et al. 1979; Aro et al. 1993), in which gold appli- oral lichen planus but an increased risk for oral
cations, such as crowns, bridges, and dentures, lichen planus in the presence of dissimilar metals
soon after insertion gave problems in the oral in contact with each other in the mouth as well as
mucosa, and in which tests were positive for amalgam corrosion (Martin et al. 2003). A single
gold salts and no history of gold jewelry intoler- patient with oral lichenoid reactions and contact
ance was found prior to this event. Oral mucosal allergy to gold from dental restorations deterio-
reactions ascribed to gold allergy are rare, and the rated when stented with a gold-plated intra-
reason for this is thought to be due to the low coronary implant. When the dental gold was
solubility of metallic gold. Still, the moist oral removed, the patient slowly recovered in the
environment with bacteria, enzymes, and other mouth (Svedman et al. 2006).
substances in the saliva may dissolve gold and
thus form allergenic gold compounds (Aro et al.
1993; Björkman et al. 1998) (Fig. 3). 13 Occupational Exposure
In the last 10–15 years, it has been shown that and Allergic Contact Dermatitis
gold-based dental restorations seem to be an
important risk factor for gold allergy. A significant Sporadic cases of occupational contact dermatitis to
correlation was found between the amount of gold gold salts in gold electroplaters have been reported
(Somov and Khaimovsky 1964; Schmollack 1971;
Cronin 1980; Adams 1983; Goh 1988; Larsen et al.
1992); nevertheless, gold salts should be considered
as significant sensitizers in electroplaters. The rea-
son sensitization seems uncommon is claimed to be
due to the infrequent contact with the salts by
workers, as factory supervisors only are allowed
to handle and prepare the salts. These salts are
usually locked away due to their toxicity (Goh
1988). Potassium dicyanoaurate sensitized a Chi-
nese electroplater leading to a subacute dermatitis
on exposed skin, beginning 2 weeks after starting
the work (Goh 1988).
Fig. 3 Parodontitis in a gold-allergic individual with a Those who gild porcelain, enamel, and glass,
ceramic crown on a gold-alloy post where gold hydroxide, potassium, and sodium
680 M. Isaksson
gold trichloride are often used, may contract aller- necklaces and earrings. She reacted positively to
gic contact dermatitis (Björkner et al. 1994). a patch test to GSTS. Cotton gloves improved her
Gold cyanide sensitized Russian workers gild- hand dermatitis markedly (Felix and Ducombs
ing watches, and patch testing was performed 1993). Another gold allergic jewelry saleswoman
using 1.0% gold cyanide (Somov and had severe hand dermatitis which resolved
Khaimovsky 1964). Another woman worked in completely when she took leave of absence from
gilding of fountain pens and prepared the gold salt work (Sperber et al. 2003).
bath. Hand eczema and asthmatic dyspnea soon A merchant jeweler had fingertip dermatitis
followed, and patch testing showed her to be and experienced great difficulty in handling jew-
allergic to the gold bath (Sidi and Hincky 1965). elry. A positive reaction to gold leaf showing as a
Airborne dermatitis has also been reported in bright erythema was noted. A generalized purpu-
those involved in gold smelting, gilding, and gold ric eruption resembling allergic vasculitis flared
plating, particularly involving the eyelids and on three patch-test occasions utilizing gold leaf.
neck (Giorgini et al. 2010; Tan and Delaney The authors state, that the cutaneous vasculitis
1996; Estlander et al. 1998). was produced through prolonged cutaneous expo-
In Germany, gold plating with potassium sure to elemental gold, although they do not rule
dicyanoaurate led to a hand and face contact der- out a toxic reaction due to topical absorption from
matitis in three of ten workers. The eruptions the patient’s hands or the gold dental fillings the
came after 3 weeks to 3 months of starting work. patient had had for several years (Roenigk and
The patients were positive to 1.0% gold tri- Handel 1974).
chloride at patch testing and two of these also to In a study from Italy, the incidence of allergic
0.01% potassium dicyanoaurate aqueous contact dermatitis due to gold in 60 jewelers
(Schmollack 1971). (13 men, 47 women) was evaluated. Among
A gold-allergic glass etcher had hand dermati- them, 18% (two men and nine women, 82%) of
tis attributed to her gold-etching instrument, the individuals had a contact allergy to gold as
which resulted in the dispersion of gold particles shown with a positive patch test to gold chloride
during etching. She improved when she stopped 0.1% aqueous (Vassilopoulou and Bertazzoni
etching glass (Sperber et al. 2003). 1997). A machinist in a gold jewelry manufactur-
A man accidentally rested his bare right fore- ing plant had a hand eczema that went away when
arm on a laboratory bench where crystals of gold he was off work and relapsed when at work. Patch
trichloride were present, and irritation and subse- testing to GSTS 0.5% was positive (Collet et al.
quent sensitization to gold followed, presenting as 1994).
pigmented papules and with no eczematous Dentists, dental technicians, those who work in
change. A pathological specimen of a papule gold recycling, and gold miners may be exposed
showed lymphoma-like features, and a patch test to gold and may become sensitized (Björkner
to gold trichloride 1.0% appeared as a local, et al. 1994).
delayed, papular, noneczematous reaction, Japanese students involved in the manufacture
whereas a patch test to gold potassium chloride of prosthetic materials in a dental clinic were
1.0% resulted in an eczematous picture clinically shown to be hypersensitive to gold (Kawahara
(Shelley and Epstein 1963). et al. 1993). An Estonian study comprising
Gold trichloride is said to cause dermatitis 80 employees of dental clinics and 80 sex- and
among photographers who use it in their work age-correlated dermatitis patients were patch
(Fox et al. 1961). tested with GSTS 2.0% pet. No difference in
After working 10 years, a female sales clerk in gold allergy was shown. 21.3% of the dental per-
jewelry had dyshidrotic eczema of the fingers and sonnel and 27.5% of the dermatitis patients
intolerance to wearing gold jewelry, such as reacted to gold (Kaur et al. 2006).
46 Gold 681
14 Occupational Exposure nodosum, pemphigus flares, exfoliative derma-

and Irritancy titis, and toxic epidermal necrolysis, which is
sometimes fatal. Loss of taste, metallic taste,
When refining and extracting gold from other and glossitis are also reported (Thomas 1987).
metals sometimes present in ores, workers are Side effects may prompt up to 45% of patients to
exposed to skin, eye, and mucous membrane- discontinue therapy (van Gestel et al. 1994). It
irritating chemicals, such as hydrocyanic acid was suggested that some of the frequent cutane-
and sulfur monochloride (Adams 1990). In the ous side effects of systemic gold therapy were
gold electroplating industry, irritating gold salts due to a previous, but unrecognized, contact
such as gold potassium cyanide and gold sodium allergy to gold (Möller et al. 1996). Speaking
cyanide are used, and they bare a high level of against this theory is a study involving 55 rheu-
irritancy because of their acidity (Cronin 1980). A matoid arthritis (RA) patients, 35 of whom had
man worked with cleaning gold electrode contacts received gold therapy and 20 who had not; these
and in the mixture where these were placed, gold individuals were patch tested with GSTS 0.5%
potassium cyanide was formed. After 2 years and 0.05% petrolatum. All but one, who had
without mishap, he suddenly developed scattered never received gold, was negative (Fleming
sterile pustules on the backs of the fingers of the et al. 1998). Skin testing for contact allergy to
right hand and erosions of the lower lip. When he gold was also carried out in 77 patients with RA;
was off work for 2 weeks, both sets of lesions positive skin tests to gold were found to be
healed, but a purplish-brown discoloration and 10.4%. When dividing the 77 into a retrospec-
partial onycholysis of the free ends of most of tive group, i.e., treatment with gold previously,
his fingernails on the right hand developed. A and a prospective group (intended for gold ther-
month later, the nails had returned to normal apy), gold allergy was observed in 1 of
(Budden and Wilkinson 1978). A woman made 57 (1.8%) and in 7 of 20 (35.0%) patients,
up solutions of potassium gold cyanide for 1 year, respectively. The almost nonexisting gold
when she then presented with eczema on the volar allergy in the rheumatic patients after long-
surfaces and sides of her fingers. Patch testing term administration of gold salts was hypothe-
with different gold salts gave irritant responses sized to be due to a hyposensitization phenome-
(Cronin 1980). A man cleaning gold clock faces non. The authors conclude that RA patients
at work presented with erythematous pruritic der- intended for chrysotherapy should probably
matitis with papules on the trunk and forearms, first be investigated for gold allergy, but that a
where patch testing showed a positive reaction positive skin test to gold does not necessarily
only to gold chloride 0.1%. He was seen with an contraindicate further treatment with gold.
erythematous circular plaque at the site of the Starting with a low dose of gold and gradually
former patch test, 8 months later. The patch test increasing it seems to work in selected cases
was repeated but with a negative result. The for- (Möller et al. 1997).
mer test was interpreted as false positive (Monti
et al. 1983).
16 When Should Gold Be Patch
Tested?
15 Chrysotherapy
• Gold should be tested in dental series and metal
The most common side effects of gold therapy series.
are mucocutaneous reactions (Svensson and • Gold should be tested in cases of eyelid and/or
Theander 1992), such as pruritus, lichen planus facial dermatitis or when jewelry allergy is
and pityriasis rosea-like eruptions, erythema suspected. Testing should also be considered
682 M. Isaksson
when there is dermatitis of the ears, hands, Armstrong DKB, Walsh MY, Dawson JF (1997) Granulo-
or neck. matous contact dermatitis due to gold earrings. Br J
• Gold should be tested in potential occupational Aro T, Kanerva L, Häyrinen-Immonen R, Silvennoinen-
exposure. Kassinen S, Konttinen YT, Jolanki R, Estlander T
(1993) Long-lasting allergic patch test reaction caused
by gold. Contact Dermatitis 28:276–281
Asthner B (1990) Textbook of electrolytic and chemical
17 Treatment and Prevention finishing (in Swedish). Ytforum Förlags AB,
Linköping
Dermatitis caused by metallic gold and gold salts Björkman L, Ekstrand J, Lind BB (1998) Determination
occurring on the skin is treated as other cases of of gold released from dental alloys in saliva (abstract).
J Dent Res 77:765
contact dermatitis are treated. As gold salts are Björkner B, Bruze M, Möller H (1994) High frequency of
strong sensitizers and irritants, the latter mainly contact allergy to gold sodium thiosulfate. An indica-
due to their acidity, care should be taken to pre- tion of gold allergy? Contact Dermatitis 30:144–151
vent direct skin contact with these chemicals. Björkner B, Bruze M, Möller H et al (2008) Allergic
contact dermatitis as a complication of lid loading
Proper protective equipment, such as gloves and with gold implants. Dermatitis 19:148–153
other protective garments, is sufficient. Bowyer A (1967) Epidermal reactions and prolonged der-
Dental patients with gold allergy should not be mal reactions to patch testing with gold salts. Acta
given dental gold restorations. However, if they Derm Venereol 47:9–14
Brown DH, Smith WE, Fox P, Sturrock RD (1982) The
already have such restorations and have no signs reactions of gold (0) with amino acids and the signifi-
of mucosal lesions, there is no need to remove the cance of these reactions in the biochemistry of gold.
gold from the mouth. Inorg Chim Acta 67:27–30
Gold-allergic patients should refrain from Bruze M, Björkner B, Möller H (1995a) Skin testing with
gold sodium thiomalate and gold sodium thiosulfate.
using the gold jewelry that gives them problems. Contact Dermatitis 32:5–8
Gold-allergic patients with facial or eyelid derma- Bruze M, Hedman H, Björkner B, Möller H (1995b) The
titis and that wear make-up or physical blocker development and course of test reactions to gold
sunscreens should refrain from either skin prod- sodium thiosulfate. Contact Dermatitis 33:386–391
Bruze M, Björkner B (1996) Patch testing with gold
ucts containing titanium dioxide or wearing gold sodium thio-sulfate. Abstract 49, Jadassohn Centenary
jewelry for several months to see whether this Congress, London
alleviates or cures the dermatitis. Budden MG, Wilkinson DS (1978) Skin and nail lesions
from gold potassium cyanide. Contact Dermatitis
4:172–173
Cavelier C, Foussereau J (1995) Kontaktallergie gegen
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Some Other Metals
47
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
3 Aluminum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
4 Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
5 Beryllium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
6 Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
7 Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
8 Mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
9 Palladium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
10 Platinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
11 Rhodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
12 Silver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
13 Tin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Abstract Pure metals, alloys, and metal compounds

Several metals such as aluminum, beryllium, have different abilities to cause sensitization
copper, gold, mercury, palladium, platinum, and dermatitis. Furthermore many of the
and rhodium are able to cause skin sensitiza- metals and their compounds are also known
tion, allergic contact dermatitis, and other skin to cause systemic toxicity and cancer.
effects. The clinical relevance of patch test reactiv-
ity to some of these metals is not known. The
prevalence of contact allergy in occupationally
exposed groups, consumers, or dermatitis
A. Julander (*) · C. Lidén
Institute of Environmental Medicine, Karolinska Institutet, patients is also not known for all of these
Stockholm, Sweden metals. However, some of the precious metals
e-mail: anneli.julander@ki.se; carola.liden@ki.se

https://doi.org/10.1007/978-3-319-68617-2_47
are increasingly used in dental alloys and jew- effect in exposed workers, consumers, and derma-
elry and may pose new health risks. titis patients. The knowledge base consists mainly
of case reports and few workplace studies. Even
Keywords less is known about the causes and levels of skin
Alloys · Aluminum · Arsenic · Beryllium · exposure or the properties of the pure metals and
Cadmium · Copper · Dentistry · Granuloma · their alloys in contact with the skin. There is also
Jewelry · Metal compounds · Mercury · Metal limited experience of patch testing with the
salts · Occupational exposure · Palladium · metals, except palladium. Table 2 summarizes
Platinum · Rhodium · Silver · Systemic patch test substances used, but it should be noted
toxicity · Skin effects · Tin that the experience of their use is limited. Consid-
erably more is known concerning systemic expo-
sure by inhalation or oral intake of some of the
1 Core Messages most toxic metals.
To improve diagnosis and prevention of work-
• Several metals such as aluminum, beryllium, related skin disease caused by metals, it is essen-
copper, gold, mercury, palladium, platinum, tial to learn more about skin exposure and prop-
and rhodium are able to cause skin sensitiza- erties of metals and their compounds in contact
tion, allergic contact dermatitis, and other skin with the skin. This is important also for the pre-
effects. vention of systemic toxicity by skin absorption of
• Pure metals, alloys, and metal compounds metals. Acid wipe sampling is a method for
have different abilities to cause sensitization assessing skin exposure to nickel, chromium,
and dermatitis. and cobalt, which can be used also for other
• Many of the metals and their compounds are metals (Julander et al. 2010; Lidén et al. 2008).
known to cause systemic toxicity and cancer. Metals are often categorized based on their
• The clinical relevance of patch test reactivity to physical or chemical characteristics or cost.
some of the metals is not known. Some of the commonly used and overlapping
• The prevalence of contact allergy to many categories are light, heavy, precious, platinum,
metals in occupationally exposed groups, con- transition, toxic, essential, and soluble metals.
sumers, or dermatitis patients is not known. However, the terminology is not used consis-
• Some of the precious metals are increasingly tently, and it may sometimes be confusing but
used in dental alloys and jewelry and may pose also helpful for understanding.
new health risks.
3 Aluminum
2 Introduction
Aluminum (Al) is the most frequently occurring
Several metals besides nickel, chromium, and metal in the earth’s crust, and it is present as
cobalt may cause adverse skin effects. The most bauxite in nature. The production requires much
well-known skin effects caused by metals and energy, and recycling of aluminum has increased
their compounds are allergic and irritant contact significantly during recent decades. Aluminum
dermatitis, but also granuloma and pigmentation and aluminum alloys are used in a wide range of
occur (Table 1). Nickel, chromium, cobalt, and materials and products, many of which come in
gold are reviewed separately in other chapters in contact with the skin of workers and consumers.
this book, and some other metals are briefly Examples are construction materials, vehicles,
described below. packaging of food and beverages, and cookware.
Very little is known concerning the other In an extensive health risk assessment report
metals and the prevalence of contact allergy, aller- (Krewski et al. 2007), it was concluded that
gic and irritant contact dermatitis, and other skin workers in aluminum production and user
47 Some Other Metals 689
Table 1 Potential of metals or metal compounds to cause et al. 1999). Chromium, cobalt, gold, and nickel are
contact dermatitis or other skin effects (Lidén et al. 2011; described in other chapters of this book
Rietschel and Fowler 2008; Lidén et al. 1995; Burrows
Metal or metal Irritant contact Allergic contact
compound dermatitis dermatitis Other skin effect
Aluminum (Al) x x Granuloma
Arsenic (As) x – Folliculitis, ulcerations, pigmentation,
keratosis, cancer
Beryllium (Be) x x Granuloma, ulcers
Cadmium (Cd) x – Granuloma, phototoxic reactions
Chromium (Cr) x x Granuloma
Cobalt (Co) x x Urticaria, granuloma
Copper (Cu) x x Pigmentation
Gold (Au) x x Pigmentation, granuloma
Mercury (Hg) x x Pigmentation, depigmentation, granuloma
Nickel (Ni) x x
Palladium (Pd) – x Granuloma, urticaria
Platinum (Pt) – x Urticaria
Rhodium (Rh) – x
Silver (Ag) x – Pigmentation (argyria)
Tin (Sn) x –
x = confirmed; = less certain or not known
Table 2 Examples of patch test preparations for other metals industries experience considerable exposure.
and metal compounds than those included in the European
Asthma-like symptoms (potroom asthma) and
baseline series. It should be noted that experience from testing
with many of the substances is limited and scientific literature neurological symptoms have been extensively
should be consulted before testing (Lidén et al. 2011; investigated. Sufficient evidence to bladder can-
Rietschel and Fowler 2008) cer and to a lesser extent lung cancer has been
Concentration reported in aluminum smelters (IARC 2012). Alu-
Metal Substance in vehicle minum production is classified as carcinogenic to
Aluminum Aluminum chloride 2% or 10% humans (Group 1) by IARC. There are still large
(Al) hexahydrate, pet100% (patch
research needs to assess these risks. The safety of
andaluminum metal test chamber)
Arsenic (As) Sodium arsenate 1% or 10% aq
aluminum in cosmetics has been assessed by the
Beryllium Beryllium chloride 1% pet Scientific Committee on Consumer Safety
(Be) or sulfate (SCCS) (SCCS 2014). It was concluded that alu-
Cadmium Cadmium chloride 0.5% pet minum is a known systemic toxicant at high
(Cd) doses, but owing to the lack of data on dermal
Copper (Cu) Copper sulfate 2% pet penetration from cosmetics, a risk assessment
Mercury Mercuric chloride 0.05% aq could not be performed.
(Hg)
Aluminum is a weak skin sensitizer, and con-
Palladium Palladium chloride 1% pet
(Pd) tact allergy to elemental aluminum is considered
Platinum (Pt) Ammonium 0.25% pet very rare. Aluminum-adsorbed vaccines have
tetrachloroplatinate caused contact allergy to aluminum and persistent
Rhodium Rhodium chloride 1% aq subcutaneous nodules from hyposensitization
(Rh) therapy (Bergfors and Trollfors 2013). Water-
Silver (Ag) Silver nitrate 1% aq soluble aluminum salts are widely used as anti-
Tin (Sn) Tin chloride 1% or 0.5% pet perspirants and may cause axillary derm-
pet = petrolatum; aq = water atitis, generally irritant contact dermatitis, or
granulomatous reactions (Böhler-Sommeregger Arsenic dermatitis is seen mainly in smelter

and Lindemayr 1986). workers and also in mining and glass production.
Occupational exposure to aluminum has been Irritant contact dermatitis and follicular reactions
reported to cause itch and contact dermatitis in are most frequent. Cases of allergic contact der-
aluminum production, in aircraft manufacture, matitis have been described (Rietschel and Fowler
and in a machine construction plant (Peters et al. 2008; Burrows et al. 1999).
1998; Lidén et al. 2011). Cold sealing of alumi- Occupational risk for skin cancer by arsenic
num with nickel fluoride constitutes a risk of exposure occurs in the manufacture of insecticides
contact dermatitis when handling aluminum prod- or herbicides; by agricultural exposure to pesti-
ucts, however not from aluminum but from nickel cides; in smelting of copper, lead, and zinc; and
ions on the surface of cold-sealed items (Lidén mining of arsenic. Systemic absorption via inges-
1994). tion is considered to be the main exposure route
Patch testing is generally performed with an rather than skin absorption (Gawkrodger 2004).
empty Finn Chamber (elemental aluminum) and One percent or 10% sodium arsenate in water
with aluminum chloride hexahydrate 2% in pet. may be used for patch testing.
Aluminum-allergic persons may sometimes have
a false-negative response when tested, and a pos-
itive result may not always be reproducible. A 5 Beryllium
study by repeated testing concluded that reactivity
to aluminum varies over time and that retesting Beryllium (Be) is a light metal, which is hard and
may be needed when contact allergy to aluminum has a relatively high melting point. It is used as the
is suspected (Siemund et al. 2017). metal in alloys and as its oxide. Most is used as
hardening agent in alloys, particularly in copper-
beryllium. Beryllium alloys have wide applica-
4 Arsenic tions such as in nuclear weapons, aerospace,
ceramics, fluorescent lights, medical equipment,
Arsenic (As) is a widely distributed metalloid. dental alloys and orthodontics, electronic equip-
Inorganic arsenic is present in groundwater, salt ment, and also consumer items that come into
water, and metal ores. Organic arsenic compounds contact with the skin (golf clubs, fishing rods,
are primarily found in fish and shellfish. Arsenic jewelry, etc.). The majority of beryllium is pro-
compounds are used as wood preservatives, insec- duced in the USA.
ticides, herbicides, and rodenticides. They are Beryllium is extremely toxic. Exposure may
added to animal food and have had medical use. cause acute inflammation of the lungs and pneu-
White arsenic (arsenic trioxide) is a by-product of monitis. Chronic occupational exposure by inha-
the smelting of copper and other metals. lation may result in chronic beryllium disease
Inorganic arsenic is acutely toxic, and intake of (berylliosis), in which granulomatous lesions in
large quantities may lead to death. Exposure to the lungs reduced lung capacity and general
arsenic is mainly via food and drinking water, and symptoms are seen. Chronic beryllium disease is
long-term exposure to arsenic in drinking water is a cell-mediated immune response. Sensitization
related to increased risks of skin cancer but also can be measured with a beryllium-specific lym-
some other cancers (Vahter et al. 2007). Occupa- phocyte proliferation test (Kreiss et al. 2007).
tional exposure to arsenic, primarily by inhala- IARC has classified beryllium and beryllium
tion, is associated with lung cancer (Järup 2003; compounds as carcinogenic to humans (Group 1).
Wild et al. 2009) and several nonmalignant lung Beryllium may cause irritant contact dermati-
pathology findings (Ergun et al. 2017). The Inter- tis, allergic contact dermatitis, chemical ulcers,
national Agency for Research on Cancer (IARC) ulcerating granulomas, and allergic dermal gran-
has classified arsenic and inorganic arsenic com- ulomas (Berlin et al. 2003). It is a skin sensitizer as
pounds as carcinogenic to humans (Group 1). shown by human maximization test (HMT),
guinea pig maximization test (GPMT), and local food and smoking (Vahter et al. 2007; Järup
lymph node assay (LLNA) (Kligman 1966; 2003). Cadmium red (cadmium selenide) has pre-
Wahlberg and Boman 1985). viously been used for coloration of dentures. Yel-
In 1951, contact allergy to beryllium was first low cadmium sulfide is used as a pigment for
diagnosed by patch testing with various beryllium yellow and red tattoos.
salts in workers at two beryllium plants (Curtis According to the EU chemicals regulation
1951). Since then, cases of contact allergy have (REACH), cadmium and its compounds are
been described, among them a dental technician restricted in many mixtures and articles including
with hand eczema and dental patients with stoma- new plastic materials, paints, and jewelry.
titis from beryllium-containing dental alloys (Ber- According to the EU directive on electric and
lin et al. 2003; Rietschel and Fowler 2008; electronic equipment (RoHS Directive), cadmium
Burrows et al. 1999). A worker in beryllium is restricted in electrical and electronic equipment,
alloy production developed simultaneously gran- including batteries but with exception for cad-
ulomatous eruptions on the arms and legs and mium platings. Acute toxicity may be fatal, and
symptoms of chronic beryllium disease (Berlin chronic toxicity affects many organs (kidney,
et al. 2003). lung, bones, hematopoietic system, and cardio-
Attempts to prevent chronic beryllium disease vascular system). The itai-itai disease in Japan
by reduction of inhalation of beryllium have often affected mainly women (Vahter et al. 2007;
failed. A study of levels of beryllium in workplace Järup 2003). IARC has classified cadmium and
air, on work surfaces, and on necks and faces of cadmium compounds as carcinogenic to humans
employees was performed at a beryllium alloy (Group 1).
facility. It was concluded that the skin may be an The skin sensitizing potential of cadmium
important route of exposure for sensitization and chloride was evaluated in a guinea pig maximiza-
chronic beryllium disease and that it is necessary tion test (GPMT), and no statistically significant
to minimize also skin exposure to beryllium salts reactivity was noted in induced animals compared
and fine particles (Day et al. 2007). It has recently to controls (Wahlberg and Boman 1979). Cad-
been shown that beryllium ions are released from mium sulfides in tattoos may cause phototoxic
particulate beryllium materials, copper-beryllium reactions and sarcoid-like granulomas.
alloys, and copper-beryllium tools in artificial Three large series of dermatitis patients were
sweat, suggesting that skin exposure is a pathway patch tested with different preparations of cad-
for sensitization and chronic beryllium disease mium chloride. The overall conclusion from test-
(Stefaniak et al. 2011). ing with cadmium chloride 2% in water
Patch testing has been performed with beryl- (Wahlberg 1977) and cadmium chloride 1% in
lium chloride or sulfate 1% in petrolatum. petrolatum (Gebhart and Geier 1996) was that
seen reactions were irrelevant. 0.5% has been
recommended for patch testing (Geier et al. 1996).
6 Cadmium
Cadmium (Cd) belongs to the heavy metals. It is 7 Copper

one of the most toxic metals and environmental
poisons. Cadmium occurs naturally together with Copper (Cu) is an important metal in the industry.
zinc and is a by-product of zinc production. The Pure copper is soft and has high electrical
major part is used in rechargeable nickel- and thermal conductivity. More than half of the
cadmium batteries. Cadmium and cadmium com- production is used in electrical equipment, and
pounds are also used as pigment in paints, for other high-volume uses are in roofing and plumb-
plating, and as stabilizer in plastic materials. The ing. Copper is widely used in alloys; copper-tin
main industrial exposure is to fumes and dust by alloys are called bronzes and may contain also
inhalation, and environmental exposure is via other metals; copper-zinc alloy is called brass.
Copper-nickel alloys have a wide use in coinage, Mercuric sulfide (cinnabar) is a red pigment used
and copper is used in gold and silver alloys. Cop- in tattoos.
per sulfate and organic copper salts are used in Due to its toxicity, mercury has been banned or
agriculture as fungicide and algaecide. restricted for certain applications in many coun-
The skin sensitizing potential of copper sulfate tries. According to the EU batteries directive,
and other copper compounds was evaluated in ani- mercury is banned in batteries, and it is banned
mal experiments; in the guinea pig maximization in thermometers, barometers, and some other
test (GPMT), it was graded as a weak sensitizer or instruments. According to the EU directive on
grade I allergen (Karlberg et al. 1983; Basketter electric and electronic equipment (RoHS Direc-
et al. 1996); in the local lymph node assay tive), mercury is restricted in electrical and elec-
(LLNA), it was a sensitizer (Karlberg et al. 1983; tronic equipment. Mercury and its compounds are
Basketter et al. 1996; Fukuyama et al. 2008). highly toxic to the environment and humans. The
Concentrated solutions of copper sulfate are nervous system, kidneys, and other organs are
corrosive and cause skin irritation. This is an affected. Methylmercury poisoning may be very
effect due to the oxidation of elemental copper severe and even fatal. Intake of contaminated fish
occurring when in contact with sweat on the skin, and of mercury-polluted grain resulted in large
which also facilitates copper ions penetrating skin catastrophes in Japan and in Iraq (Järup 2003).
layers (Pirot et al. 1996b; Pirot et al. 1996a; Systemic mercury poisoning in the industry is
Hostynek and Maibach 2006). caused by contamination by mercury from broken
Copper has generally been considered a rare thermometers, etc. Occupational exposure to
skin sensitizer, and only few occupationally metallic mercury is also caused by dental amal-
related cases have been described (Rietschel gam in dentists, dental nurses, and dental techni-
and Fowler 2008; Lidén et al. 2011; Hostynek cians who may develop contact allergy (Kanerva
and Maibach 2004; Fage et al. 2014). Cases of et al. 1993; Lee et al. 2001; Burrows et al. 1999).
systemic eczematous dermatitis have been Non-occupational exposure to mercury-
related to copper-containing intrauterine contra- containing antiseptics (merbromin), preservatives
ceptive devices (IUCD), and cases of oral lesions (thimerosal) in vaccines and contact lens solution,
have been related to dental fillings and orthodon- cosmetics, skin-lightening creams, shampoos and
tic materials. When copper sulfate (2% in petro- antifungal agents, and mercuric sulfide (cinnabar)
latum) was used for patch testing in two large in tattoos may cause sensitization and dermatitis
series of dermatitis patients, 1% and 3.5% of the (Burrows et al. 1999). Mercury may also permeate
patients were test positive, but the reactions were through the skin, but this process is highly depen-
considered to be uncertain or non-relevant dent on the skin dose applied (Sartorelli et al.
(Karlberg et al. 1983; Wöhrl et al. 2001). Also 2003).
other patch test concentrations have been There is no general consensus regarding which
suggested. mercury compounds to use for patch testing. Mer-
cury compounds may be irritant to the skin, and
aqueous solutions of mercury salts may react with
8 Mercury aluminum in Finn Chambers to produce irritant
compounds. Patch test reactivity to thimerosal is
Mercury (Hg) belongs to the heavy metals, and it considered to indicate mercury allergy.
is liquid at room temperature. Mercury is one of
the most toxic metals and environmental poisons.
Mercury and its compounds are used in many 9 Palladium
industrial processes and products: in the chlor-
alkali process, dental amalgam, cosmetics and Palladium (Pd) is a silvery-white metal, belonging
medicines, as preservative and pesticide, in ther- to the platinum group of metals and the precious
mometers, fluorescent lamps and batteries, etc. metals. It has high resistance to corrosion. Its main
uses are as a catalyst and in electric and electronic is more suitable for patch testing (Muris et al.
equipment as contacts, platings, and solders. 2008). The clinical relevance of routine patch
It is used in jewelry, mainly as whitener in white testing with palladium has been questioned,
gold. Palladium nanoparticles are used widely because few clinically relevant cases of palladium
in applications such as jewelry, catalytic allergy have been reported, and the significance of
converters, biomedical applications, and elec- the reactions is not fully understood. Patch testing
tronic devices. Palladium is increasingly used with metallic palladium has been negative (Bur-
in dental alloys. Palladium-containing dental rows et al. 1999; Lidén et al. 2011; Faurschou
restorations have caused oral lichenoid lesions, et al. 2011).
xerostomia, allergic contact dermatitis, and metal- Palladium nanoparticles have been shown to
lic taste in patients (Muris et al. 2015). Occupa- penetrate into and accumulate in both intact and
tional asthma and urticaria are known to be caused damaged human skin, using in vitro diffusion
by the platinum group of metals, including palla- cells (Larese Filon et al. 2016).
dium in refineries and electroplating and catalyst
and recycling industry (Daenen et al. 1999;
Cristaudo et al. 2005). 10 Platinum
Palladium chloride has been shown to be a
potent skin sensitizer in the guinea pig. Animals Platinum (Pt) is a gray-white metal, belonging to
induced with palladium chloride do also react to the platinum group of metals and the precious
nickel sulfate and vice versa. The results are metals. It has high resistance to corrosion. Its
interpreted as being due to cross-reactivity main uses are in jewelry, electronics, dental indus-
(Wahlberg and Lidén 1999; Wahlberg and try, and as a catalyst in vehicle emission control.
Boman 1992). Occupational exposure to platinum occurs in min-
Since the 1980s, palladium chloride has been ing, refineries, and manufacturing of catalysts and
included in routine patch testing in many clinics. jewelry.
Patch test results between 1981 and 2008 Exposure to platinum salts is known to cause
concerning palladium allergy were compiled asthma, rhinitis, eye irritation, contact urticaria,
from numerous publications (Faurschou et al. and contact dermatitis. Occupational asthma and
2011). The median prevalence in dermatitis urticaria and positive skin prick tests to platinum
patients and dental patients was equal (7.8% and salts were shown in studies of precious metal
7.4%, respectively), and only small proportions in refinery workers (Baker et al. 1990) and workers
both groups were allergic to palladium without in catalyst manufacturing (Cristaudo et al. 2005).
concomitant nickel allergy. These findings sup- Single cases of occupational contact allergy to
port that patch test reactions to palladium gener- platinum salts have been described in refinery
ally are explained by cross-reactivity in nickel- workers, a chemical process worker, and an ana-
sensitized individuals, as in animal experiments. lytical chemist (Watsky 2007; Lidén et al. 2011).
Only single cases of occupational contact der- Ammonium tetrachloroplatinate is a skin sen-
matitis from palladium have been reported includ- sitizer according to the local lymph node assay
ing two analytical chemists working in precious (LLNA) (Basketter et al. 1999). Platinum metal
metal analysis (Munro-Ashman et al. 1969; has however been questioned as a cause of skin
Watsky 2007). They had work-related hand sensitization. When 446 dermatitis patients were
eczema or facial lesions and were patch test pos- patch tested with ammonium tetrachloroplatinate
itive to palladium chloride. One case was also test (0.25% in water) to assess the prevalence of
positive to nickel, the other to platinum and gold allergy, only 2 were patch test positive (Fowler
sodium thiosulfate. et al. 2008).
Patch testing is generally performed with pal- Ammonium tetrachloroplatinate (0.25%) and
ladium chloride 1% in petrolatum. It has been ammonium hexachloroplatinate (0.1%) have
suggested that sodium tetrachloropalladate (3%) been used for patch testing. The experience is
however limited, and they may cause irritant reac- 12 Silver

tions. Platinum salts and nanoparticles are able to
penetrate into and retain in the human skin, shown Silver (Ag) is a white and soft precious metal with
with in vitro diffusion cell experiments (Mauro the highest electrical and thermal conductivity.
et al. 2015; Franken et al. 2014). Among the main uses of silver are in photography
and jewelry and industrial applications. The use of
silver in photography is however declining, while
11 Rhodium silver is increasingly used as biocide for surface
treatment of products in contact with the skin.
Rhodium (Rh) is a hard, corrosion-resistant sil- This is controversial due to the environmental
very-white metal, belonging to the platinum toxicity of silver and also due to known and
group of metals and the precious metals. The suspected health risks.
main uses are as catalyst and in jewelry and Bluish-gray discoloration of the skin (argyria)
electronics, and among other things, it is used or eyes (argyrosis) is an adverse health effect of
in high-reflective mirrors and nozzles for glass- exposure to soluble silver. The lesions from
fiber spinning. Rhodium is often alloyed with direct contact are considered to be localized
platinum or palladium, and sterling silver and and reversible but generalized and irreversible
white gold are often plated with a thin layer of from inhalation, ingestion, or injection. Expo-
rhodium. sure to soluble silver compounds may also
Little is known about the toxicology of rho- cause other toxic effects, while metallic silver
dium. Rhodium chloride is a potent sensitizer in appears to pose little risk to health (Drake and
guinea pigs. Animals induced with rhodium chlo- Hazelwood 2005).
ride also reacted to cobalt chloride indicating Argyria has been described in the photographic
cross-reactivity, the clinical relevance of which industry, from wound dressings, and from other
is not known (Lidén et al. 1995). Rhodium ions applications. Silver-treated textiles are used in the
were not released from a range of gold- and treatment of atopic dermatitis. The increasing use
rhodium-containing jewelry alloys stored in arti- of silver in healthcare is controversial. The effec-
ficial sweat for 1 and 3 weeks (Lidén et al. 1998). tiveness has not been proven; silver resistance of
Elemental rhodium has not been described as a antibiotic-resistant bacteria and penetration of sil-
sensitizer. ver nanoparticles through a wounded skin have
Reports have been published on contact allergy been described (Drake and Hazelwood 2005;
to rhodium salts, in platers, gold- and silversmiths, Lidén et al. 2011; Rietschel and Fowler 2008). A
and a precious metal refinery worker (Goossens study of exposure to silver-containing garment in
et al. 2011; Lidén et al. 2011). Seven hundred healthy individuals and atopic dermatitis patients
twenty consecutive dermatitis patients in Italy showed no increased silver concentration in urine
were patch tested with rhodium chloride. Two or altered expression of inflammatory cytokines in
were test positive to rhodium chloride; the signif- the skin (Pluut et al. 2015).
icance was however unknown (Stingeni et al. Silver is not a skin sensitizer. It is often used
2004). Patch testing has been performed with together with nickel in jewelry and other items,
rhodium chloride 1% in water, but experience is which may result in nickel dermatitis. Nickel
limited. silver (also called German silver or alpaca) is
In vitro diffusion cell experiments showed pen- an alloy of Cu/Ni/Zn which often is silver
etration of rhodium salts and nanoparticles into, coated. Silver nitrate is widely used to mark
but low or no permeation through, an intact patch test sites, for wound healing, and for cau-
human skin. Permeation increased when the skin terizing bleeding. Silver nitrate might be a skin
was damaged or when the pH on the skin was sensitizer, and it may cause local toxic reactions
decreased (Franken et al. 2014; Mauro et al. 2015; when used as a patch test marker. Silver nitrate
Jansen Van Rensburg et al. 2017). 1% in water has been used for patch testing, but it
may cause irritant reactions, particularly if the vaccines-prognosis and outcome after booster vaccina-
solution is old (Lidén et al. 2011; Rietschel and tion. Eur J Pediatr 172(2):171–177
Berlin JM, Taylor JS, Sigel JE, Bergfeld WF, Dweik RA
Fowler 2008). (2003) Beryllium dermatitis. J Am Acad Dermatol
49(5):939–941
Böhler-Sommeregger K, Lindemayr H (1986) Contact
13 Tin sensitivity to aluminium. Contact Dermatitis
15(5):278–281
Burrows D, Adams RM, Flint GN (1999) Metals. In:
Tin (Sn) is widely used in solders alloyed with lead, Adams RM (ed) Occupational skin disease.
for tin-plating of steel, and in brass and other alloys. W.B. Saunders Company, Philadelphia, pp 395–433
Tin is used in dental amalgam alloyed with mercury, Cristaudo A, Sera F, Severino V, De Rocco M, Di Lella E,
Picardo M (2005) Occupational hypersensitivity to
silver, copper, and zinc. Organotin compounds are metal salts, including platinum, in the secondary indus-
used as biocides and catalysts. Tributyltin (TBT) try. Allergy 60(2):159–164
compounds are highly toxic to the environment. Curtis GH (1951) Cutaneous hypersensitivity due to beryl-
Tributyltin oxide is severely toxic to humans, lium; a study of thirteen cases. AMA Arch Derm
Syphilol 64(4):470–482
and it is a strong skin irritant. Acute foot derma- Daenen M, Rogiers P, Van de Walle C, Rochette F,
titis in 70 soldiers was caused by socks disinfected Demedts M, Nemery B (1999) Occupational asthma
with tributyltin oxide (Molin and Wahlberg 1975). caused by palladium. Eur Respir J 13(1):213–216
An outbreak of irritant contact dermatitis in pain- Day GA, Dufresne A, Stefaniak AB, Schuler CR, Stanton
ML, Miller WE, Kent MS, Deubner DC, Kreiss K,
ters was caused by exposure to tributyltin oxide- Hoover MD (2007) Exposure pathway assessment
containing paints (Goh 1985). Tin chloride is a at a copper-beryllium alloy facility. Ann Occup Hyg
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48
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
2 The Evolution of Cement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
3 Chromate in Cement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
3.1 Reduction and Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
3.2 The Origin of Chromate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
4 Clinical Patterns of Cement Eczema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
4.1 Irritant Cement Eczema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
4.2 Allergic Cement Eczema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
4.3 Hereditary Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
5 Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
5.1 General Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
5.2 Individual Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
Keywords Cement eczema is of an irritant and allergic

Cement eczema · Chromium · Chromate · nature. Water-soluble hexavalent chromate, Cr
Potassium dichromate · Ferrous sulfate · (VI), in the cement causes chromium allergy that
Prevention · Irritant cement eczema · Allergic may cause the development of allergic cement
cement eczema · Building industries · eczema. The medical course of allergic cement
Cement · Mortar · Concrete · Cement workers · eczema is often of a chronic nature. The develop-
Construction workers · Reduction ment of allergic cement eczema may be prevented
by adding ferrous sulfate to the cement, with
ferrous sulfate reducing the highly water-soluble
allergenic Cr(VI) to Cr(III) with a lower solubility.
D. Bregnbak
Department of Dermatology and Allergy, Herlev-Gentofte
e-mail: davidbregnbak@hotmail.com
C. Avnstorp (*)
Dermatology Clinic, Rødovre, Denmark
e-mail: avnstorp@dadlnet.dk

https://doi.org/10.1007/978-3-319-68617-2_48
700 D. Bregnbak and C. Avnstorp
1 Introduction mix, and carba mix (Akasya-Hillenbrand and

Özkaya-Bayazit 2002).
Irritant dermatitis caused by cement was In a survey from Taiwan, the most important
described as early as 1700 (Calnan 1960). In source of chromate exposure was cement. There
1908, the first cases of cement eczema since the are about 846,000 construction workers in Taiwan
introduction of modern Portland cement were (about 12% of all laborers), and this was the most
seen among workers building the Metro in Paris common occupation of the individuals who were
and were described as “la gale du ciment” (Martial sensitized to chromate. In fact, 21% of construc-
1908). In 1950, Jaeger and Pelloni brought to light tion workers have experienced occupational der-
the importance of the chromium content of matitis. The prevalence of chromate-sensitized
cement as the cause of chromium allergy among individuals did not change much over time
workers with cement eczema. In 1970, Høvding (4.7% in 1978–1990 to 4.4% in 1991–2003)
published an epidemiological study in which (Cheng et al. 2008). This study is based on data
20 (5.5%) from a group of 366 bricklayers and from the National Taiwan University Hospital.
bricklayers’ assistants had cement eczema. Sev- The hospital is a tertiary referral center. Therefore
enteen of these workers with cement eczema these data are not representative for the conditions
(85%) reacted positively to patch tests with chro- on the working places. Taiwan has introduced
mate (Høvding 1970). chromate reduction in 2003 (Chia-Yu, 2010, per-
Since then, cement eczema has been found to sonal communication).
be one of the most serious occupational health In Finland incidence rates of occupational
problems in building trades and industries. This allergic dermatitis among men were found highest
has been further illustrated by the high frequency due to chromium allergy. Among these a high
of cement dermatitis in underground workers proportion was caused by cement contact
during construction of the English Channel Tun- (Kanerva et al. 2000). In the UK 22184 cases of
nel between England and France (Irvine et al. occupational contact dermatitis were reported by
1994), among workers from the construction dermatologists in the period 1993–2004. This
industry in Taiwan (Sun et al. 1995), construc- comprised 77% of all types of occupational skin
tion workers in Spain (Conde-Salazar et al. diseases reported. Of these chromium supported
1995), and developing countries such as Senegal to play a role in 1226 cases (6%). The commonest
(Niang et al. 2007). In the United States, the occupations were within building and construc-
Occupational Health Foundation has been focus- tion (Athavale et al. 2007).
ing on the problem (Occupational Health Foun- In Brazil apparently there have been no
dation 1996). changes in allergenic substances, contrary to
In Singapore, being a high active building and what is happening in more socially and econom-
construction area, prevalences of chromium allergy ically developed countries, where the use of fer-
decreased from 6.3% in 1984–1985 to 2.7% in rous sulfate has been adopted to decrease
1986–1990 but increased again to 5.6% in the sensitization to chromium and precautions have
years 2001–2003 (Goon and Goh 2005). Another been taken in rubber manufacture. In the period
study from the same area showed increasing num- May 2000 to December 2005, workers who were
bers of workers from the building and construction submitted to the Outpatients Clinic of Skin
trades affected by irritant contact dermatitis to Allergy and Occupational Dermatoses in Sao
cement and chromium being a constant sensitizer Paulo, where patch tested with the standard
from 1989–1998 to 2003–2004 (Lim and Goon series of the Brazilian Contact Dermatitis
2007). In a retrospective study from Turkey, occu- Research Group (GBEDC). In the study period,
pational contact dermatitis was diagnosed in 77 of 596 patients were patch tested. Of these 86 were
the patients with positive reactions (27.5%), most construction workers. The five most frequent
of these being construction workers and house allergens among the construction workers were
painters who showed relevant sensitizations to potassium dichromate (57.0%), carba mix
potassium dichromate, cobalt chloride, thiuram (34.9%), cobalt chloride (30.2%), thiuram
48 Cement 701
mix (27.9), and neomycin (19.8%) (Macedo 2014, it was shown that almost 10% of a
et al. 2007). chromium-sensitive population had experienced
No legislative interventions have yet been dermatitis directly caused by cement (Bregnbak
enforced in Australia in regard to cement. A recent et al. 2014). In Sweden there has been a recent
retrospective study focus on prevalence rates from reporting of three/five workers from a plant pro-
Australia in regard to occupational contact derma- ducing concrete wall panels and beams that devel-
titis to chromium attributed to sensation through oped dermatitis and reacted to potassium
cement (Wong et al. 2015). They found no signif- dichromate (Mowitz et al. 2016).
icant changes in the prevalence rates between Further information about those being
January 1993 and December 2013 and estimates affected by cement eczema is detailed in
that a minimum of 24 new cases of occupational ▶ Chaps. 136, “Cement Workers” and ▶ 142,
contact dermatitis patients are found yearly in “Construction Workers.”
Australia. Earlier reports from Australia includes
248 cases of occupational contact dermatitis over
an 8-year period in Western Australia (Wall and 2 The Evolution of Cement
Gebauer 1991) and from New South Wales a
6-year retrospective study looking on a patch test Cement is a material which binds together solid
population with 18% (40/218) of those with occu- bodies (aggregate) by hardening from a plastic
pational contact dermatitis from chromium state. The Latin word “cementum” means crushed
(Rosen and Freeman 1992). stone. In 1824 Joseph Aspdin, a British builder,
Latest data on chromium allergy related to patented a cement produced by firing a mixture of
cement exposure are summarized in Table 1. limestone and clay (Bogue 1949). He called his
By adding ferrous sulfate to the cement, it product Portland cement because it was similar in
is possible to prevent the development of appearance to a building stone quarried on the
allergic cement eczema. This was illustrated in island of Portland of the south coast of England.
an epidemiological intervention study from In 1845, the first Portland cement, in the modern
Denmark (Avnstorp 1992) and in a 12-year sense of the term, was produced by firing such a
follow-up study also from Denmark (Johansen mixture to temperatures from 1200 C to 1400 C
et al. 2000). (Cement and Concrete Association Publication
The same trends have been reported from Fin- 98.001 1977).
land, Sweden (Roto et al. 1996), and in the UK Portland cement is a hydraulic cement. Hydraulic
(Stocks et al. 2012). The total burden of chromium cements are defined as cements that not only harden
on the body has shown to decrease after adding by reacting with water but also form a water-
ferrous sulfate to cement, especially among resistant product. Portland cement is produced by
cement workers with severe and continuous pulverizing clinkers consisting essentially of
hand dermatitis (Chou et al. 2008). This is an hydraulic calcium silicates, usually containing one
essential finding that put further light to the induc- or more of the forms of calcium sulfate as an
tion and chronicity of allergic cement eczema interground addition. Clinkers are 5–25-mm-diam-
among workers daily exposed to Cr(VI) in eter nodules of a sintered material which is produced
cement-containing products. Regardless the addi- when a raw mixture of limestone and clay is heated
tion of ferrous sulfate cases of allergic dermatitis to high temperatures (Mehta 1986). The chemical
caused by exposure to cement still exists. In a reactions taking place in the cement kiln system can
questionnaire study performed in Denmark from be approximately represented as shown in Fig. 1.
Table 1 Latest Prevalences in percentages

epidemiological data on
Singapore 5.6 Goon and Goh (2005)
chromium allergy related to
cement exposure Taiwan 4.4–4.7 Cheng et al. (2008)
UK 6.0 Athavale et al. (2007)
Fig. 1 Basic chemical

reactions taking place in the
cement kiln system
The concrete used today is a mixture of chromium compounds in the raw materials, by
Portland cement, sand, stones, and water. Mortar the kiln lining and by chromium steel abrasion
consists of a mixture of Portland cement, sand, during the grinding processes (Skomorowski
water, and often also hydrated lime. The exact 1985). The Cr(VI) content of cement varies from
composition depends on the purpose for which country to country according to variations in the
the product is to be used. amount of chromium in the raw materials (Fregert
The potential source of water-soluble hexa- and Gruvberger 1972).
valent chromate Cr(VI) in cement is the trivalent
Cr(III) compound (Cr2O3) in the raw materials
from which it is produced. Cr(III) compounds 3.1 Reduction and Solubility
are oxidized to Cr(VI) compounds (CrO2-/4)
when heated in the kilns to temperatures Ferrous sulfate reduces Cr(VI) in cement to
of approximately 1400 C. The content of Cr(III) (Fig. 2). Burckhardt et al. (1971) reported
chromium in cement is determined by the that 62/78 chromium-allergic patients did not
presence of chromium compounds in the raw react to a solution of 40% cement in water to
materials, by the kiln lining and by chromium which 0.3% ferrous sulfate had been added. In a
steel abrasion during the grinding pro- study including eight chromium-hypersensitive
cesses (Skomorowski 1985). The Cr(VI) content individuals, negative reactions were obtained
of cement varies from country to country according after patch testing with 1.76 ppm of potassium
to variations in the amount of chromium in the dichromate in water solution. Furthermore, no
raw materials (Fregert and Gruvberger 1972). reactions were found from patch testing with buff-
ered cement after ferrous sulfate was added
(Bruze et al. 1990a).
3 Chromate in Cement Chromate is highly water soluble (Gamm-
elgaard et al. 1992).
The potential source of water-soluble hexavalent
chromate Cr(VI) in cement is the trivalent Cr(III)
compound (Cr2O3) in the raw materials from 3.2 The Origin of Chromate
which it is produced. Cr(III) compounds are oxi-
dized to Cr(VI) compounds (CrO2-/4) when In Danish Portland cement, the chromium
heated in the kilns to temperatures of approxi- content is 40.5 ppm, and, of this, 9.6 ppm is
mately 1400 C. The content of chromium in water-soluble chromate (Lund 1977). Cr(III)
cement is determined by the presence of compounds have lower solubility with increasing
48 Cement 703
(Danish Working Environment Service 1983).

Since then, both Finland (in 1987) and
Sweden (in 1989) have established the same
regulation. Since 1999 the same regulation has
been performed in the European Union
(EU Directive 1999/45/EF).
The chromate in both bagged cement and
bulk cement will remain in a reduced state, as Cr
(III) compounds, for 8 weeks. The type of storage
conditions used may be essential, especially
if bagged cement is stored in open sacks or
exposed to moisture, because the Cr(VI) will not
be reduced when the cement is subsequently
mixed with water (Bruze et al. 1990b). These
findings were supported in Taiwan where it
was noticed that the effects of ferrous
sulfate added during production was poor due to
the hot and humid environment. Therefore, fer-
rous sulfate has been provided with the
cement and then added on location at the
building places since 2003 (Chia-Yu, 2010, per-
sonal communication).
Fig. 2 The chemical reaction in the reduction of water-
soluble chromate by the addition of ferrous sulfate
4 Clinical Patterns of Cement

pH (Gammelgaard et al. 1992). The addition of Eczema
0.35% (w/w) ferrous sulfate to cement reduces a
Cr(VI) content of 20 ppm to very Cement eczema may be of an irritant nature, aller-
low concentrations (Fregert et al. 1979). In vitro gic, or both.
studies on the human skin showed no statistically
significant difference in chromium content of skin
layers between skin exposed to cement suspensions 4.1 Irritant Cement Eczema
with the content of 2.1 ppm Cr(VI) and unexposed
skin. The content in the dry cement was 3.3 ppm Depending on exposure, concentration and time,
(Fullerton et al. 1993). These findings support the and individual factors, different clinical manifes-
theory that dry cement should not contain more tations of irritant cement eczema are seen
than approximately 2 ppm of water-soluble (Avnstorp 1995).
chromium.
In 1981, Aalborg Portland A/S (Ltd), the only 4.1.1 Acute Reactions
manufacturer of cement in Denmark, patented Cement eczema may initially develop as a result of
a method whereby the amount of chromate daily irritation of the skin by contact with cement.
in the cement could be reduced, thus reducing The skin of those who have daily contact with wet
the content of water-soluble chromate in cement cement becomes irritated by the hygroscopic and
to not more than 2 ppm at a cost of about 1% of alkaline constitution of the cement. Erythema and
the total value of the cement. Legislation dry skin on the dorsal aspects of the hands and
stating that the content of water-soluble chro- fingers are the most frequent findings. Itching of
mate in dry cement must not exceed 2 mg/kg the hand and fingers is the most important symptom
(2 ppm) was passed in Denmark in 1983 (Avnstorp 1983). Acute reactions may develop
within weeks. Cement burns are mostly seen in 4.1.3 Noneczematous Skin Changes
“amateurs,” who are not familiar with the handling Minor skin complaints are accepted as normal
of cement products. These caustic reactions among workers who have daily contact with wet
develop on the lower legs after prolonged contact cement products (Avnstorp 1983). Mechanical
with wet cement (Vickers and Edwards 1976). traumas from the handling of bricks, tools, and
machines cause occupational stigmata in the
4.1.2 Chronic Reactions form of hyperkeratoses, with fissures on the pal-
By repetition of the same stimulus or by combi- mar aspects of the hands and fingers. This phe-
nations of varying stimuli, the degree of impair- nomenon is particularly seen among individuals
ment surpasses a critical level (Malten 1981). working outdoors in cold weather (Avnstorp
Repeated and continual contact with wet cement 1992). In a field study among bricklayers and
products in combination with other physical bricklayers’ assistants in Norway, the prevalence
traumas due to the work processes may lead to of such skin changes was found to be 10%
the development of chronic irritant cement (Høvding 1970).
eczema. This may take months or years. The
efflorescences may vary with time. These are ery-
thema, lichenification, and hyperkeratoses on the 4.2 Allergic Cement Eczema
dorsal and volar aspects of the hands, fingers, and
fingertips and also on the wrists (Fig. 3). Eczema Allergic cement eczema is primarily located on
may be nummular in morphology (Fig. 4) or the hands, fingers, and wrists (Burrows and
include the whole skin on the affected area. Ves- Calnan 1965; Høvding 1970; Avnstorp 1983).
icles are seldom found (Calnan 1960; Høvding Eczema on the dorsal aspect of the right hand, in
1970; Avnstorp 1983). particular, has been shown to be associated with
In general, irritant cement eczema cannot be chromium hypersensitivity (Avnstorp 1983). Fur-
differentiated from allergic cement eczema clini- thermore, allergic cement eczema has been found
cally. This differentiation should be made after to have a greater extent of involvement than irri-
patch testing. If the test reveals a positive reaction tant cement eczema (Avnstorp 1991). Fissures
to chromate, the eczema must be classified as may occur together with nail dystrophy (Fig. 5).
allergic cement eczema (Avnstorp 1992). The Allergic cement eczema may also spread to the
severity of irritant cement eczema with respect to forearms, the feet, and sometimes the face and
extension has been found to be mild to moderate, parts of the trunk (Fig. 6).
whereas allergic cement eczema has tended to be Heat and high humidity exacerbated allergic
more severe (Avnstorp 1991). cement eczema among workers in Kuwait. This
Fig. 3 Hyperkeratotic
cement eczema
48 Cement 705
Fig. 4 Nummular cement

eczema
Fig. 5 Allergic cement

eczema with nail dystrophy
phenomenon was explained by the fact that daily life, including exposure to leather fabrics
excessive hydration of the skin could lead to (Mälkönen et al. 2009). Leather contains both Cr
increased leaking of chromium through the skin (III) and Cr(VI) compounds that may elicit
(Kanan 1972). In Singapore, where the climate is eczema (Hansen et al. 2006). Chromated
hot and humid year-round, the number of heat- metal products may be another source (Geier
related dermatoses was, nevertheless, lower than et al. 2009).
expected, possibly due to the use of air condi-
tioning and good factory ventilation (Goh and 4.2.1 Concomitant Sensitizations
Soh 1984). Concomitant sensitivities to cobalt and rubber
Although workers with chromium allergy chemicals have been found significantly
may not be exposed to high levels of chromate more often among chromium-hypersensitive
in cement, their eczema tends to be chronic, workers than among those not hypersensitive
having a poor medical and occupational out- to chromium (Fregert and Rorsman 1966;
come. One explanation could be that the expo- Høvding 1970; Fregert 1975; Avnstorp 1983;
sure to chromium compounds is abundant in Macedo et al. 2007; Akasya-Hillenbrand
1978). In cement eczema, cobalt sensitivity is

therefore probably secondary to the chromium
hypersensitivity.
Nickel is a contaminant of cement in the form
of insoluble NiO which, in contrast to the cobalt
oxides, is not allergenic (Wahlberg et al. 1977). In
a study using multivariate regression analysis, no
statistically significant association between nickel
allergy and cement eczema was found (Avnstorp
1983, 1989).
Epoxy sensitivity has been observed with
relatively high frequency. Bricklayers
and workers engaged in precast concrete
building component factories are exposed to
products containing epoxy resins (van Putten
et al. 1984; Avnstorp 1992; Conde-Salazar et al.
1994).
4.3 Hereditary Factors

Fig. 6 Allergic cement eczema on the leg Combined influences of endogenous and exoge-
nous factors may lead to the development or to
and Özkaya-Bayazit 2002). Among 172 chro- aggravation of hand eczema (Nilsson 1985).
mium-allergic workers from the Spanish Atopic eczema in childhood has been found
building industry, 82 (47.6%) were sensitized to be a more important predictive factor for hand
to rubber chemicals. It was suggested that eczema than occupational exposure (Meding
chromium allergy facilitated the rubber sensiti- and Swanbeck 1990). In a population of
zation, particularly when gloves were worn in an individuals with atopic dermatitis in childhood,
almost occlusive way for many hours over 57% developed sporadic or continuous hand
eczematous skin (Conde-Salazar et al. 1995). A eczema during concrete work (Rystedt 1985).
similar correlation has been described among When compared with other occupations, such as
workers from a factory in Singapore manufactur- the metal industry, cleaning, and even office work,
ing precast concrete building components (Goh equal prevalences were found. Atopic dermatitis
and Gan 1987). and occupational hand eczema have been found to
Cobalt could be regarded as a co-senzitization be independent risk factors for sick leave
to primary chromium allergy (Goon and Goh (Cvetkovski et al. 2005).
2005). Mälkönen et al. (2009) found respiratory atopy
In a study from Taiwan, only one-third of to be a significant risk factor for the chronicity of
cobalt-sensitized individuals were found not occupational contact dermatitis.
co-sensitized to nickel or chromate. Construction In a prevalence study among concrete workers
workers were found to be the second most com- from the building industry, up to 13% of
mon occupation among individuals sensitized to the workers reported previous episodes of
cobalt (Cheng et al. 2008). eczema other than hand eczema; among those,
Cobalt occurs in cement as water-insoluble approximately 50% developed hand eczema
oxides but forms complexes with amino (Avnstorp 1983).
acids in eczematous skin, thereby possibly Even if in epidemiological terms atopic
forming haptens (Fregert and Gruvberger dermatitis is an effect modifier, it can be argued
48 Cement 707
that irritant contact dermatitis associated allergic cement eczema could be brought to a
with atopy is primarily an exacerbation of very low level by the addition of ferrous sulfate
underlying atopic dermatitis (Coenraads and to the cement (Avnstorp 1992). Ferrous sulfate
Diepgen 2006). reduces the allergenic Cr(VI) to Cr(III) in
The validity of the information about the cement (see Sect. 3.1). In Scandinavian
previous eczema and, therefore, also about countries, this intervention has shown to be a
atopic heredity may be significantly influenced significantly effective method in the prevention
by the accuracy of recall. It will decrease with of allergic cement eczema (Avnstorp 1992;
time, since those persons who did not have Roto et al. 1996; Zachariae et al. 1996). In the
symptoms recently more often will forget their period 1996–2000, a decrease in chromium
previous eczema episodes. allergy in ten European centers was found
Age may influence the development of by monitoring the European standard series in
irritant cement eczema. Workers in the age group 26,210 patients. Although there was a moderate
of 26–30 years are more affected by the irritant difference in results between the centers,
properties of cement (Geiser and Girard 1965). the overall percentage of chromium allergy,
The reason may be that younger, inexperienced 4.6, suggested that the sensitization rate for
workers tend to be more careless and, thereby, are chromium was decreasing. This could reflect
more frequently exposed (Goh et al. 1986). the addition of ferrous sulfate to cement
With respect to the development of chronic (Bruynzeel et al. 2005). In a prospective study
occupational hand eczema, age more than from Germany, the incidence of occupational
45 years has been found to be a risk factor skin disease in the construction industry was
(Mälkönen et al. 2009) calculated from 1990 to 1999. The most impor-
Psoriasis may be triggered by repeated tant allergen was found to be Cr(VI). In about
mechanical traumas from handling bricks, tools, half of all cases of sensitization, this was the
and machines and from daily contact with wet relevant allergen (153 of 335). In Germany
cement products. cement has partially been Cr(VI)-reduced since
Filaggrin is a structural protein of the cornified 1998. Full reduction was performed in 2002.
envelope and important for the formation of the Therefore future data will reveal whether the
epidermal skin barrier. Heterozygosity for non- German measure will be effective (Bock and
functional mutations in the fillagrin gene may Schmidt 2003).
contribute to the manifestation and maintenance Changes in the cement manufacturing process
of a particular chronic hand eczema subtype that is by using slag as a substitute for clinker propor-
characterized by the combination of allergic and tionally decreases the Cr(VI) concentration of
irritant contact dermatitis (Molin et al. 2009). cement. This phenomenon was considered to
Tumor-necrotizing factor-alpha promoter and be one of the reasons for a periodical decline
GST-T1 genotype may predict the development in the prevalence of cement dermatitis among
of chromium allergy in workers exposed to construction workers in Singapore (Goh and
cement containing high values of chromate Gan 1996). But since then, it has been rising
(Wang et al. 2007). again (Goon and Goh 2005). These results sup-
port that prevention of allergic cement eczema
needs general prophylaxis in the form of Cr
5 Prophylaxis (VI) – reduction of cement by the addition of
ferrous sulfate.
5.1 General Prophylaxis Reduced numbers of statements and approved
claims of cement eczema have been found
Irritant cement eczema should, in part, be pre- following the addition of ferrous sulfate to
vented by automation of work processes cement in Denmark and Finland (Avnstorp
whenever possible. The risk of developing 1992; Roto et al. 1996. Skoet et al. 2004).
This economic benefit should be included in In workers with chromium allergy, the use of
the calculation together with spared costs for leather gloves may deteriorate the dermatitis
medical support, lost working days, and personal because of the chromium tanning (Fregert and
suffering of the workers developing allergic Gruvberger 1979). The use of rubber gloves can
cement eczema. cause secondary sensitization to rubber chemicals
(Conde-Salazar et al. 1995). Often gloves also
contain the remains of cement spills and may be
5.2 Individual Prophylaxis soaked with mould oil (Fig. 7). Moderate use of
gloves may be advisable to protect against trauma
The dynamics of the development of occupational from specific work processes, but prolonged
hand eczema are not fully understood, but irrita- occlusion of the skin with gloves should be
tion and contact sensitivity, together with individ- avoided.
ual constitutional factors, influence its Barrier creams and ointments containing
development. Theoretically, at least one of the chemicals such as ethylenediaminetetraacetate
triggering factors could be eliminated if the (EDTA), ascorbic acid, and combinations
workers used individual preventive measures. of sodium pyrosulfite, tartaric acid, and glycer-
Skin protection creams alone had a small effect ine have been used in an attempt to reduce
on the skin barrier in workers in the building Cr(VI) to Cr(III) and to chelate Cr(III) on the
industries compared with skin care alone or in skin (Samitz and Pomeranz 1958; Samitz
combination with skin protection (Winker et al. and Gross 1962; Samitz 1970; Shuppli
2009). Use of gloves, protective hand creams, and 1970; Amphoux et al. 1975; Romaguera et al.
handwashing were not found to influence 1985). The effect of these measures under
the propensity for developing irritant cement actual working conditions is, however, doubt-
eczema (Avnstorp 1991). Furthermore, no ful. A thin layer of cream can easily be rubbed
additional effect was found from individual and washed off, and it can hardly be thought
preventive measures. The absence of influence of as an effective barrier for those carrying
from individual preventive measures could out manual work. The creams themselves
be explained by the possibility that the work pro- do not inhibit the absorption of chromium
cesses are so hazardous that they overwhelm the (Wahlberg 1971). In general barrier creams
protective effect. It could also be that the preven- cannot replace other protective measures
tive initiatives were not conducted systematically and should be maximally used to inhibit
or carefully enough. low-grade irritants or in combination with
Fig. 7 Leather gloves

soaked with cement and
mould oil
48 Cement 709
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Occupational Skin Products
49
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
3 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
4 Protective Creams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
4.1 Chemistry and Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
5 Emollients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
5.1 Chemistry and Mode of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
5.2 Efficacy of Emollients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
5.3 Adverse Effects and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
5.4 Mild Cleansers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727

Emollients · Fluorescence technique · Natural
moisturizing factor (NMF) · Protective • The external formulations applied on the skin
creams · Repetitive irritation test (RIT) · for the purpose of occupational protection, col-
Sodium lauryl sulfate (SLS) · Three-step skin lectively referred to as occupational skin prod-
protection concept ucts, are part of the three-step program:
– Pre-exposure protective (barrier) creams, or
protective products
– Cleansing products
D. Antonov · P. Elsner (*) – Skin-care products (postexposure creams,
Department of Dermatology, University Hospital Jena, emollients, moisturizers)
Jena, Germany
• Such formulations may provide protection
e-mail: dimitar.antonov@med.uni-jena.de; elsner@derma-
jena.de only against weak irritants and cannot replace
the use of other protective means such as
S. Schliemann
Department of Dermatology, University Hospital Jena, gloves.

https://doi.org/10.1007/978-3-319-68617-2_112
• Studies show that some external products fail Table 1 Dermatological skin protection at the workplace
to provide the declared anti-irritant efficacy (the three-step model of pre-exposure, mild cleansing, and
postexposure preparations)
and may actually aggravate irritation.
• It is therefore recommended that occupational Protective products Oil-water emulsions,
(barrier creams, protective water-oil emulsions,
skin products within the three-step program creams) tannery substances, zinc
should be tested experimentally against the oxide, aluminum
relevant irritants from the occupations they chlorohydrate, talcum,
are to be used in. perfluoropolyethers,
chelating agents,
• The efficacy of the protective creams is based ultraviolet protectors,
mainly on skin physiology studies with healthy dimethicone, quaternium-
volunteers; only one RCT demonstrated a ben- 18 bentonite, chelating
efit in a real occupational setting. agents, Teflon-like
polymers, etc.
• Worker education is needed to provide optimal
Cleansing products Detergents, solvents,
use and achieve the optimal protection from natural and synthetic grits
the three-step program. Postexposure skin care Emollients, moisturizers,
humectants, lipids
2 Introduction
from the skin, and skin care is intended to enhance
Contact dermatitis is the most frequent manifesta- epidermal barrier regeneration (Wigger-Alberti
tion of occupational skin disease. Since the course and Elsner 1997b; Kutting and Drexler 2003;
may be chronic leading to disability, and since treat- Fartasch et al. 2015). Many other (and sometimes
ment is frequently of limited efficacy, prevention misleading) terms have been used for protective
should be emphasized to reduce the incidence and creams, such as “invisible glove,” “antisolvent
prevalence of irritant contact dermatitis (ICD) and gels,” “protective ointments,” and others (Zhai
allergic contact dermatitis (ACD). Apart from total and Maibach 2007), both in scientific literature
elimination of cutaneous exposure to hazardous and in marketing. The term “protective creams”
substances and the use of gloves or protective cloth- (PCs) is considered to be the most accurate one
ing, protective creams (PCs), often referred to as by many (Kresken and Klotz 2003), and the new
barrier creams, are targeted as one of the classical German guideline prefers the term protective
means of skin protection against noxious chemicals products, but the older term “barrier cream” is
from the environment (Zhai and Maibach 2007). traditionally most widely used. Terms such as
“invisible glove” should be avoided, because
they imply a false sense of security. This chapter
3 Definitions uses the terms “skin protective products”
and “protective creams” synonymously and
Skin protection with external preparations in interchangeably.
the workplace consists of pre-exposure PCs, The PCs cannot be definitely distinguished
mild skin cleansers, and postexposure skin-care from the moisturizers or emollients in general,
products such as emollients or moisturizers as they share many common characteristics.
(the so-called “three-step skin protection con- In some articles they are altogether referred to as
cept,” Table 1). A recent guideline from Germany moisturizers (Yokota and Maibach 2006), and
summarizes the evidence and the recommenda- the question has been raised that distinguishing
tions for the use of these products and terms between pre- and postexposure creams may
them collectively “occupational skin products” be neither necessary nor justified (Kutting and
(Fartasch et al. 2015). While PCs are designed to Drexler 2003). However, the distinction is useful
prevent skin damage due to irritant contact, skin in terms of their intended effects and applications
cleaning should remove aggressive substances (Zhai and Maibach 2007), and some studies have
49 Occupational Skin Products 715
proven the superiority of the three-step skin pro- in Germany that the PCs to be used in a given
tection concepts using different pre- (PCs) and industry should undergo efficacy testing with
postexposure (emollients) products and dedicated respect to the intended exposure to ensure they
cleansing products, when compared to the single are indeed protective against the irritants present
components only (Berndt et al. 2002; Kutting in the respective occupational setting (Fartasch
et al. 2010). Furthermore, as the pre- and post- et al. 2008, 2015). The testing procedures against
exposure formulations are designed to pursue lipophilic irritants are generally less developed
different objectives, certain ingredients may be and standardized than the methods against hydro-
inappropriate for either the pre- or the post- philic irritants (Schliemann et al. 2013).
exposure preparations. Therefore, many manu- While emollients are designed to restore
facturers follow the three-step model when the irritated skin, many PCs may not be suitable
formulating their products. The three-step concept for diseased skin. Formulations may have irritant
is also easy to understand and, therefore, best properties on inflamed skin (Fowler 1994).
accepted by the workers (Elsner and Wigger- Therefore, it has to be taken into account to apply
Alberti 2003), has the highest compliance such PCs on intact skin only. Other PCs are formu-
(Kutting et al. 2010), and is altogether considered lated in a way not to irritate inflamed skin or even to
most practicable. alleviate itching and burning (Slade et al. 2008).
It is clear that for both PCs and after-work
emollients to be effective, they must be applied
4 Protective Creams frequently enough in adequate amounts and to
all skin areas that need protection. Particular atten-
PCs can have protective effects only against weak tion should be paid to the proper application in
irritants, such as water, detergents, and cutting the interdigital spaces.
fluids. They are of limited use against allergens, A simple method to determine and quantify
since they cannot prevent the elicitation of contact how exactly self-application of a PC was
dermatitis in already sensitized persons and it has performed at the workplace has been introduced
not been proven whether they can reduce the risk (Wigger-Alberti et al. 1997a). Using a fluores-
of sensitization. However, single products are cence technique (Fig. 1), it was shown that the
claimed to protect against particular material, application was mostly incomplete in different
such as poison ivy and others (Schalock and Zug professional groups and patients with hand
2007) (see below). PCs cannot protect against eczema (Wigger-Alberti et al. 1997a), especially
high-risk and corrosive substances and, therefore, in the dorsal aspects of the hands, the interdigital
cannot substitute gloves or other protective cloth- areas, and the wrists (Fig. 2). These findings
ing. However, PCs can be used in combination indicated that many people miss certain areas
with gloves or in an alternating manner, in order when applying PCs. This observation offers a
to reduce the time of constant glove use. possible explanation for the noted discrepancy
Additionally, PCs are the only options in work- between some principally good results achieved
places or manual procedures where gloves cannot with the PCs in laboratory studies with volun-
be worn due to impaired dexterity or due to safety teers and the still high prevalence of occupa-
regulations in the context of rotating machines tional contact dermatitis in practice (Kutting
(Schliemann 2007). and Drexler 2003). Individuals should apply the
The PCs may target a certain irritant or a group cream systematically by anatomic regions,
of related irritants and may have no protective ensuring that each region is adequately covered.
effect or even adverse effects with other irritants It was shown that the fluorescence technique is
(unpublished observation). Additionally, there are also very helpful in the educational demonstra-
published examples of PCs which aggravated the tion of the most common mistakes compared
irritation instead of protecting from it (Goh 1991; with the use of an instructive videotape
Frosch et al. 1993c). It is, therefore, recommended (Wigger-Alberti et al. 1997b).
Fig. 1 The fluorescence technique used to evaluate how workplace and at educational seminars (Wigger-Alberti
well the protective creams are applied and to demonstrate et al. 1998)
skipped areas. This technique can be used both at the
Fig. 2 Application of a
protective cream by 150 4 3 15 16
volunteers with
occupational contact to 5 2 14 17
irritants evaluated using a 9 21
fluorescence technique. 10 8 20 22
Results are given as an 7 19
average percentage of
sufficient application for all 26
1 13 25
volunteers, indicating 24
skipped areas at the dorsal 6 18
aspects of the fingers, the
interdigital spaces, and the 11 23 27
wrist (Wigger-Alberti et al.
1997a)
12 28
right palm right dorsal aspect
90%–100% 80%–89% 70%–79% 60%–69% < 60%
PCs are to be applied before contact with no irritants or allergens are trapped under the
irritants. Most of the PCs claim duration of effect PC. For some PCs a more frequent application
around 4 h, so repeated application during the may be required, or there could be specific man-
workday is necessary, such as an application ufacturer’s instructions (Zhai and Maibach
after every break. The skin should be cleaned 2007). Furthermore, the relation between the
and dried before PC application, to ensure that amount of PC applied and the achieved efficacy
is insufficiently explored. A study on the PC (SLS) and against the solvent toluene (TOL)
application in nurses showed the average (Frosch et al. 1993b). Other preparations include
amount of applied PC to be close to 1 mg per a fatty amine amide acetate that binds to nega-
square cm (median 0.88 with interquartile range tively charged carboxyl groups of keratin and the
from 0.57 to 1.25 mg/cm2) (Schliemann et al. positive fatty ammonium ion of these substances
2012). This is 4–20 times less the quantity tradi- that binds firmly to the negative charge of the
tionally used in in vivo studies with volunteers epidermis. This was supposed to build up a firm
(Schliemann et al. 2012). Another recent study second layer on the skin, which prevents penetra-
demonstrates the dose-dependent manner of the tion of various agents in a steric manner (Frosch
PC efficacy and shows lack of effect of an exam- and Kurte 1994).
ple product at 2 mg/cm2 (Schliemann et al. 2014). Currently the principle that the lipo- or hydro-
Additionally, the influence of the frequency of philic properties of the PCs define their effects
application on the duration of the protective against lipo- or hydrophilic irritants and allergens
effects has not been systematically investigated is considered oversimplistic (Frosch and Kurte
up to now. Accordingly, it is desirable that the 1994). Although it may be valid for some PCs,
recommendations of the manufacturers in the there are examples of hydrophilic PCs providing
future should be better backed by standardized protection against hydrophilic irritants or deter-
efficacy tests. gents and of lipophilic PCs protecting against
lipophilic allergens/irritants. In general, this prin-
ciple does not correctly predict the protective
4.1 Chemistry and Mode of Action properties of a given PC and is considered to be
weak or sometimes outright wrong in practical
4.1.1 Lipo-/Hydrophilic Properties conditions (Frosch and Kurte 1994; Zhai and
In the past, the prevailing opinion was that PCs are Maibach 2007).
effective in a pure physical way because their A recent study reveals the difficulties with
composition creates a barrier, which can hardly testing lipophilic irritants, including the choice
be penetrated. In agreement with this common of model irritants, the application procedure, and
dogma, lipophilic ointments (w/o emulsions) the choice of suitable parameters to evaluate effi-
were recommended against hydrophilic irritants, cacy (Schliemann et al. 2013). In this randomized
while hydrophilic ointments (o/w emulsions) double-blind study, all six commercial products
against lipophilic irritants. Water-in-oil emulsions tested failed to prevent solvent-induced cumula-
were, therefore, mainly recommended against tive skin irritation (Schliemann et al. 2013).
water-soluble irritants such as detergents, acids, According to another hypothesis, the PCs may
alkalis, metal-work fluids, and even plain water. facilitate the washing off of dirt, especially sticky
Oil-in-water emulsions were offered for use ones, thereby reducing the need for aggressive
against lipophilic irritants such as oils, varnishes, cleansers (Mathias 1990). There is little evidence
and organic solvents. to support this suggestion, but it has also never
Special attempts were undertaken to develop been questioned and is largely accepted (Kutting
preparations with a dualistic mode of action and Drexler 2008; Fartasch et al. 2015). It has
to combine the different effects of hydrophilic been reported that in nuclear medicine the PCs
ingredients, such as propylene glycol, glycerol make it easier to wash away radionuclides
and sorbitol, and lipophilic ingredients, such as after accidental contamination (McCormick et al.
stearic acid and dimethylpolysiloxane. However, 2000). The cutaneous penetration was markedly
a foamy skin protector (“invisible glove”), reduced, if the technicians had applied a PC.
claimed to form a two-dimensional network of With no PC before contamination, even multiple
crystalline stearic acid (impermeable to hydro- washings with prolonged scrubbing could not sig-
philic agents), failed in a repetitive irritation test nificantly reduce the radioactivity (McCormick
against the anionic detergent sodium lauryl sulfate et al. 2000).
4.1.2 The Effects of Additional manufacturers now to ensure a better claim sup-
Ingredients port. In addition, European Community (EC) reg-
Some ingredients, such as natural or synthetic ulations require the employer to provide PCs to
tannery substances, zinc oxide, talcum, perfluor- workers at exposed workplaces for prevention of
opolyethers, chelating agents, and other sub- ICD. It is in the employers’ interest that this
stances that can bind metal ions or reduce the investment is not based on unfounded claims but
penetration through the skin (Table 1), are claimed on scientific data. Double-blind, placebo-con-
to have special protective properties. Zinc oxide trolled, randomized clinical tests of PCs are scarce
has a covering effect. Tannin is supposed to for reasons of methodological difficulties, ethical
harden the skin in order to increase the mechanical doubts, and enormous expenditure for tests
resistance of the skin surface against microtrauma. regarding the preventive benefit of PCs in prac-
Tannery agents cause a local decrease of perspi- tice. Actually, various in vitro and in vivo tests are
ration which seems to be helpful while wearing used for the evaluation of PC efficacy though they
gloves (Jepsen et al. 1985). The decrease of swell- are often considered not to be close to real work-
ing is caused by direct binding of the tanning place situations. This applies especially to single
substance to keratin. Aluminum chlorohydrate is exposure tests which are not capable to imitate the
used for reduction of perspiration by reversibly natural repeated exposure setting at workplaces.
blocking eccrine sweat excretion. Some chelating Repeated exposure test models have to be pre-
agents are claimed to protect against sensitizing ferred. Through such testing the protective effects
substances. Tartaric acid and glycine chelate chro- of many PCs have been demonstrated in labora-
mate can reduce chrome VI to chrome III, which tory conditions, as well as instances have been
is less allergenic (Romaguera et al. 1985). identified, where certain PCs fail to protect against
There are additional ingredients, which are the relevant irritants or a model irritant
beneficial in postexposure emollients, but are (Schliemann et al. 2013) (reviewed in Yokota
considered inappropriate for PCs, because they and Maibach 2006; Zhai and Maibach 2007).
actually enhance the penetration of irritants or A standardized testing procedure with hydrophilic
allergens. These include urea, propylene glycol, irritants has been developed in Germany which
and some emulsifiers (Schliemann 2007). allows the comparison of commercial protective
Whatever the intended effects of the constitu- products against to reference samples, and the
ents and the physical properties of the formula- transferability and reproducibility of the method
tions may be, their protective effects need to be were demonstrated (Fartasch et al. 2015). The
proved against the relevant irritants, present in the testing procedures for lipophilic irritants are not
occupational setting where the PCs are to be used. yet that developed and standardized (Schliemann
This is a request toward industry that has been et al. 2013).
made in Germany by scientists but is still hetero-
geneously and insufficiently fulfilled (Fartasch 4.1.4 In Vivo and In Vitro Tests
et al. 2008). Since Suskind (1955) introduced the “slide test”
to evaluate PCs in the 1950s, much effort has been
4.1.3 Efficacy of Protective Creams undertaken to develop valid methods to evaluate
Though the use of PCs is one of the common the benefit of PCs. Besides various in vitro
measures to prevent ICD, their actual benefit at methods (Boman et al. 1982; Loden 1986; Treffel
the workplace is subject to debates (Wigger- et al. 1994), noninvasive biophysical measure-
Alberti and Elsner 1998; Kutting and Drexler ments have achieved great importance, especially
2008). Because PCs are treated not as drugs for clinically weak reactions (Mahmoud et al.
but as cosmetics, only a principle proof of their 1984; Mahmoud and Lachapelle 1985; Marks
efficacy is mandatory before they are released et al. 1989; Frosch et al. 1993a, b, c; de Fine
to the market. However, new European Union Olivarius et al. 1996; Schluter-Wigger and Elsner
(EU) laws for cosmetic standards force 1996). Cumulative patch tests, repetitive washing
procedures with SLS, and other tests have been 1999a). Such protocol has been developed and
presented and summarized (Wigger-Alberti and validated in a multicenter trial (Schnetz et al.
Elsner 1998; Zhai et al. 1998; Zhai and Maibach 2000). It was named “repeated short-time occlu-
2007). As chronic ICD is a major clinical prob- sive irritation test” (ROIT) and involved appli-
lem, a test model with repeated exposure to sub- cation of a standard irritant 0.5% SLS
clinical doses of irritants might be helpful in under occlusion for 30 min, twice daily with an
predicting the efficacy of pre-applied PCs. interval of 3.5 h between the applications, for
Frosch and Kurte (1994) introduced the repet- 5 days. Although there were inter-center varia-
itive irritation test (RIT) with a cumulative irri- tions in the values of the measured parameters,
tation over a 2-week period by standard irritants the ranking of the tested protective creams was
such as SLS, sodium hydroxide, lactic acid, reproducible.
and toluene. This model has been shown to be A recent study demonstrates the dose-depen-
suitable for comparing PCs simultaneously to a dent manner of PC efficacy and recommends a PC
non-pretreated control site. A specific profile of quantity to be used in laboratory model investiga-
efficacy could be demonstrated by quantifying tions with volunteers to be no more than 2 mg/cm2
irritant cutaneous reactions by noninvasive mea- (Schliemann et al. 2014). The traditionally used
surements, and it has been used in modified quantities were probably based on the filling vol-
studies (Figs. 3 and 4) (Schluter-Wigger and ume of a standard Finn chamber being 4–20 times
Elsner 1996; Elsner et al. 1998; Wigger-Alberti higher than the quantities used in real-life situa-
et al. 1998). As petrolatum is effective against tions (Schliemann et al. 2012), thus probably
water-soluble and water-insoluble irritants, it overestimating the efficacy of the protective
was recommended as a standard substance creams (Schliemann et al. 2014).
against which PCs may be compared (Wigger- A procedure similar to ROIT, called tandem
Alberti and Elsner 1997a). However, manufac- repeated irritation test (TRIT), employs consec-
turers of skin-care products prefer easy study utive application of two irritants, for example,
protocols that provide valid data in short time 0.5% SLS and undiluted toluene (Wigger-
with less restrictions for the volunteers; there- Alberti et al. 2002). With TRIT the protective
fore, short duration and easy application given in properties of PCs against the combined effects of
a 1-week test using the forearm of healthy vol- different irritants can be established. While PCs
unteers is highly desirable (Wigger-Alberti et al. might be relatively irritant-specific and may
5
SLS 10%
4.5
4
3.5
3
2.5 cream A
cream B
2
cream C
1.5 petrolatum
1 control
0.5
0
1 2 3 4 5 8 9 10 11 12 days
Fig. 3 The effect of three barrier creams (a–c) and petro- significant suppression of erythema during each week for
latum on the irritation induced by 10% sodium lauryl all products compared with the untreated control (Wigger-
sulfate after 2 weeks, measured by the daily visual score Alberti et al. 1998)
(0–5). Results are given as means. The results show a
3
TOL undiluted
2.5
2
cream A
1.5
cream B
1 cream C
petrolatum
0.5 control
0
1 2 3 4 5 8 9 10 11 12 days
Fig. 4 The effect of three barrier creams (a–c) and petro- showed a significant protective effect, while cream C had
latum on the irritation induced by toluene after 2 weeks, no benefit and cream B even showed a significant amplifi-
measured by the daily visual score (0–5). Results are given cation of the irritant reaction to toluene (Wigger-Alberti
as means. Regarding erythema, cream A and petrolatum et al. 1998)
sometimes even aggravate the effects of other without fluorescent model substances (Bird
irritants, in many occupational settings, the skin et al. 2008). In another test method, the effects
is exposed to diverse irritating factors. Tandem of PCs on the penetration of metal ions can be
tests allow discriminating the most suitable PCs examined, by determining the quantity of the
for such situations. Tandem tests have been used metal ions in stripped layers of the epidermis
to study the combined effects of multiple physi- by means of laser-induced breakdown spectros-
cal and chemical irritants (reviewed in Kartono copy (Sun et al. 2000). However, all these
and Maibach 2006). methods are not as widely used as the bioengi-
neering methods.
4.1.5 Penetration Models
With the advance of the laser scanning micros- 4.1.6 PCs Against Allergens
copy, the protective properties of PCs can be Although PCs have been shown to reduce ACD
evaluated, in comparison to a reference standard in sensitized individuals under experimental
such as petrolatum, by tracking in vivo the skin conditions (Blanken et al. 1987a), their use in
penetration of fluorescent model substances the prevention of ACD has been disappointing
(Rieger et al. 2007). Similar approach has been under practical conditions. However, published
used in the past with dyes penetrating into examples indicate a benefit for some PCs used as
the stratum corneum (SC). In such models “active” creams in the prevention of ACD-like
with dyes, layers of SC, stripped by glues, nickel dermatitis or poison ivy/oak ACD
would be analyzed by chromametry to show if (Romaguera et al. 1985; Grevelink et al. 1992;
the tested PCs would diminish the penetration Fullerton and Menne 1995; Gawkrodger et al.
of the model dyes (Zhai and Maibach 1996). 1995; Marks et al. 1995; Wohrl et al. 2001). Such
Using model substances would always raise con- PCs contain as active ingredients quaternium-18
cerns of how well they correspond to the real bentonite (against urishiol), Teflon-like poly-
irritants/allergens, especially as the model dyes mers, chelating agents, ion-exchange resins,
and the fluorescent model substances are chosen and others (reviewed in (Schalock and
due to their lipo- or hydrophilic properties and Zug 2007)). Methacrylate wound sprays have
this concept is not always valid. Another laser also shown protective properties against
scanning microscopy technique, called fluores- allergens, but their applicability in real
cence lifetime imaging (FLIM), may allow working environments is unknown (Schalock
observation of the trans-epidermal penetration and Zug 2007).
4.1.7 Studies from Real Occupational accepted indicator for the skin barrier function.
Settings and the Relative Another problem was the high number of trial
Contribution of PCs for the participants lost to follow-up – of the 1006
Overall Skin Protection recruited, only 483 could be included in the anal-
Apart from the multiple model studies with vol- ysis. Because there were differences between the
unteers, there are also interventional studies and two industrial branches examined and between
randomized controlled trials (RCTs). These two the genders, these 483 participants had to be ana-
groups of studies demonstrated the benefit of lyzed in three separate groups, like three separate
skin protection with topical preparation in the trials. The participants were randomized into four
occupational settings of hospital nurses, health- arms, which received, respectively, either all of
care workers, kitchen workers, dental technicians, the components of the three-step skin protection,
and others (Berndt et al. 2000; McCormick et al. only a barrier cream and a mild cleanser, only a
2000; Perrenoud et al. 2001; Yokota and Maibach skin-care product with the mild cleanser, or only
2006). The interventional studies usually show the cleanser (which arm served as control). The
the usefulness of the skin protection with topical biggest improvement in skin barrier function was
preparations together with other primary and observed in the arms with all of the components,
secondary prevention measures, such as gloves, followed by the slightly smaller improvement in
protective clothing, educational measures, and the arms with skin care. The TEWL decrease for
others. In the RCTs, the PCs are compared to the skin protection did not reach significance.
their vehicles (Berndt et al. 2000; Perrenoud There were gender differences, which could be
et al. 2001), to a control emollient (McCormick due to a better skin care in the female participants.
et al. 2000; Frosch et al. 2003), or to no protection The results were interpreted as showing that the
(Goh and Gan 1994). The RCTs also demonstrated skin protection program with topical preparations
the benefit of the skin protection, as there was an can bring benefit mainly on the regeneration of
improvement in the skin status of the participants. the skin, while the protective effects are small.
However, they were not able to prove the superi- According to the authors, application of a cream
ority of a given PC over its vehicle or a control after work was clearly beneficial, application one
topical preparation. The RCTs, in which the PCs more time (before work, as a protective cream)
were compared to their vehicles, showed no dif- brought additional discrete advantage, but appli-
ference in efficacy (Berndt et al. 2000; Perrenoud cation of only a prework cream seemed to be less
et al. 2001). In the studies comparing the PCs to useful (Winker et al. 2009).
emollients, the emollients showed better results The relative contribution of the components of
(McCormick et al. 2000; Frosch et al. 2003). the three-step model has been investigated in a
However, these RCTs usually had small numbers laboratory study which has produced quite the
of participants (with the exception of Frosch et al. opposite results. In a modified ROIT with SLS
2003), many of whom had mild or severe derma- (2 h between the repeated application, four con-
titis, and, therefore, examined together the healing secutive days), all the relevant combinations of
and the preventive effects. As the vehicles of the components of the three-step model were ran-
PCs also have emollient properties (Berndt et al. domly applied on four test fields on the forearms
2000), these factors may have prevented the dem- of 40 healthy volunteers (Berndt et al. 2002).
onstration of the PCs’ protective effects. The best protective effect was achieved when all
These issues were addressed in a large RCT, the components were combined. The protective
which examined the effectiveness of skin protec- cream clearly had the biggest protective value,
tion with the three-step model in a real-life setting with or without the postexposure emollient. The
(Winker et al. 2009). Because the planned primary benefit of only a postexposure emollient was
outcome – the incidence of eczema – was too low, negligible.
the conclusions were based on the change in the Currently only one RCT has succeeded in
trans-epidermal water loss (TEWL), a generally demonstrating the benefit of the PCs in a real
occupational setting (Kutting et al. 2010). In this better controlled laboratory conditions. Apart
trial, 1020 workers from 19 factories in Germany from the low number of participants, an example
were randomized to receive either both pre- and of such limitations could be the inadequate
after-work creams, only a protective (prework) cream application (Wigger-Alberti et al. 1997a)
cream, only a skin-care (after-work) cream, or no and the low compliance. In the RCT of Winker et
recommendations for skin protection (control al. (2009), only two thirds of the
group). The participants used the available prep- participants applied the topical products daily.
arations provided by the employer, instead of The laboratory studies with volunteers could
special study preparations, and were randomized have overestimated the efficacy of the protective
per factory, so that all the workers in a given creams due to unrealistically large quantities tra-
factory were in the same group. The primary ditionally used (Schliemann et al. 2014).
outcome was the change in the skin condition Another review concluded that the efficacy of
of the hands after 1 year, expressed by a skin PCs to prevent the de novo development of CD
score. All intervention groups showed statisti- (primary prevention) remains unproved and
cally significant difference to the control group, there is only evidence for their effects to prevent
but the largest improvement was seen in the the recurrence of CD (secondary prevention)
group with both skin protection and skin-care (Kutting and Drexler 2008). A similar conclu-
creams, followed by skin protection alone as sion was reached by a Cochrane review (Bauer et
second best. This result is in contrast to that of al. 2010) which however did not include the later
Winker et al. with respect to the relevance of the published Kutting study (Kutting et al. 2010).
skin protection. This study also confirmed a sig- Both experimental studies and RCTs agree,
nificant difference in skin condition in relation to however, that the best results were achieved
the size of the factories. Workers from small when all the elements of the three-step skin pro-
factories (with less than 20 workers) had worse tection model were used together. The workers
skin condition compared to workers from larger from the RCT of Winker et al. (2009) also had
factories. This could be due to a better imple- highest subjective perception of improvement
mentation of occupational safety measures in the in the arm with the three components together,
larger factories as well as most probably to the although their ratings were not coincident with
involvement of small-factory workers in diverse the TEWL measurements. In the largest RCT
tasks, which leads to exposure to the combined (Kutting et al. 2010), the highest compliance
effects of various irritants. was also observed in the group with all the
With the exception of the last RCT (Kutting components together. Similar observations,
et al. 2010), there is a discrepancy between that the three-step model is best accepted by
the results obtained from laboratory and field the workers, have also been made earlier (Elsner
research. Based on the results from most of the and Wigger-Alberti 2003), and the three-step
RCTs, it may be argued that topical preparations model is recommended as the standard in
can influence mainly the regenerative, rather current guidelines (Fartasch et al. 2008, 2015).
than protective, functions of the skin, and there- The recommendation to use protective creams
fore, the value of using a barrier cream is in initially healthy skin remains a consensus-
scarcely, if at all, bigger than that of a simple based rather than an evidence-based one (Elsner
moisturizer. Some published guidelines consider et al. 2016).
that the PCs by themselves are of “questionable
value,” while emollients “appear to confer some 4.1.8 Adverse Effects and
degree of protection” (Bourke et al. 2009). On Contraindications
the other hand, RCTs in skin protection have The use of protective creams may cause effects
their own limitations (discussed in (Kutting which are contrary to the expected. The PCs
et al. 2010)) and may not be capable of demon- may be inappropriate for a certain occupational
strating an effect that is clearly visible in the setting and be ineffective or even increase the
irritating effects. Published examples show synonyms. Humectants are substances belong-
increased irritation from cutting oil (Goh ing to the moisturizers and natural moisturizing
1991), toluene (Wigger-Alberti et al. 1998) n- factors (NMFs), such as urea, lactic acid, glycer-
octane and cumene (Schliemann et al. 2013), ine, sorbitol, or modern substances such as
sodium hydroxide (Frosch et al. 1993b), and hyaluronic acid and mucopolysaccharides.
others. Another adverse effect could be the They increase hydration, binding water at the
increased percutaneous penetration of industrial skin surface by retaining large amounts of
chemicals and carcinogenic substances. In- water relative to their weight. Urea is one
creased absorption of aromatic amines is such humectant, which has been shown to reduce
reported from a field study in the rubber industry susceptibility to irritation with SLS of both
(Korinth et al. 2007) which supplements normal and irritated skin and is, therefore,
earlier experimental studies with diffusion suitable as a component of the postexposure
chambers (Loden 1986; Korinth et al. 2007). emollients (Lodén et al. 2004). Close to 200
Additional problems arise when the protective compounds are used for skin hydration, but
creams are used together with gloves, where the not always hydration, and improved dryness
glove occlusion and the possible interactions leading to a better barrier function. For exam-
between the gloves and the protective creams ple, 15% glycolic acid has been shown to
need to be separately investigated (Fartasch et improve xerosis on the legs but also to
al. 2015). These published examples underline increase trans-epidermal water loss as well
the importance of the appropriate testing of the as the susceptibility to externally applied
PCs against the noxious factors from the respec- irritants (Loden 2005).
tive occupational setting. Some moisturizers also contain anti-infla-
As any other topical preparations, PCs may mmatory or epithelial growth-promoting subst-
themselves induce irritant and allergic contact ances such as alpha-bisabolol, allantoin, or
dermatitis in rare instances (Gupta et al. 1987; dexpanthenol. Efficacy in wound healing has
Pinola et al. 1993). More on the adverse effects been demonstrated for many similar substances,
of the PCs is given in ▶ Chap. 50, “Adverse and they are also used for the regeneration of the
Effects of Skin Protective Products, Including epidermal barrier function.
Sunscreens.” The exact mechanism of action of moisturizers
and emollients is still unknown, but there is accu-
mulated efficacy data regarding their occlusive
5 Emollients properties, lipid content, and pH. However, nei-
ther of these characteristics alone can predict their
5.1 Chemistry and Mode of Action effects to treat and prevent contact dermatitis nor
can explain why some emollients improve,
Postexposure skin-care products that are while others may deteriorate the barrier function
designed to counteract the damaging effects of of the skin.
irritants on skin barrier function are mostly The increased trans-epidermal water loss
water-in-oil or oil-in-water varieties, which (TEWL) after barrier disruption is a signal trig-
belong to the moisturizers or emollients. Mois- gering the barrier-repair mechanisms, including
turizers are designed to actively increase the lipid and DNA synthesis and keratinocyte pro-
water content of the skin. Emollients are liferation (Proksch et al. 2008). While keeping
designed to smooth the skin and to increase the epidermis moist and preventing dryness are
the water content indirectly by creating an occlu- essential for the healing process, preserving the
sive film on the skin surface, thereby trapping trans-epidermal water flux is also necessary for
the water in the upper layers of the stratum the normal repair (Grubauer et al. 1989). Mois-
corneum (Gabard 1994). On many occasions turizers exert their effects not only through the
“emollients” and “moisturizers” are used as actions of their individual ingredients; they
should also provide optimal occlusion. How- 5.2 Efficacy of Emollients

ever, the occlusive properties alone do not solely
account for the effects of moisturizers on the There is increasing amount of data that moistur-
barrier function, for example, moisturizers with izers are capable of both preventing and treating
similar occlusive properties may have different irritant contact dermatitis (Zhai and Maibach
effects on the barrier function (Buraczewska et 1998; Yokota and Maibach 2006). In addition to
al. 2007b). previous studies that documented the efficacy of
Externally applied moisturizers may contain moisturizers using noninvasive bioengineering
either physiologic or non-physiologic lipids, or methods in healthy volunteers with normal skin
both. While the non-physiologic lipids provide (Blichmann et al. 1989; Serup et al. 1989), studies
the occlusive properties of a moisturizer, the with more clinically relevant settings have been
physiologic lipids penetrate the epidermis and performed. These focused on the efficacy in the
can influence the processes of lipid synthesis epidermis after various types of acute and chronic
and secretion (Feingold 2007). If the external skin damage or during everyday exposure
preparations contain optimal ratios of the major to irritants (Hannuksela and Kinnunen 1992;
classes of physiologic lipids, they can enhance Halkier-Sorensen and Thestrup-Pedersen 1993;
the barrier regeneration (Feingold 2007). Con- Treffel and Gabard 1995; El Gammal et al.
versely, unbalanced ratios of physiologic lipids 1996; Gabard et al. 1996; Loden and Andersson
may have a negative influence on the skin barrier 1996). Theoretically, after-work emollients may
function. Negative effects can also be caused by be helpful in repairing skin barrier disruption
non-physiologic lipids (Buraczewska et al. after repetitive irritation, and it was demonstrated
2007a) and some emulsifiers (Barany et al. that these products could reduce trans-epidermal
2000) which may interfere with the organization water loss (TEWL) alterations in skin that had
of lipids in the stratum corneum. Other emulsi- been exposed to irritants (Blanken et al. 1989).
fiers have shown properties to improve the A regularly used moisturizer was demonstrated to
barrier function of SLS-irritated skin (Barany improve the skin hydration state (capacitance) in
et al. 2000). cleansers and kitchen workers (Halkier-Sorensen
The role of acidic pH for the restoration of and Thestrup-Pedersen 1993), and El Gammal
the barrier function has been shown in experi- et al. (1996) demonstrated a significant decrease
ments with mice (Mauro et al. 1998) and in dryness grades and scaling for a preparation
human volunteers (Kim et al. 2009). However, tested in a soap-induced xerosis human model.
a study with experimental SLS irritation in Different types of emollients that were used regu-
18 healthy volunteers did not detect differ- larly prevented irritant dermatitis from a detergent
ences between emollients with pH 4 (acidic) measured by TEWL and laser Doppler flowmetry.
and pH 7 (neutral) in terms of both barrier The rate of healing was slower for untreated skin
repair and irritability by SLS rechallenge (Bura- than for skin with an emollient (Hannuksela and
czewska and Loden 2005). Kinnunen 1992).
The long-term application of moisturizers In addition to their regeneration effects, emol-
(7 weeks) was shown to affect the expression of lients have also been shown not only to treat but
mRNA in healthy volunteers (Buraczewska et al. also to prevent ICD. A study showed on exper-
2009a, b). The affected genes are involved in imentally irritated skin both a significant preven-
keratinocyte differentiation, corneocyte forma- tive effect and a therapeutic effect of a
tion, and desquamation. The same studies show moisturizer (Ramsing and Agner 1997). The
that depending on their composition, the moistur- product tested prevented irritant skin reaction
izers may not only evoke divergent effects on the due to SLS, and it accelerated regeneration of
skin barrier function, but they also influence dif- skin barrier function of SLS-irritated skin of the
ferently the mRNA expression (Buraczewska hands judged by measurements of TEWL and
et al. 2009b). electrical capacitance.
5.3 Adverse Effects and lipid content, pH, or humectant content, can
Contraindications account alone for the observed differences. It is
suggested that by influencing the hydration
Similarly to PCs, not all emollients are effective in dynamics of the stratum corneum, the organiza-
promoting the regeneration of the skin barrier tion of the lipid structures, and the ion flux, the
after irritation. For example, the emollients tested moisturizers may affect the signaling pathways
did not enhance regeneration of irritated skin in a regulating the barrier function (Buraczewska
study performed by Blanken et al. (1987b). In a et al. 2009a, b). More on the adverse effects of
study performed with machinists exposed to cut- the emollients is given in ▶ Chap. 50, “Adverse
ting fluid, an after-work emollient cream did not Effects of Skin Protective Products, Including
appear to have any significant effect against either Sunscreens.”
cutting fluid dermatitis or TEWL changes (Goh The topical preparations of the three-step pro-
and Gan 1994). Some ingredients may worsen gram, the PCs, and the emollients, are frequently
ICD. For example, the use of urea in moisturizers used together with gloves. The possible interac-
may increase skin permeability, and it was also tions are reviewed in ▶ Chap. 50, “Adverse
found to be an efficient enhancer for the penetra- Effects of Skin Protective Products, Including
tion of several substances, for example, hazardous Sunscreens.” There are published examples of
substances at the workplace (Wohlrab 1984; topical preparations both increasing (Baur et al.
Duval et al. 2003). Urea is, therefore, considered 1998) and decreasing (Allmers 2001) the hyper-
unsuitable for creams intended for prework and sensitivity reactions to latex from gloves in
during-work application. Additionally, similar to patients with known latex hypersensitivity. This
PCs, emollients themselves may induce ICD and demonstrates the potential of the topical prepara-
ACD due to ingredients such as preservatives, tions to influence the release of allergens from the
cream bases, emulsifiers, and fragrances. gloves. Additional concerns are the possibility for
Skin hydration through emollients is not compromising the insulating properties of the
always and not in all circumstances beneficial gloves, degrading the glove material, and ulti-
for the skin barrier. It has been shown that some mately leading to increased penetration of aller-
moisturizers may be harmful to the skin barrier gens and irritants (Schliemann 2007). As the
function, when applied for longer periods wearing of gloves has an occlusive effect with
(4 weeks and more) in healthy volunteers. Appli- hyperhydration and swelling of the stratum
cation of a moisturizer three times per day for corneum, the desirable properties of the PCs to
4 weeks led to increased susceptibility to SLS- be applied together with gloves include the reduc-
induced irritation (Held et al. 1999). In a study tion of perspiration, the reduction of SC swelling,
comparing five emollients applied for 7 weeks, and a no interference with the glove material
four of them increased, and only one decreased (Schliemann 2007; Fartasch et al. 2015).
the susceptibility to irritation with SLS
(Buraczewska et al. 2007a). In a comparison
between two moisturizers (Held and Agner 5.4 Mild Cleansers
2001), after only 5 days of application, the lipid-
rich one increased the susceptibility to SLS irrita- The effects of surfactants on the stratum
tion. Increased reactivity against nickel in allergic corneum (SC) have been extensively studied,
subjects, after treatment with a lipid-rich moistur- although not within the three-step program for
izer for 7 days, has also been documented skin protection (Ananthapadmanabhan et al.
(Zachariae et al. 2003). It is unclear why some 2004). The irritant properties of the surfactants
moisturizers improve, while others deteriorate the are related to their ability to take away from the
skin barrier function. These effects are related to skin lipids, proteins, and substances from the so-
the composition of the emollients, but no single called natural moisturizing factor (NMF). Sur-
characteristic, such as their occlusive properties, factants can interact with SC proteins, leading to
swelling during washing, reduced barrier func- cleansers but also the mechanic irritation from
tion, and subsequent dryness. They also alter the rubbing the skin during the washing procedure
lamellar organization of the SC lipids (Elsner et al. 2014). Using this method together
(Ananthapadmanabhan et al. 2004). A correla- with standard model types of synthetic dirt and
tion between the pH of cleansers and their irritant standard reference cleansers will allow calculat-
potential has also been established (Baranda ing an “irritation factor” and a “cleansing factor”
et al. 2002). The various surfactants differ in for any commercial cleansing product which
their irritant properties and mechanisms. Sodium could be used similarly to the sun protection
lauryl sulfate (SLS) is used in experimental stud- factor for the sunscreens. Additionally, this
ies as a model irritant. Apart from surfactants, study showed that through the development of
the industrial hand cleansers may contain other special cleansers targeting specific types of
aggressive and harmful-to-the-skin substances. dirt, it is possible to separate the irritant
Such may be solvents and/or grits (natural and and the cleansing properties of the cleansing
synthetic abrasives), needed to adequately products so that a stronger cleansing effect
remove industrial dirt (Wigger-Alberti et al. would not necessarily cause more irritation
1999b; Klotz et al. 2003). (Elsner et al. 2014).
Similarly to the PCs, different laboratory In certain occupations, such as in the health-care
models have been developed for examining the sector, hand disinfection may replace or reduce
irritant properties of the cleansers. Such are the handwashing. In a RCT with hospital workers,
corneosurfametry (Pierard et al. 1994); one-time alcohol-containing hand disinfectants were found
occlusive test; repeated occlusive test; repeated to be more effective than washing with liquid soap
open test; wash tests, like the repetitive forearm in reducing the bacterial contamination of the
wash test; use test; and others (Wigger-Alberti hands. These disinfectants also caused less skin
et al. 1999b; Spoo et al. 2002; Bornkessel et al. irritation in the same trial (Winnefeld et al. 2000).
2005). Standardized washing of artificial dirt The lower irritating properties of the alcohol-based
may be used to assess the cleaning power hand disinfectants compared to detergents are well
(Klotz et al. 2003). It was shown with the help established from laboratory experiments with vol-
of this model that aggressive cleansers with unteers (Pedersen et al. 2005a; Slotosch et al.
higher irritant qualities, like the ones with sol- 2007). When a propanol-based hand rub was com-
vents, do not necessarily have better cleaning pared to SLS in such a study (Slotosch et al. 2007),
properties (Klotz et al. 2003). In another study, it not only was lower than SLS and comparable to
employing a modified ROIT (Berndt et al. 2002), water in terms of irritancy but even improved the
the cleanser alone did not cause irritation but SLS-induced irritation when applied after SLS in
amplified the irritating effect of SLS, even the combined SLS/hand rub tests. In other studies,
though it was a mild synthetic detergent with the alcohol-based disinfectants alone and the com-
skin-hydrating properties. Therefore, the bined use of such disinfectants with detergents
cleansers should be chosen to be as mild as were better tolerated than the detergent alone
possible yet appropriate for the dirt in the respec- (Pedersen et al. 2005b). A drawback of these
tive occupation (Berndt et al. 2002; Kutting and hand disinfectants is that they cause burning and
Drexler 2008). The work should also be orga- stinging when applied on already irritated skin. In
nized in a way that permits the number such cases, the personnel may start to apply the
of washings per day to be minimal. A survey disinfectant less frequently or in insufficient quan-
on cleansing products used in the occupational tity, compromising the procedure (Winnefeld et al.
setting concluded that uniform methods for 2000). Alternatively, the people with irritated
establishing the product efficacy and tolerability skin may tend to replace the use of disinfectants
are needed (Terhaer et al. 2010). Such a method with more frequent washing, thus further
has been proposed in the meantime which allows irritating the skin and forming a vicious cycle
modeling not only the irritant properties of the (Slotosch et al. 2007).
6 Conclusion References
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Adverse Effects of Skin Protective
Products, Including Sunscreens 50
Sibylle Schliemann
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
Abstract 1 Core Messages

Adverse effects to skin protective products are
rare in general. Potential side effects include The overall incidence of adverse reactions to skin
aggravation of preexisting disease, e.g. irritant protection products seems to be low. Possible
contact dermatitis, and allergic contact derma- types of adverse reactions include aggravation of
titis. Potential contact allergens include preser- preexisting irritation, induction of allergic contact
vatives, emulsifiers, and fragrances. It is dermatitis, photocontact dermatitis, and enhance-
recommended to include patient’s own skin ment of percutaneous absorption of particular
protection products when patch testing in case chemicals.
the hand dermatitis does not improve or is even Skin protection products may have unsatisfac-
worsening in spite of secondary prevention tory protective action or they may even aggravate
efforts. Confirmatory repetitive open applica- the preexisting disease, such as irritant contact
tion tests (ROAT) may be useful in doubtful dermatitis (ICD). In rare instances, the product
reactions. ingredients themselves may induce allergic con-
tact dermatitis (ACD). In addition, the potential of
Keywords some preparations to enhance penetration of cer-
Allergic contact dermatitis · Barrier cream · tain hazardous substances through the epidermal
Photoallergic contact dermatitis · Sunscreens · barrier in the experimental setting caused concern.
Systemic absorption Altogether, barrier and after-work creams appar-
ently only rarely induce adverse effects, judging
by the low number of published case reports on
intolerance reactions and experimental studies in
the scientific setting.
While many authors reported a satisfactory
S. Schliemann (*) protective action of PCs, others found no protec-
tion (see also ▶ Chap. 49, “Occupational Skin
e-mail: schliemann@derma-jena.de Products”) or even aggravation of ICD in the

https://doi.org/10.1007/978-3-319-68617-2_49
732 S. Schliemann
experimental setting. A particular “skin protector”

aggravated irritation due to sodium hydroxide and
failed to provide action against two other irritants,
SLS and toluene, in a guinea-pig study (Frosch
et al. 1993). Also using a guinea-pig model, it was
shown that treatment with inappropriate BCs may
increase skin irritation induced by cutting oil
fluids (Goh 1991). Especially, protection against
organic solvents such as toluene, cumene, and
octane appears to be a difficult field (Wigger-
Alberti et al. 1998; Schliemann-Willers et al.
2001; Schliemann et al. 2014). Experimental effi-
cacy testing of six skin protection products that
were claimed to protect against “organic solvents” Fig. 1 Positive ROAT example, clinical picture showing
numerous itchy erythematous papules
in a human repetitive irritation test failed to show
benefit of any product, while two out of six prod-
ucts even aggravated skin irritation induced by n- differentiate mild irritant reactions (Hannuksela
octane and cumene significantly (Schliemann and Salo 1986). Preservatives, emulsifiers, and
et al. 2013). These examples illustrate that the fragrances are the main potential allergens. Fra-
protective action of prework creams may be grances are ubiquitous and part of many domestic
highly specific and depend on the type of irritant and occupational products intended for hand
chosen. Accordingly, it is highly desirable that exposure (see also ▶ Chap. 40, “Fragrances and
manufacturers should provide efficacy proofs for Essential Oils”). Hands with impaired epidermal
skin protective products resulting from standard- barrier function are more prone to secondary con-
ized efficacy testing. Preferably, this should be tact sensitization. Therefore, the results of a sys-
performed by using in vivo test models that tematic literature research revealing a possible
should take the various fields of intended use association between fragrance allergy and hand
and different types of irritants into account eczema is not surprising (Heydorn et al. 2003).
(Fartasch et al. 2015). In the EU, 26 fragrances have to be labelled in
Apart from insufficient efficacy against irri- cosmetics according to current regulation. As a
tants or even amplification of barrier damage, result, a tendency of manufacturers to avoid those
cream constituents may induce allergic contact fragrances in favor of alternatives that they do not
dermatitis. Intolerance of skin protection products have to declare is observed in Germany (Fartasch
or after-work creams should be considered in case 2009). The allergenic potential of those fragrances
of worsening of the preexisting hand eczema is unknown in many cases. It is recommended that
without other potential explanation. Patch testing manufacturers should avoid well-known sensi-
should not only include the product as is but tizers in their products and at best fragrances at
also the ingredients should be ordered from the all. Potent fragrance allergens such as limonene
manufacturer and patch tested in appropriate con- and geraniol may cause ACD in barrier creams
centration(s) and vehicles according to the perti- (Tanko et al. 2009) and even when contained in
nent literature (de Groot 2009). It is important to rinse-off products such as hand cleansers
identify the single responsible allergen in order to (Topham and Wakelin 2003) or washing-up liq-
prevent further relapses caused by the same ingre- uids used at the work place (Murphy and White
dient in other cosmetics used on the impaired skin 2003). Methyldibromo glutaronitrile is a mean-
or by working material. A subsequent confirma- while historic preservative that has caused an epi-
tory repeated open application test (ROAT) with demic of contact allergy in Europe (Schnuch et al.
the product (Fig. 1) can be very useful in cases of 2011), with creams and lotions accounting for
doubtful reactions, especially in atopics, to 31% of the identified causative products and
50 Adverse Effects of Skin Protective Products, Including Sunscreens 733
liquid soaps for 23% (Johansen et al. 2005). The the unfavorable effects of prolonged occlusion on
substance was as well found to be relevant in work the epidermal barrier that are caused by gloves.
creams (Wong and Beck 2001). From 2008 on, it Studies investigating the effects of barrier creams
has been totally banned both from all leave-on and on leaching of allergens from glove material are
rinse-off cosmetic products in the EU and will scarce and produced conflicting results either by
therefore no longer be found in barrier creams showing reduced or enhanced release (Baur et al.
and after-work creams in Europe (Communities 1998; Allmers 2001). Ideally, skin protection
2007). Methylisothiazolinone (MI) and the poten- products recommended to be used under gloves
tial cross-reacting to methylchloroisothiazolinone should be tested in this context.
(MCI) is the biocide actually causing an epidemic Topical sunscreens are recommended in out-
of allergic contact dermatitis in Europe and the door professions as a part of a comprehensive UV
USA in cosmetics but also in household and protection strategy for outdoor workers to prevent
industrial products (Pesonen et al. 2015; Vauhkala acute sunburns, cumulative actinic skin damage,
et al. 2015). 1.5% out of 2536 patients tested in and nonmelanoma skin cancer (Glanz et al. 2007;
Denmark reacted to MI, and exposure from cos- Schmitt et al. 2011). Sunscreen chemicals, in par-
metic products, such as soaps and moisturizers, ticular UV filters, may as well cause allergic or
accounted for 32% of contact dermatitis caused photoallergic contact dermatitis. The diagnostic
by MI (Lundov et al. 2010). Contact allergy to method in case of suspected photoallergy is
MCI/MI or MI has not yet been explicitly photopatch testing. Photopatch testing should be
published in the context of being a constituent considered in case a dermatitis predominantly
of barrier – or after-work creams – but has been affects UV-light exposed sites and in patients
found in skin care products, and more often, in with chronic actinic dermatitis or obviously
liquid soaps, hand cleansers, and skin wipes photoaggravated eczema. A European consensus
(Vauhkala et al. 2015). Quaternium 15 is one statement on methodology, test materials, and
example of a group of formaldehyde donors interpretation of photopatch testing was given
used as preservatives in cosmetics. It may induce by the European Taskforce for Photopatch Testing
allergic contact dermatitis in persons allergic to (Bruynzeel et al. 2004). Benzophenones ranged
formaldehyde, such as health care workers, as among the most common sunscreen photo-
has been described after usage of a moisturizing allergens in several studies (Schauder and Ippen
lotion, (Microshield ®) (Cahill and Nixon 2005). 1997; Bryden et al. 2006; Agin et al. 2008; Victor
Chlorocresol is an antiseptic and preservative et al. 2010) (reviewed in (Wong and Orton 2011).
used not only in topical medications but also Other common sensitizers are para-aminon-
rarely in cosmetics. In a single patient from Aus- benzoic acid PABA, isopropyl dibenzoylmethane
tralia, it was identified as the cause of a severe (de Groot et al. 1987; Schauder and Ippen 1997),
contact allergy after application of a common butyl methoxydibenzoylmethane (Bryden et al.
moisturizer, Sorbolene ®, as a barrier cream 2006), oxybenzone (Cook and Freeman 2001),
(MacKenzie-Wood and Freeman 1997). Coconut and octyl dimethyl, 4-tert-butyl-40 -methoxy-
diethanolamide (CDEA), manufactured from dibenzoylmethane in the USA (Victor et al.
coconut oil, is used as a surface-active agent in 2010). Isoamyl p-methoxycinnamate appears
cosmetics and altogether a rare contact allergen. to be a rare photocontact allergen (Darvay et al.
Anyhow in Finland, two out of six patients were 2001; Ghazavi and Johnston 2011). Octocrylene
sensitized from a barrier cream, while three got (2-ethylhexyl 2-cyano-3,3-diphenyl-2-pro-
sensitized from a hand-washing liquid and one penoate) is a filter covering UVB and short UVA
from either hand-washing liquid or metalwork- that was recently shown to be both a photocontact
ing fluid (Pinola et al. 1993). allergen and a contact allergen (Avenel-Audran
Skin protection products are commonly used et al. 2010; Karlsson et al. 2011; Uter et al. 2017)
together with protective gloves, and some prod- and in addition has been reported as a cause of
ucts are explicit omit spacely claimed to reduce contact urticaria (Haisma and Schuttelaar 2017).
734 S. Schliemann
Other constituents of sun protection products factors on the percutaneous absorption of aro-
might cause contact allergies as well. Recently, matic amines (AA) in the rubber industry
four cases of copolymer allergy to C30–38 olefin/ (Korinth et al. 2007). The use of a protective
isopropyl maleate/MA copolymer (CAS 75535- cream and frequent washing were associated
27-2) in a sunscreen were reported. Copolymers with increased systemic exposure to AA. The
are chemical compounds that are used in many other protective measures, such as breathing
consumer products. They can be found in sun- masks, prolonged wearing of gloves, and after-
screens, other cosmetic types, and topical medi- work creams were associated with decreased
cations and have been reported as a cause of exposure. The authors suggest that some PCs
contact allergy in cosmetics and adhesives (Kai may facilitate the adhesion of particles from the
et al. 2011). Other cases of allergic contact der- air to the skin in certain industries, as in the
matitis were reported from Decyl Glucoside as a rubber industry the aromatic amines in the air
component of Tinosorb® (Andrade et al. 2010), are mainly bound to particles (Korinth et al.
from tetrasodium EDTA (Sanchez-Pedreno et al. 2007). There are other examples, such as exper-
2009), and case reports upon further ingredients imental studies with diffusion chambers or
were reviewed in (Avenel-Audran 2010). microdialysis that generated conflicting results,
An additional concern regarding PCs is the depending on the PC preparations and chemicals
possibility for enhanced penetration of particular used (Loden 1986; Boman and Mellstrom 1989;
industrial chemicals and carcinogenic sub- Klede et al. 2005). These studies show that a
stances. Skin protection preparations are aimed potentially increased systemic toxicity risk of
at prevention of irritant barrier impairment and specific hazardous chemicals, due to epidermal
not at prevention of systemic absorption. How- penetration facilitated by barrier creams, should
ever, they are used also on already damaged skin be considered in selected industries.
and should not facilitate epidermal penetration of
chemicals. Recent research demonstrated that it
cannot be generally assumed that prework References
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chemicals, although there are examples of stud- Agin PP, Ruble K, Hermansky SJ, McCarthy TJ (2008)
ies showing diminished dermal penetration, e.g., Rates of allergic sensitization and irritation to
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Dermatol 46(4):284–285 Schmelz M (2005) Transcutaneous penetration of
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allergic contact dermatitis to sunscreens seen at protective gloves on percutaneous absorption
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16(5):249–254 absorption of water, benzene, and formaldehyde into
Fartasch M (2009) Skin protection. From TRGS 401 to excised human skin. Contact Dermatitis 14(5):292–296
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Hautarzt 60(9):702–707 Prevalence and cause of methylisothiazolinone contact
Fartasch M, Diepgen TL, Drexler H, Elsner P, John SM, allergy. Contact Dermatitis 63(3):164–167
Schliemann S (2015) S1 guideline on occupational skin MacKenzie-Wood AR, Freeman S (1997) Severe allergy to
products: protective creams, skin cleansers, skin care sorbolene cream. Australas J Dermatol 38(1):33–34
products (ICD 10: L23, L24)–short version. J Dtsch Murphy LA, White IR (2003) Contact dermatitis from
Dermatol Ges 13(6):594–606 geraniol in washing-up liquid. Contact Dermatitis
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The repetitive irritation test (RIT) in the guinea pig. Krecisz B, Kiec-Swierczynska M, Bauer A, Mahler V,
Contact Dermatitis 28(2):94–100 John SM, Schnuch A, Uter W, E. network (2015) Patch
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736 S. Schliemann
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49(2):108–109
Acrylic Resins
51
Kristiina Aalto-Korte
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
3 Chemical Structures and Main Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
3.1 Acrylic Acid and Its Esters (Acrylates) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
3.2 Methacrylic Acid and Its Esters (Methacrylates) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
3.3 Cyanoacrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
3.4 Epoxy Acrylates (Acrylated Epoxy Resins) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.5 Combinations with Other Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.6 Acrylamide and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.7 Acrylonitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
3.8 Radiation Curing Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
4 Allergic Contact Dermatitis from Acrylic Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
4.1 Dental Acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
4.2 Nail Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746
4.3 Acrylic Glues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
4.4 Paints, Varnishes and Coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
4.5 Printing Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
4.6 Allergic Contact Dermatitis from Epoxy Acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
4.7 Allergic Contact Dermatitis from Acrylamide Derivatives and Acrylonitrile . . . 751
5 Patch Testing with Acrylic Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
6 Skin Irritation and Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
7 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
8 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
Keywords
Acrylate · Methacrylate · Cyanoacrylate ·
Epoxy acrylate · Glue · Artificial nail · Paint ·
K. Aalto-Korte (*) Coating · Varnish · Printer · UV-cure ·
Occupational Medicine, Finnish Institute of Occupational Beautician · Nail technician · Dentist · Dental
e-mail: kristiina.aalto-korte@ttl.fi

https://doi.org/10.1007/978-3-319-68617-2_50
738 K. Aalto-Korte
nurse · Dental technician · Lash extension · of resins such as epoxies, polyurethanes, polyes-
Assembler ters, and polyethers. The term “‘acrylate” is often
used for all acrylic compounds, not only for esters
of acrylic acid.
1 Core Messages
• The cured end products of acrylic resin sys- 3 Chemical Structures

tems (e.g., acrylic plastic or dental fillings) do and Main Uses
not normally sensitize or cause symptoms in
previously sensitized individuals, as they do 3.1 Acrylic Acid and Its Esters
not contain enough reactive monomers. (Acrylates)
Uncured products, in turn, contain sensitizing
monomers. Acrylic acid and its esters, which are also known
• Contact allergy to acrylic resin monomers is as acrylates (Fig. 1), are flammable, volatile, col-
most often induced by artificial nails, dental orless liquids. They all polymerize very easily.
products, and glues. These products contain Polymerization is catalyzed by heat, light, and
methacrylates and exposure to them usually peroxides, and inhibited by stabilizers such as
leads to methacrylate allergy. the monomethyl ether of hydroquinone or hydro-
• Acrylate contact allergy is less common than quinone itself. These phenolic inhibitors are only
methacrylate contact allergy and usually effective in the presence of oxygen (Ohara et al.
derives from UV-cured printing inks, lacquers, 2010).
paints, varnishes, or glues. The primary role of acrylic acid in the
• Beauty sector workers (nail and lash techni- production of acrylates is as an intermediate.
cians), assemblers of machines and mechanical Acrylic esters are used exclusively for the
devices, dentists, dental nurses, dental techni- production of polymers (polyacrylates). Polymers
cians, printers, painters, and workers in paint are used mainly in coatings, paints, adhesives,
factories are at risk of developing occupational binders for leather, paper, and textiles. About 80%
allergic contact dermatitis from acrylic of the methyl acrylate (MA) produced is used as a
compounds. copolymer component of acrylic fibers. Ethyl acry-
• Fingertip dermatitis is the typical clinical pre- late (EA) is used for both solvent- and water-based
sentation of contact allergy to acrylic paints, and in textiles as a binder in non-woven
compounds. fabrics and flocking. Butyl acrylate (BA) is mainly
used in water-based paints and adhe-
sives. 2-Ethylhexyl acrylate (2-EHA) is used for
2 Introduction almost the same purposes as butyl acrylate, in stick-
on labels, and in the caulking of building materials.
Acrylic resins are a group of plastic substances The abovementioned acrylates have only one
derived from acrylic acid, methacrylic acid, and reactive acrylic group and are called monoacrylates
other related compounds. Acrylic acid is a carbox- (Fig. 1). Compounds with at least two reactive
ylic acid with a carbon-carbon double bond groups are called multifunctional acrylates.
connected to its acid functionality (Fig. 1). The Representative multifunctional acrylates comprise
carbon-carbon double bond (a vinyl group) is the trimethylolpropane triacrylate (TMPTA), penta-
reactive group responsible for the formation of erythritol triacrylate (PETA), 1,4-butanediol
plastics by polymerization. The monomers diacrylate (1,4-BUDA), 1,6-hexanediol diacrylate
include acrylic acid and methacrylic acid and (1,6-HDDA), and poly(ethylene glycol) diacrylates
their esters, cyanoacrylic acid and its esters, acryl- (Figs. 2, 3, and 4). These esters of polyhydric
amides, and acrylonitrile. A large number of dif- alcohols are used as cross-linking agents and mod-
ferent acrylic polymers are formed from the ifiers in rubber and synthetic resins, in adhesives,
monomers and can be combined with other types and as active diluents in photosensitive resins. They
51 Acrylic Resins 739
are also applied in the coating and ink industries acid (Fig. 1). Compounds with one methacrylic
because they can be cured with ultraviolet light or group are called monomethacrylates (Fig. 1), and
electron-beam radiation. Examples of two industri- those with at least 2 methacrylic groups are called
ally significant esters are 2-hydroxyethyl acrylate multifunctional methacrylates (Figs. 3 and 4).
(2-HEA) and 2-hydroxypropyl acrylate (2-HPA), Methacrylic acid and methacrylate esters are used
which are particularly used as cross-linking agents to prepare a wide range of polymers. Polymethyl
in heat-cured paints, adhesives, and textile prepara- methacrylate (PMMA) is the primary polymer in
tions, etc. (Fig. 1) (Ohara et al. 2010). this category and provides water-clear, tough plas-
tics that are used in sheet form in glazing, signs,
displays, and lighting panels. Automotive lighting
3.2 Methacrylic Acid and Its Esters lenses and similar products can be prepared from
(Methacrylates) moulding pellets. Methyl methacrylate, incorpo-
rated into copolymers, forms the basis for durable
Methacrylates are esters of methacrylic acid, which coatings and inks. Higher methacrylate polymers
has an additional methyl group compared to acrylic are useful in the manufacture of oil additives,
Acrylic acid Cyanoacrylic acid Methacrylic acid
H2C CH C OH H2C C C OH CH3
O C O H2C C C OH
N
O
Ethyl acrylate (EA) Methyl methacrylate (MMA)

H2C CH C O CH2CH3 CH3
O H2C C C O CH3
Ethyl-2-cyanoacrylate (ECA) O
H2C C C O CH2CH3
C O Ethyl methacrylate (EMA)

N
Butyl acrylate (BA) CH3

H2C C C O CH2 CH3
H2C CH C O CH2CH2CH2CH3
O
O
2-Hydroxyethyl methacrylate
2-Ethylhexyl acrylate (2-EHA) (2-HEMA)
CH3
H2C CH C O CH2CH CH2CH2CH2CH3
H2C C C O CH2 CH2 OH
O H2C CH3
O
2-Hydroxyethyl acrylate (2-HEA) 2-Hydroxypropyl methacrylate

(2-HPMA)
H2C CH C O CH2CH2OH
O CH3
H2C C C O CH2 CH CH3
O
OH
Fig. 1 Acrylic acid, cyanoacrylic acid, methacrylic acid and their monoesters
740 K. Aalto-Korte
solvent-free inks and coatings, and binders for exclusively as instant adhesives. Methyl, ethyl,
xerography. Salts of polymethacrylic acid can butyl, allyl, and methoxyethyl 2-cyanoacrylates
serve as the basis for water-soluble thickeners and are available for a wide field of applications. They
detergent additives (Bauer 2010). As regards contact are used in the electrical and electronics industries,
allergy, important applications include dental restor- as well as in many areas of mechanical engineering
ative materials, dentures, artificial nails, UV-curing such as automobile, ship, and aircraft construction.
nail polishes, glues, and orthopedic cements. In addition to these purely technical applications,
2-cyanoacrylates are used in medicine to close
wounds and in artificial nail glues (Ohara et al.
3.3 Cyanoacrylates 2010). Eye lash extensions glues are a new popular
application for cyanoacrylates. Artificial lashes are
Cyanoacrylates are based on cyanoacrylic acid attached lash by lash by a technician to the client’s
(Fig. 1). 2-cyanoacrylates are utilized almost natural lashes with a cyanoacrylate glue.
Fig. 2 Some Trimethylolpropane triacrylate (TMPTA)

multifunctional acrylates CH3
CH2 O
H2C CH C O CH2 C CH2 O C CH CH2

O CH2
O
C
O CH
CH2
Pentaerythritol triacrylate (PETA)
OH
CH2 O
H2C CH C O CH2 C CH2 O C CH CH2
O CH2
O
C
O CH
CH2
Dipropyleneglycol diacrylate (DPGDA)

O
H2C CH C O CH2 CH O CH2 CH O C CH CH2
O CH3 CH3
Tripropyleneglycol diacrylate (TPGDA)
H2C CH C O CH2 CH O CH2 CH O CH2 CH O C CH CH2
O CH3 CH3 CH3 O

Fig. 3 Some 1,4-Butanediol diacrylate (1,4-BUDA)

multifuntional (meth) O
acrylates (does not require
copyright) H2C CH C O CH2CH2CH2CH2 O C CH CH2
1,4-Butanediol dimethacrylate (1,4-BUDMA)

O
H2C C C O CH2CH2CH2CH2 O C C CH2
CH3 O CH3
1,6-Hexanediol diacrylate (1,6-HDDA)

O
H2C CH C O CH2CH2CH2CH2CH2CH2 O C CH CH2
Fig. 4 (Poly)ethylene Ethyleneglycol dimethacrylate (EGDMA)

glycol di(meth)acrylates
(does not require copyright) CH3 O
H2C C C O CH2CH2 O C C CH2
O CH3
Diethyleneglycol dimethacrylate (DEGDMA)
CH3 CH3
H2C C C O CH2CH2 O CH2CH2 O C O CH2
O O
Triethyleneglycol dimethacrylate (TREGDMA)
CH3 CH3
H2C C C O CH2CH2 O CH2CH2 O CH2CH2 O C C CH2
O O
Diethyleneglycol diacrylate (DEGDA)
O
H2C CH C O CH2CH2 O CH2CH2 O C CH CH2
Triethyleneglycol diacrylate (TREGDA)
H2C CH C O CH2CH2 O CH2CH2 O CH2CH2 O C CH CH2

O O
742 K. Aalto-Korte
3.4 Epoxy Acrylates (Acrylated 3.7 Acrylonitrile

Epoxy Resins)
Acrylic textile fibers are by far the largest end-use
Epoxy resins are reacted with acrylic acid to form product for acrylonitrile, which is also used for
epoxy acrylates (Fig. 5), which can be cured by nitrile rubber and in the production of acryl-
light (most commonly UV lights) or electron onitrile-butadiene-styrene and styrene-acry-
beams. Epoxy diacrylate, named also bis-GA, lonitrile resins. These products are used to
2,2-Bis[4-(2-hydroxy-3-acryloxypropoxy)phe- fabricate components for automotive and recrea-
nyl]-propane or epoxy acrylate, is the diacrylate of tional vehicles, pipe fittings, house ware, electri-
the diglycidyl ether of bisphenol A (DGEBA) cal appliances, suitcases, and disposable dishes
epoxy resin. Major applications include coatings (Bjorkner 2006; Langvardt 2010).
for overprint varnishes, wood substrates, and plas-
tics. Both aromatic and aliphatic epoxy acrylates
exist, as well as acrylated epoxidized oils such as 3.8 Radiation Curing Systems
soybean oil and linseed oil (Bjorkner 2006; Pham
and Marks 2010). In the 1960s, the first epoxy Radiation curing is a relatively new technology
methacrylate, 2,2-bis[4-(2-hydroxy-3-methacry- which uses electromagnetic (mainly UV) or ion-
loxypropoxy) phenyl]propane (bis-GMA also izing (mainly accelerated electrons) radiation to
named bisphenol A diglycidylmethacrylate or initiate a chain reaction in which mixtures of
epoxy dimethacrylate), was developed for dental polyfunctional compounds are transformed into
composite resins. It is manufactured by reacting a cross-linked polymer network. During irradia-
DGEBA with methacrylic acid, or bisphenol A tion with UV light, the reactive species are formed
with glycidyl methacrylate (Jolanki et al. 2000b). by the chemical decomposition of a photo initi-
2,2-Bis[4-(methacryl-oxyethoxy)phenyl] propane ator. Radiation-cured systems can be based on
(bis-EMA) and 2,2-bis[4-(methacryloxy)phenyl]- several resin systems. Prepolymers and mono-
propane (bis-MA) have been developed as sub- mers bearing acrylic functionalities dominate the
stitutes for bis-GMA market. Products with methacrylic groups have
special end uses, e.g., in dental products and in
the electronics industry. Other resin systems
3.5 Combinations with Other include polyester-styrene mixtures, thiol-thiene
Plastics mixtures, and epoxy resins (Streitberger et al.
2010).
Acrylic resins can be combined with other resins A UV-curable acrylate system usually contains
to form, e.g., urethane acrylates, polyester acry- four main components: prepolymer(s), monomer(s),
lates, polyether acrylates. These compounds are photo initiator(s), and additives. The most com-
used as prepolymers in dental composites, mon prepolymers are acrylated epoxy resins. In
UV-curable inks, varnishes, and coatings. acrylated urethanes, an isocyanate-functional
prepolymer with a polyol backbone can be reacted
with a hydroxy-functional monomer (e.g., 2-HEA
3.6 Acrylamide and Derivatives or 2-HPA). Polyester acrylates are another exam-
ple of commercially significant prepolymers; they
Acrylamide is used to produce water-soluble are used in a wide range of applications from
polymers or copolymers used for paper overprinting varnishes to lithographic (offset)
manufacturing, waste treatment, mining applica- inks. In radiation-curable systems, the solvent is
tions, and enhanced oil recovery (Langvardt replaced by reactive diluents (monomers) which
2010). Acrylamide and its derivatives are also are incorporated into the network during cross-
used in the production of photopolymer printing linking. These monomers have two important
plates and polyacrylamide electrophoresis. functions: they reduce the viscosity of the
CH3 OH CH3 O
H2C C C O CH2CH CH2O C O CH2CH CH2O C C CH2
O CH3 OH CH3
Bis-GMA
CH3 CH3 O
H2C C C O CH2 CH2O C O CH2 CH2O C C CH2
O CH3 CH3
Bis-EMA
CH3 CH3 O
H2C C C O C O C C CH2
O CH3 CH3
Bis-MA
OH CH3 O
H2C CH C O CH2CH CH2O C O CH2CH CH2O C CH CH2

O CH3 OH
Epoxy diacrylate (Bis-GA)
O O
H2C CH CH2 O C C CH2
CH3
Glycidyl methacrylate
Fig. 5 Epoxy (meth)acrylates
mixture, and they strongly influence the physical laminated paper on pressboard (wood-grain
and chemical properties of the final coating. papers to simulate natural wood). Inks and over-
Monomers can be divided into three groups: print varnishes for the graphic art industry, high-
(1) Monofunctional monomers, e.g., isobornyl gloss overprint varnishes for magazine covers,
acrylate (IBA), N-vinylpyrrolidone, (2) difunc- record jackets, and various other consumer items
tional monomers, e.g., 1,6-HDDA, tripropylene are also often radiation-cured, as are plastic coat-
glycol diacrylate (TPGDA), and (3) tri- or tetra- ings for interior and exterior applications. The
functional monomers, e.g. TMPTA, PETA and coating of wood is another important use of radi-
pentaerythtritol tetraacrylate (which increase ation curing, and UV-curable coatings are also
the cross-linking density of the final coating). used for cork in Spain and Portugal. Industrial
Compounds such as benzophenone, thioxan- metal applications also exist: electronics applica-
thone, and benzoin ethers are used as photo tions, photoresists, solder masks, potting com-
initiators. Additives include, e.g., pigments, pounds, and conformal coatings are all products
fillers, defoamers and wetting agents, flatting based on UV-curable materials. Optical fibers are
agents, surfactants, and slip aids (Streitberger coated with a protective layer of UV-curable
et al. 2010). materials. Radiation-curable inks are applied to
Radiation curing is used for protective coat- metal, paper, wood, and plastics. Lithographic
ings, inks, adhesives, and in other minor areas. (offset) and screen printing inks are the main
Coatings for paper include clear-coats for printing inks, but flexographic inks, intaglio
744 K. Aalto-Korte
inks, and ink-jet printing are also used. In the 1978; Whittington 1981; Kiec-Swierczynska
printing industry, flexographic printing plates are et al. 2005). In many occupations, dermatitis
manufactured from UV-curable materials. typically affects the fingertips; sometimes also
UV-cured adhesives on the other hand are often the hands, the forearms, and the face.
used in lamination, and some UV-curable pres-
sure-sensitive adhesives are used in the automo-
tive industry. 4.1 Dental Acrylates
An interesting application is three-dimen-
sional modelling (stereo lithography), in which Dental fillings are now often composed of resin-
a solid part is made from a vat of UV-curable based composites, various glass-ionomers, and
liquor by the use of UV lasers controlled by combinations of composite resins and glass-
computers using CAD/CAM software. Release ionomers (see also ▶ Chap. 144, “Occupational
coatings (casting paper, caul sheet, labels) Contact Dermatitis in Dental Personnel”). These
are manufactured by electron beam curing. essentially consist of an organic methacrylate
Other new applications of radiation curing functional resin matrix, inorganic fillers, and cou-
include binders for magnetic media, leather pling agents. Light-curing systems are popular
coatings, and paper upgrading (Streitberger (Onusseit et al. 2010a). The key chemical in den-
et al. 2010). tal restorative resins is bis-GMA (epoxy
dimethacrylate). Today, monomer mixtures of
bis-GMA and triethylene glycol dimethacrylate
4 Allergic Contact Dermatitis (TREGDMA), some other dimethacrylates
from Acrylic Resins which act as diluents, and certain urethane
dimethacrylates are used. The resins are used
The cured end products of acrylic resin together with inorganic filler, usually silica, to
systems do not normally sensitize or cause form the composite resins. The inorganic filler
symptoms in previously sensitized individuals, material is treated with special silanes, e.g.,
as they do not contain enough reactive mono- 3-methacryloxypropyltrimethoxysilane, in order
mers, which represent the actual contact to enable a chemical bond between matrix and
allergens. filler. In a more recent development, glass parti-
Uncured products, in turn, contain sensitizing cles (barium or strontium silicate glass) are mixed
monomers. Contact allergy to acrylic resin mono- with silica. The composites were formerly used as
mers is most often induced by artificial nails, two-paste systems: base paste and catalyst paste.
dental products, and glues (Guerra et al. 1993; Today, light-cured one-component polymers are
Tucker and Beck 1999; Geukens and Goossens more common. They contain a photo initiator
2001; Sood and Taylor 2003; Goon et al. 2006; system: to cure the composites, visible light is
Teik-Jin Goon et al. 2007; Aalto-Korte et al. 2008; used with camphoroquinone as the initiator, and
Christoffers et al. 2013; Ramos et al. 2014). aliphatic and aromatic amines as polymerization
These products usually contain methacrylates, to promoters, and only common halogen lamps
which patients have allergic reactions more or blue LED lights are required (Craig et al.
commonly than to acrylates. 2-Hydroxyethyl 2010). In ormocer-based filling material, the
methacrylate (2-HEMA), ethyleneglycol dime- main component of the monomer matrix is an
thacrylate (EGDMA), and 2-hydroxypropyl organically modified ceramic. This is a cross-
methacrylate (2-HPMA) are the most commonly linked silicone oligomer bearing methacrylate
positive allergens. Some products contain mainly groups. Dimethacrylates are used as diluents
acrylates, e.g., UV-cured printing inks and lac- (Craig et al. 2010).
quers (Emmett 1977), paints and varnishes Carious lesions can potentially arise in the
(Conde-Salazar et al. 2007), and glues (Fregert fissures of the posterior teeth. However, when
these fissures are sealed with thin layers of When commonly used dental restorative
bis-GMA or related compounds, the occlusal sur- materials in the Finnish market were analyzed,
faces can largely be protected from caries. The bonding materials most often contained
sealant resins, such as restorative resins, are avail- 2-HEMA and bis-GMA, the composite resins
able as either cold-cured or light-cured systems bis-GMA and TREGDMA, and glass ionomers
(Craig et al. 2010). 2-HEMA and TMPTA (Henriks-Eckerman et al.
The acid-etch technique has been used to bond 2004) (Table 1).
enamel to composite resins. The dental enamel Dentists and dental nurses are most commonly
surface is first roughened with an approximately exposed to 2-HEMA, TREGDMA, and bis-GMA;
35% solution of phosphoric acid. A thin layer of they most often react to 2-HEMA, sometimes
resin of the bis-GMA type is then applied to the also to TREGDMA, but rarely to bis-GMA
etched surface, and finally, the restorative resin is (Goon et al. 2006; Aalto-Korte et al. 2007b).
applied (Craig et al. 2010). Among dental technicians, MMA and EGDMA
PMMA has a dominant position in denture base are the most significant allergens (Aalto-Korte
resins. Methacrylates are available as powder and et al. 2007b). Reactions to 2-HPMA, tetrahydro-
liquid. The polymer powder is mixed with the furfuryl methacrylate (THFMA), ethyl methacry-
liquid monomer. Mineral pigments are the princi- late (EMA), butanediol dimethacrylate (BUDMA),
pal coloring agents used; organic dyes less so. To and urethane dimethacrylate (UDMA) are quite
avoid formation of stress cracks and to improve common among dental workers, but these reactions
mechanical properties, the liquid monomer gener- possibly represent cross-allergy to other methacry-
ally contains up to 10% of a cross-linking agent, lates (Aalto-Korte et al. 2007b).
usually EGDMA. Depending on the polymeriza- At FIOH in the 1980s, contact allergy to
tion initiator used, four types of materials can be epoxy acrylates was found in five dental profes-
distinguished: heat-, cold-, light-, and microwave- sionals and was always connected with reactions
cured polymers. In heat-cured polymers, dibenzoyl to DGEBA-based epoxy resin (Kanerva et al.
peroxide is generally used. In cold-cured polymers, 1986; Kanerva et al. 1989; Kanerva and
the polymerization is initiated by a two-component Zwanenburg 2000). These cases, along with the
redox system, which is usually composed of ter- patch tests of other epoxy allergic patients at
tiary amines, e.g., N,N-dimethyl-p-toluidine and FIOH, indicated that exposure to DGEBA-
peroxides, dibenzoyl peroxide in particular. The epoxy resin results in cross-reactivity to epoxy
addition of UV stabilizers is customary to reduce acrylates and vice versa (Kanerva and
discoloration. Instead of MMA, diesters of Zwanenburg 2000; Kanerva 2001). In a 1984
methacrylic acid with high molecular mass diols animal study, impurities in commercial products
similar to bis-GMA, or high molecular mass ure- of bis-GMA had a high sensitizing capacity, for
thane dimethacrylates, are used as the monomer in which the presence of epoxy resin was a proba-
light-cured polymers. The reaction of microwave- ble explanation (Bjorkner et al. 1984). In 1991,
cured polymers is almost the same as for heat- dental restorative materials were analyzed at
cured materials. Dental technicians also use similar FIOH, and small amounts (0.01–0.06%) of
methacrylates in artificial teeth, crowns, and brid- DGEBA-epoxy resin were present in all of the
ges (Craig et al. 2010). seven dental restorative materials that contained
Orthodontic treatment corrects the position of bis-GMA (Aalto-Korte et al. 2007b). In 2001,
the teeth. For removable orthodontic devices, DGEBA epoxy resin oligomers were no longer
cold-cured polymers are used. For fixed orthodon- detected in analyses of bis-GMA-containing
tic appliances, resins very similar in chemical dental materials at FIOH (Aalto-Korte et al.
composition to those used in cold-cured restor- 2009). Although dental composite resins still
ative materials are employed as adhesives (Craig contain bis-GMA, contact allergy to it was rare
et al. 2010). in a recent series at FIOH, possibly either
746 K. Aalto-Korte
Table 1 Abbreviations because the products no longer contain sensitiz-

Acrylic monomer Abbreviation ing impurities or because the use of gloves pre-
Acrylates vents sensitization to this high-molecular-weight
Methyl acrylate MA compound and its possible impurities.
Ethyl acrylate EA Patients sensitized to methacrylates may
Butyl acrylate BA develop symptoms such as stomatitis, cheilitis,
2-Ethylhexyl acrylate 2-EHA or perioral dermatitis after dental care, but these
2-Hydroxyethyl acrylate 2-HEA usually disappear in 1–2 weeks. The relevance of
2-Hydroxypropyl acrylate 2-HPA contact allergy to symptoms of longer duration
1,4-Butanediol diacrylate BUDA and to conditions such as burning mouth syn-
1,6-Hexanediol diacrylate HDDA drome is difficult to ascertain.
Diethyleneglycol diacrylate DEGDA
Triethyleneglycol diacrylate TREGDA
Pentaerythritol triacrylate PETA
4.2 Nail Products
Dipropyleneglycol diacrylate DPGDA
Tripropyleneglycol diacrylate TPGDA
The use of artificial nails has gained much popu-
Trimethylolpropane triacrylate TMPTA
larity in recent decades (see also ▶ Chap. 143,
Isobornyl acrylate IBA
Oligotriacrylate 480 OTA480
“Cosmetologists”). With the increasing number
Urethane diacrylate, aliphatic al-UDA of nail studios, artificial nails are nowadays the
Urethane diacrylate, aromatic ar-UDA main causes of (meth)acrylate contact allergy
Methacrylates (Sood and Taylor 2003; Christoffers et al. 2013;
Methyl methacrylate MMA Ramos et al. 2014; Montgomery et al. 2016;
Ethyl methacrylate EMA Muttardi et al. 2016).
N-Butyl methacrylate BMA There are various types of artificial nails: pre-
2-Hydroxyethyl methacrylate 2-HEMA formed plastic nail tips (press-on nails), “silk nails,”
2-Hydroxypropyl methacrylate 2-HPMA and sculptured nails, which include so-called chem-
Ethyleneglycol dimethacrylate EGDMA ically-cured “acrylic nails” and photo-bonded “gel
Diethyleneglycol dimethacrylate DEGDMA nails.” Nail tips and silk nails are usually glued
Triethyleneglycol dimethacrylate TREGDMA using cyanoacrylate products, but more sensitizing
Tetraethyleneglycol dimethacrylate TETEGDMA acrylic monomers may also be used. In the “acrylic
Pentaethyleneglycol dimethacrylate PEGDMA nail” method, liquid monomer and powdered poly-
Tetrahydrofurfuryl methacrylate THFMA
mer are mixed and painted onto the nail and exten-
1,4-Butanediol dimethacrylate BUDMA
sion template. The liquid monomer is typically
N,N-Dimethylaminoethyl methacrylate DMAEMA
composed of EMA or another monomethacrylate,
Urethane dimethacrylate UDMA
and the polymer powder usually contains PMMA
Polymethyl methacrylate PMMA
Others
or polyethyl methacrylate (PEMA). The liquid
Ethyl cyanoacrylate ECA monomer is highly sensitizing, but the polymer
N,N-Methylenebisacrylamide MBAA may also contain traces of monomers, e.g., MMA
Epoxy (meth)acrylates and EMA (Kanerva et al. 1996). In light-cured
Epoxy diacrylate (epoxy acrylate) bis-GA sculptured “gel nails,” the resins are similar to
2,2-bis[4-(2-Hydroxy-3-methacryl- bis-GMA dental bonding resins: they are serially applied in
oxypropoxy)phenyl] propane many layers, first a primer and then the acrylic nail
2,2-bis[4-(Methacryl-oxyethoxy) BIS-EMA resin, after which the layer is cured in a “photo-
phenyl] propane
bonding box,” and the procedure is repeated. A
2,2-bis[4-(Methacryloxy) bis-MA
primer can be composed of methacrylic acid or
phenyl]propane
Glycidyl methacrylate GMA
2-HEMA, but traces of other undeclared monomers
Diglycidyl ether of bisphenol A DGEBA can also be found. The resin part is typically based
(epoxy resin) on epoxy acrylates (bis-GMA) or acrylated
urethane as matrix monomers in combination with and Taylor 2003) (see also ▶ Chap. 61, “Adhe-
mono- and polyfunctional cross-linking monomers sives and Glues”). Anaerobic sealants are typical
such as TREGDMA, EGDMA, 2-HPMA, glue products that cause contact allergy (Conde-
TPGDA, and 2-HEA (Kanerva et al. 1996; Sauni Salazar et al. 1988; Guerra et al. 1993; Holme and
et al. 2008). Knowledge of the exact composition Statham 2000; Sood and Taylor 2003; Aalto-
of nail acrylics is sparse. Korte et al. 2008).
Both nail beauticians and their customers are Anaerobic adhesives are mixtures of acrylic
in danger of being sensitized to acrylic resins. esters which remain liquid when exposed to air
Nail beauticians often wear artificial nails them- but harden when confined between metal sur-
selves. Allergic contact dermatitis from (meth) faces. These mixtures can be used for a large
acrylates in artificial nails usually affects the number of industrial purposes such as locking
hands, especially the fingertips. With nail cus- threaded fasteners; sealing threaded pipe connec-
tomers, periungual involvement may lead to tions; retaining cylindrical machine components;
onycholysis and deformations of the nail bed, sealing flange joints; bonding structural compo-
while nail technicians develop symptoms on the nents; sealing porous metal castings, welds and
face and forearms more commonly than their powdered metal parts; and many other applica-
customers (Constandt et al. 2005; Lazarov tions (Onusseit et al. 2010b). Anaerobic adhesive
2007). In a Belgian study of 27 nail acrylate compositions usually consist of mixtures of
patients, nearly all reacted to 2-HEMA, and this methacrylate esters or methacrylated urethanes,
allergen was recommended together with ethyl initiators, accelerators, and other additives. Tradi-
cyanoacrylate (ECA) for screening contact tionally, methacrylate esters are polyether types
allergy from artificial nail products (Constandt based on oligomeric polyethylene or polypropyl-
et al. 2005). Although 2-HEMA has also been ene glycols (Onusseit et al. 2010a).
among the most commonly positive allergens in In chemical analyses at FIOH, the main com-
other nail patient series (Lazarov 2007; Teik-Jin ponents of anaerobic glues was found to be
Goon et al. 2007), the results are difficult to TREGDMA, and diethyleneglycol dimethacry-
compare because patients have not been tested late (DEGDMA) and 2-HPMA were used as
with a similar tray of allergens and there is little reactive diluents (Kanerva et al. 1997). Further
information on the chemical composition of analyses of anaerobic products have also detec-
the products. In general, the nail patients have ted methacrylates 2-HEMA, EGDMA, tetra-
allergic reactions to the same methacrylates ethyleneglycol dimethacrylate (TETEGDMA),
as the dental cases, but sensitization to cyanoac- and pentaethyleneglycol dimethacrylate (PEG-
rylates, epoxyacrylates, and acrylates is also DMA), and MMA (Aalto-Korte et al. 2008) and
possible. epoxyacrylate bis-GA (Aalto-Korte et al. 2009).
UV-curing nail polishes have recently been The typical clinical picture of allergic contact
introduced to the market. They have caused meth- dermatitis due to anaerobic glues is dermatitis of
acrylate allergy in consumers in Sweden (Dahlin the distal fingers (Conde-Salazar et al. 1988).
et al. 2016). Also UV-curing gel nail kits are Typical occupations include assemblers of
directly marketed for consumers. machines and mechanical devices, mechanics,
and plumbers. The most commonly positive
acrylic monomers in patients exposed to anaero-
4.3 Acrylic Glues bic glues have been methacrylates 2-HEMA,
EGDMA, TREGDMA, and 2-HPMA (Conde-
Glues, sealants, and adhesives are a relatively Salazar et al. 1988; Holme and Statham 2000;
common occupational source of sensitization to Aalto-Korte et al. 2008). It is noteworthy that
methacrylates and acrylates, in addition to dental anaerobic glues may contain epoxy acrylates
restorative materials and artificial nails (Guerra bis-EMA, bis-GMA, glycidyl methacrylate, and
et al. 1993; Geukens and Goossens 2001; Sood bis-GA (Aalto-Korte et al. 2009). In the USA,
748 K. Aalto-Korte
three glue-related cases were positive to glycidyl distension glues (Shanmugam and Wilkinson
methacrylate, and one of them had used an anaer- 2012; Bhargava et al. 2012; Montgomery et al.
obic sealant that contained glycidyl methacrylate 2016; Muttardi et al. 2016). Cyanoacrylates have
(Dempsey 1982). Bis-GA in an anaerobic sealant to be tested separately as there is no cross allergy
had sensitized one worker in Finland (Aalto-Korte between them and other (meth)acrylates.
et al. 2009). These acrylated epoxies need to be UV-cured acrylic glues have also caused con-
tested separately, as the patients need not have tact allergy (Whittington 1981; Brooke and Beck
contact allergy to epoxy resin or acrylates. 2002; Kiec-Swierczynska et al. 2005; Minamoto
Two-component acrylate adhesives are cold- and Ueda 2005). These products may contain only
setting products which contain methacrylates acrylates, and the patients may not necessarily
or acrylates as the monomer and other polymers react to methacrylates.
(Onusseit et al. 2010b). There are a few reports of Orthopedic Adhesives (Bone Cements) are
sensitization to methacrylates in two-component used to anchor long-term implantable devices to
acrylic glue products (Kanerva et al. 1995; Aalto- the neighboring bone. Bone cements consist of
Korte et al. 2008). The patch-test-positive products separate powder and liquid components which
of these patients contained methacrylates such as are mixed prior to application. Though many
2-HEMA, EGDMA and MMA, and acrylates. The products exist, the powder components always
reaction patterns of these patients did not essen- contain methacrylate polymer, a polymerization
tially differ from those of other patients who had initiator, and a radiopaque medium. The liquid
handled mono-component anaerobic products, i.e., component contains MMA with small amounts
strong allergic reactions to many methacrylates and of accelerator for the hardening process (Onusseit
milder or fewer reactions to acrylates. et al. 2010a). Contact allergy to bone cements in
Cyanoacrylate adhesives are one-component orthopedic surgeons and nurses is rare.
polymerization adhesives. Methyl, ethyl, butyl, Window screen repair products are used for
and methoxyethyl esters of cyanoacrylic acid repairing small cracks in window screens, and
(methylcyanoacrylate, ethylcyanoacrylate, butyl- the systems can be UV-cured. Two windscreen
cyanoacrylate, methoxyethylcyanoacrylate) are repairers at FIOH, and four other previously
used for these products; soluble polymers and reported cases have reacted to 2-HEMA (Bang
plasticizers are incorporated to control viscosity, Pedersen 1998; Banerjee et al. 2001; Geukens
and rubbers for elastification. Cyanoacrylate and Goossens 2001; Fremlin and Sansom 2014).
adhesives rapidly polymerize to form a high- Nonoccupational sources of sensitization
molecular-mass, but largely uncross-linked poly- include not only nail glues and instant adhesives
mers. In most cases, atmospheric moisture or the but also adhesives in electrosurgical grounding
film of moisture on the substrate is sufficient to plates, wound dressings, and skin tapes and
initiate polymerization. However, due to this sen- glues in insulin pump infusion sets.
sitivity to atmospheric moisture, the adhesives
must be stored in tightly sealed containers. Cya-
noacrylates are used for bonding small items of 4.4 Paints, Varnishes and Coatings
nearly all substrates. Cyanoacrylate adhesives are
also used in surgery and wound management Both the workers that manufacture UV-curable
(Onusseit et al. 2010b). Cyanoacrylate glues are paints, varnishes, lacquers, and coatings, and
rare sensitizers in industrial settings (Bruze et al. the workers that use these products are at risk
1995; Conde-Salazar et al. 1998) and a few cases of developing contact allergy to acrylates (see
have been reported in nail technicians, their cus- also ▶ Chaps. 181, “Painters, Lacquerers,
tomers, and hair dressers (Belsito 1987; Tomb and Varnishers in Occupational Dermatology”
et al. 1993; Constandt et al. 2005; Lazarov and ▶ 63, “Paints, Lacquers, and Varnishes in
2007). Several cases of cyanoacrylate allergy Occupational Dermatology”). Significant aller-
have quite recently been reported from eye lash gens in these products include dipropyleneglycol
diacrylate (DPGDA) (Estlander et al. 1998; inks are thus acrylates and epoxyacrylates,
Isaksson and Zimerson 2007), TPGDA (Conde- but methacrylates can also be used: 2-HEMA
Salazar et al. 2007), and 2-HEA (Geukens and together with diaminodiphenylmethane and tri-
Goossens 2001). Patients often react positively glycidylisocyanurate were the causes of allergic
to various acrylates (e.g., DEGDA), but whether dermatitis in a silk-screen printer in the manufac-
the reactions represent cross allergy or primary ture of circuit boards (Jolanki et al. 1994). Sensi-
sensitization is difficult to assess with the sparse tizing acrylamide derivatives are used in printing
information available on exact exposure. Paints plates work (see ▶ Chap. 188, “Printers and
sometimes contain methacrylates, such as Lithographers”), as is 2-HEMA (Pedersen et al.
2-HEMA (Geukens and Goossens 2001). As 1983).
regards wood coatings, nine cases of PETA
allergy from UV-curable water-based acrylate lac-
quer in a furniture factory were reported in Swe- 4.6 Allergic Contact Dermatitis
den (Saval et al. 2007). The literature contains two from Epoxy Acrylates
cases of acrylate allergy from the coating of opti-
cal fibres: one caused by urethane acrylate and Allergic reactions to bis-GMA, bis-GA, glycidyl
TMPTA (Maurice and Rycroft 1986) and another methacrylate, and bis-EMA are usually seen in
caused by phenoxyethoxy ethylacrylate (Jolanki patients with allergic contact dermatitis from
et al. 2001). Glycidyl methacrylate, an epoxy DGEBA epoxy resin, who are exposed to only
methacrylate used in the coating of spectacle epoxy resin products. About 20% of patients who
lenses, caused allergic contact dermatitis in are allergic to DGEBA epoxy resin react to some
Spain (Sanchez-Perez et al. 2008). In Finland, of the chemicals, most often to bis-GA and
TMPTA used in the manufacture of printed circuit bis-GMA (Lee et al. 2002; Aalto-Korte et al.
boards induced dermatitis in one worker (Kanerva 2009). The majority of the reactions to
et al. 1998). epoxyacrylates probably represent cross-allergy,
but some patients, however, are sensitized as a
result of specific exposure. In particular, allergic
4.5 Printing Work reactions to bis-GA without concomitant DGEBA
epoxy resin allergy point to specific sensitization.
Radiation-curable inks are applied to metal, paper, To detect the specific contact allergy, these com-
wood, and plastics (see also ▶ Chaps. 188, pounds should be tested separately, because the
“Printers and Lithographers”, ▶ 193, “Silk- patients do not necessarily have a concomitant
Screen Workers,” and ▶ 58, “Inks and Dyes”). allergy to DGEBA epoxy resin or acrylates.
Lithographic (offset) and screen printing inks are UV-cured printing inks are a significant source
the main printing inks, while flexographic inks, of bis-GA sensitization (Emmett and Kominsky
intaglio inks, and ink-jet printing are also com- 1977; Bjorkner et al. 1980; Nethercott et al. 1983;
mon. In the printing industry, flexographic print- Guimaraens et al. 1994; Kanerva et al. 2000;
ing plates are also manufactured from UV-curable Aalto-Korte et al. 2009), and bis-GA in the pro-
materials (Streitberger et al. 2010). In earlier duction of UV-cured paints has sensitized one
reports of allergic contact dermatitis from patient (Jolanki et al. 1995). In these cases, spe-
UV-cured inks, patients were often exposed and cific exposure to bis-GA led to specific sensitiza-
sensitized to TMPTA and PETA (Emmett and tion without allergy to DGEBA epoxy resin. At
Kominsky 1977; Bjorkner et al. 1980; Isaac FIOH, an assembler of hydraulic devices was
et al. 1992). In later reports, TPGDA and/or investigated. He developed dermatitis while
epoxyacrylates bis-GA and bis-GMA have been using anaerobic sealants, and in patch tests, he
the primary allergens (Goossens et al. 1998; reacted to 2-HPMA and bis-GA but not to epoxy
Scotnicki and Pratt 1998; Kanerva et al. 2000). resin. In the chemical analysis, this compound
The main allergens in UV-curable printing was detected in one of his sealants at an 8%
750 K. Aalto-Korte
concentration (Aalto-Korte et al. 2009). The liter- 2009). Bis-GMA per se has either low sensitiz-
ature nevertheless presents many bis-GA-positive ing capacity or none at all (Bjorkner et al.
cases with no shown specific exposure, but these 1984). The probable explanation for concomi-
patients usually have allergic reactions to DGEBA tant reactions is a cross-allergy between
epoxy resin and bis-GMA (Kanerva et al. 2000; DGEBA epoxy resin and epoxy (meth)acrylates
Lee et al. 2002; Aalto-Korte et al. 2009). The (bis-GMA and bis-GA) (Kanerva et al. 2000;
majority of the reactions probably represent Lee et al. 2002; Geier et al. 2007; Aalto-Korte
cross-allergy. et al. 2009).
Bis-GMA was introduced as a component of Glycidyl methacrylate was reported to be the
dental composite resin in the 1960s. Since then it cause of occupational allergic contact dermatitis
has been widely found in products used by den- in a chemist who impregnated paper and textile
tists (Estlander et al. 2006), denture materials materials to make them water- and oil-resistant
(Kanerva et al. 1993; Aalto-Korte et al. 2007b), (Matura et al. 1995), and in Sweden an allergic
artificial nail preparations (Hemmer et al. 1996; patch test reaction to glycidyl methacrylate was
Geier et al. 2007; Sauni et al. 2008), and in seen in a production worker in a paint binder
printing work (Goossens et al. 1998). According factory which used the chemical (Gruvberger
to the Finnish Product Register, it was also found et al. 1998). In the USA, three glue-related cases
in some adhesives, in a wind screen repair resin, were positive to glycidyl methacrylate, and one of
and in filler for motor vehicles (Aalto-Korte et al. them had used an anaerobic sealant that contained
2009). Contact allergy to bis-GMA has been glycidyl methacrylate (Dempsey 1982). In Spain,
reported in dental workers (Kanerva et al. 1986; a worker developed occupational allergic contact
Kanerva et al. 1989; Rustemeyer and Frosch dermatitis due to glycidyl methacrylate in a liquid
1996; Kanerva and Zwanenburg 2000; Geukens that was used in coating spectacle lenses
and Goossens 2001; Wrangsjo et al. 2001; Sood (Sanchez-Perez et al. 2008). None of the six
and Taylor 2003; Goon et al. 2006), dental patients were reported as having DGEBA epoxy
patients (Kanerva and Alanko 1998; Lee et al. resin allergy. One case of chemical burn from
2002; Goon et al. 2006), a printer (Bong and glycidyl methacrylate has recently been reported
English 2000), a silk-screen maker (Goossens (Shimizu et al. 2008). Glycidyl methacrylate is an
et al. 1998), and a mechanic handling coating ester of methacrylic acid and epichlorohydrin; it
materials (Kanerva et al. 2000). The allergic has a methacrylate structure at one end of the
reactions to bis-GMA in these studies usually molecule and an epoxy group at the other. At
occurred concomitantly with an allergic reaction FIOH, in a series of 10 patients with allergic
to the DGEBA epoxy resin. Many of the reactions to glycidyl methacrylate, the majority
previously reported dental patients and the of the cases also reacted to DGEBA epoxy resin
mechanic were reported to have been sensitized in the baseline series and had been occupationally
to DGEBA epoxy resin before developing exposed to epoxy products. At FIOH, however, no
symptoms from materials containing bis-GMA specific exposure to glycidyl methacrylate was
(Kanerva and Alanko 1998; Kanerva et al. 2000; found (Aalto-Korte et al. 2009).
Lee et al. 2002). In a German study, six (15%) In the Finnish Product Register of Chemicals,
out of 40 bis-GMA positive patients did not bis-EMA appears in numerous glues and in some
react to DGEBA epoxy resin, and the only dental products. In the literature, some cases of
probable bis-GMA exposure was to artificial allergic reactions to bis-EMA are reported, many
nails in one patient (Geier et al. 2007). At of them in dental personnel, often with a simulta-
FIOH, all bis-GMA-positive patients also neous reaction to the DGEBA epoxy resin and
reacted to DGEBA epoxy resin. In the literature, bis-GMA. However, in the literature there are no
10–18% of the epoxy resin allergic cases had detailed descriptions of primary sensitization with
had an allergic reaction to bis-GMA (Lee et al. known exposure to bis-EMA. At FIOH, a mani-
2002; Geier et al. 2007; Aalto-Korte et al. curist with allergic reactions to bis-EMA and
glycidyl methacrylate was investigated, but these compounds. Some of the multiple reactions prob-
compounds were not mentioned in the product ably derive from cross-allergy between acrylic
declarations, and the products were not analyzed monomers. However, it is difficult to establish
(Aalto-Korte et al. 2009). an individual’s history of exposure to various
Allergic reactions to bis-MA have also been acrylic monomers in acrylic products, as he/she
reported in single dental workers. Cross-allergy to will have used various different products during
epoxy resin does not seem to be common, as their work life. Acrylic products often contain
41 epoxy-resin-allergic patients remained nega- many undeclared acrylic monomers, and differ-
tive to this substance in the USA (Lee et al. ences probably occur between different batches of
2002). In 2008, a search in the Finnish Chemical the same product (Kanerva 2001; Henriks-
Register of Chemicals yielded no products Eckerman et al. 2004). When commonly used
containing bis-MA (Aalto-Korte et al. 2009) . dental restorative materials in the Finnish market
were analyzed, SDSs proved to be unreliable:
information regarding methacrylates was pro-
4.7 Allergic Contact Dermatitis vided in only half of the products which,
from Acrylamide Derivatives according to the analysis, contained methacry-
and Acrylonitrile lates. Moreover, some methacrylic compounds
given in the safety data sheets could not be
Acrylamide used in polyacrylamide gel electro- detected (Henriks-Eckerman et al. 2004). Impuri-
phoresis may cause allergic contact dermatitis in ties in patch test preparations may also have led to
exposed workers (Lambert et al. 1988; Dooms- false interpretations of patch test results: for
Goossens et al. 1991; Beyer and Belsito 2000; instance in the 1980s technical grade raw mate-
Aalto-Korte et al. 2002). Piperazine diacrylamide, rials were sometimes used in commercial test
a cross-linker of acrylamide gel electrophoresis, preparations (Kanerva et al. 1989). Many prob-
can also sensitize (Bjorkner 2006). Secondary lems with test substances still remain to be solved,
acrylamides, such as N,N0 -methylene-bis-acryl- e.g., Chemotechnique declares that their aromatic
amide (MBAA), have been identified as sensi- urethane acrylate (ar-UDA) contains some PETA
tizers in photo polymerizing printing plates and pentaerythritol tetraacrylate. Sensitization to
(Malten et al. 1978; Pedersen et al. 1982; Pedersen PETA explains reactions to ar-UDA.
et al. 1983). Patients sensitized to the secondary In all larger patient materials, methacrylates
acrylamides used in Nyloprint ® printing plates 2-HEMA, EGDMA, and 2-HPMA have been
may react to acrylamide on patch testing (Peder- among the most commonly positive allergens
sen et al. 1982). Although printing plates may (Tucker and Beck 1999; Geukens and Goossens
contain other (meth)acrylic monomers, the 2001; Sood and Taylor 2003; Aalto-Korte et al.
patients may have monosensitization to secondary 2007b; Teik-Jin Goon et al. 2007). These three
acrylamides and thus do not react to commonly allergens are significant for patients exposed to
tested acrylic monomers. dental products, glues and artificial nails, products
A few cases of allergic contact dermatitis from which usually contain methacrylates and often
acrylonitrile have been reported (Bjorkner 2006). epoxyacrylates, but seldom acrylates (Aalto-
Korte et al. 2007b; Aalto-Korte et al. 2008). The
methacrylate-exposed patients often react not
5 Patch Testing with Acrylic only to the cross-reacting 2-HEMA, EGDMA,
Resins and 2-HPMA but also to other methacrylates,
such as MMA, EMA, TREGDMA, and
It is common that (meth)acrylate allergic patients THFMA. Reactions to acrylates occur but are
have simultaneous allergic reactions to several not very common. Patients with strong allergic
(meth)acrylate test substances, although they reactions to some methacrylate(s) tend to react to
have probably not been exposed to all the positive large numbers of methacrylates, as well as to some
752 K. Aalto-Korte
acrylates. The most commonly positive acrylates should be adjusted to the concentrations of the
in methacrylate-exposed patients are EA, monomers in the product so that 2% for any
TREGDA, and DEGDA. sensitizing methacrylate monomer or 0.1% for
Contact allergy to acrylates is not as common as any sensitizing acrylate monomer is not exceeded
allergy to methacrylates. There are no large (Jolanki et al. 2000a). At FIOH, no active sensiti-
published materials on acrylate allergy, and in the zations to patients’ own products have been
available small series the relative importance of observed (Aalto-Korte et al. 2007a). The recom-
different acrylate, allergens depends on the products mendation for cyanoacrylates is 10% in petrola-
the patients have been exposed to. Among the tum. Testing acetone dilutions of cyanoacrylates
patients investigated at FIOH were several cases in in aluminum chambers yields false negative
which acrylate contact allergy was limited to the results. Acetone dilutions may be used in plastic-
chemical the patients were exposed to, and the coated aluminum chambers (Bruze et al. 1995). At
patients exposed solely to acrylates did not react to FIOH, cyanoacrylate glues are tested as is dried in
methacrylates. Thus, our results imply that although Finn-Chambers due to the simplicity of the pro-
exposure to methacrylates might induce cross- cedure (Aalto-Korte et al. 2008).
reactivity to acrylates, exposure to acrylates does
not usually lead to cross-sensitization to methacry-
lates. Guin’s textbook presents similar cross- 6 Skin Irritation and Other Effects
reactivity rules concerning monoacrylates and
monomethacrylates (Guin and Work 1995). Our Acrylic acid is moderately toxic and very corro-
acrylate-allergic patients were mainly exposed and sive. The vapor is an irritant to the eyes and
sensitized to diacrylates (TPGDA, DPGDA, respiratory tract, and skin contact may cause
DEGDA, and TREGDA) but not to monoacrylates burns. Acrylic esters are of moderately acute tox-
to the same extent. Multiple reactions to several icity, which decreases as the number of carbon
acrylates are also quite common, which imply a atoms in the alkyl group increases. Generally
cross-allergy between them. When clinical patients speaking, methacrylates are less toxic than their
are analyzed, it is difficult to draw firm conclusions corresponding acrylates. The mucous membranes
regarding cross-allergy, because concomitant expo- of the eyes, nose, and throat are particularly sen-
sure to several acrylic monomers is always an alter- sitive to irritation. Acrylic monomers can produce
native explanation. eye and skin irritation ranging from slight to cor-
While the pattern of concomitant reactions in rosive, depending on the monomer and the type of
methacrylate-exposed patients varies only slightly exposure. Liquid methyl and ethyl acrylates
according to the type of exposure, the diagnosis of severely irritate the skin and mucous membranes
contact allergy to acrylates, epoxyacrylates, cya- and are corrosive to the eyes, whereas the butyl
noacrylates, and acrylamide derivatives often and 2-ethylhexyl acrylates have less severe
requires testing with the specific allergen. effects. Methyl and ethyl acrylate vapors are
At FIOH in the1980s, acrylates EA, 2-HEA, very lachrymatory, extremely irritating to the
and 2-HPA caused active sensitization in several respiratory tract, and corrosive to the eyes, caus-
patients when tested at concentrations of 0.5–1% ing corneal injury. The lachrymatory effect of the
(Kanerva et al. 1988). The present recommended butyl and 2-ethylhexyl esters is weak. Methacrylic
concentration for acrylates is 0.1% in petrolatum, acid is more corrosive than its esters (Bauer 2010;
and most methacrylates are tested at a concentra- Ohara et al. 2010). Handling methacrylate prod-
tion of 2%. Late reactions appearing after D7 are ucts has caused respiratory problems, rhinitis, and
not necessarily due to active sensitization asthma in dental workers and nail technicians.
(Isaksson et al. 2005), and reactions to low con- In humans and laboratory animals, single or
centrations and to cross-reacting secondary aller- repeated exposure to acrylamide caused local irri-
gens in particular tend to appear later. tations on contact with the skin and neurological
When testing patients’ own products, the con- symptoms. The peripheral neuropathy is a result
centration of the methacrylate/acrylate product of long-term accumulation and appears after a
latent period. Acrylamide is readily absorbed dur- ▶ Occupational Contact Dermatitis in Dental
ing oral, inhalation, and dermal exposure. Its Personnel
genotoxicity, the formation of the genotoxic ▶ Painters, Lacquerers, and Varnishers in Occu-
metabolite glycidamide in humans, and long- pational Dermatology
term animal studies indicate that acrylamide has ▶ Paints, Lacquers, and Varnishes in Occupa-
the potential to cause cancer in humans. Accord- tional Dermatology
ingly, acrylamide has been classified as probably ▶ Plumbers and Pipe Fitters
carcinogenic to humans (Ohara et al. 2010). ▶ Printers and Lithographers
▶ Silk-Screen Workers
7 Prevention
References
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Epoxy Resins
52
Rosemary Nixon
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3 Epoxy Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3.1 Chemistry and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
3.2 Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
3.3 Allergic Contact Dermatitis to Epoxy Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
3.4 Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
3.5 Irritant Contact Dermatitis from Epoxy Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
3.6 Other Skin Disorders Caused by Epoxy Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
3.7 Skin Testing and Chemical Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
3.8 Prevention of Epoxy Chemical Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Keywords dermatitis · Contact allergy · Sensitization ·

Epoxy resin · Diglycidyl ether of bisphenol A · Irritant contact dermatitis · Contact urticaria ·
Diglycidyl ether of bisphenol F · Diluent · Patch test · Airborne · Gloves · Epoxy di(meth)
Hardener · Occupational · Allergic contact acrylate · bis-GMA · Cross-reaction
1 Core Messages
• Epoxy resin allergy is a major cause of occu-

C. Higgins · J. Cahill · R. Nixon (*) pational contact dermatitis, particularly in the
Occupational Dermatology Research and Education construction, painting, aircraft, and electronics
Centre, Skin and Cancer Foundation, Melbourne, VIC,
Australia manufacturing industries.
e-mail: clairelhiggins@gmail.com; • Allergic contact dermatitis to epoxy resin sys-
jencahill@hotmail.com; rnixon@occderm.asn.au tems may be caused by resins, hardeners, or
R. Jolanki reactive diluents.
Section of Dermatology/Control of Hypersensitivity • Diglycidyl ether of bisphenol A (DGEBA) is
Diseases, Finnish Institute of Occupational Health (FIOH), the major cause of allergic contact dermatitis
Helsinki, Finland
e-mail: riitta.jolanki@hiy.fi from epoxy resin systems; however patch

https://doi.org/10.1007/978-3-319-68617-2_51
758 C. Higgins et al.
testing solely with DGEBA will miss many 3 Epoxy Compounds

cases of epoxy allergy.
• Patch testing with workers’ own samples is 3.1 Chemistry and Properties
necessary.
• Allergic contact dermatitis to epoxy chemicals Epoxy resins are normally used in what is called
may present with dermatitis on the hands, an “epoxy resin system.” This consists of the
arms, neck, and face. epoxy resin, hardener, and reactive diluent or
• Epoxy chemicals may induce airborne allergic other additives, such as fillers, modifiers, pig-
contact dermatitis, particularly from the more ments, and reinforcements. These may all influ-
volatile reactive diluents and hardeners. ence the properties of the resulting epoxy resin
• Rubber gloves offer poor protection against system.
epoxy chemicals. Gloves made of laminated,
multilayered plastic or thick reusable nitrile are 3.1.1 Epoxy Resins
recommended. Epoxy resins contain at least two cyclic three-
• Crucial factors for the development of allergic membered ring structures containing oxygen,
contact dermatitis from epoxy resin systems called epoxy groups, oxirane, or epoxide
include the type of exposure, size of contami- groups, in their molecules. The term “epoxy
nated skin area, frequency and duration of con- resin” may refer to the resins in either the
tact, concentration of epoxy chemical, and use uncured thermoplastic or cured thermoset states
of personal protective equipment. (Lee and Neville 1967). The uncured resins can
• If a worker develops allergic contact dermatitis be cross-linked through the use of a variety of
to epoxy chemicals, consider the factors which curing agents or hardeners to form cured plastics
led to sensitization. It may be that other with insoluble three-dimensional structures.
workers are also at risk. Epoxy resins are generally prepared by the cou-
pling of epichlorohydrin [CAS 106-89-8] with
compounds that possess at least two reactive
2 Introduction hydrogen atoms (Muskopf and McCollister
1987). The reaction products of epichlorohydrin
It is reported that products now known as epoxy and bisphenol A [CAS 80-05-7] resulted in the
resins were synthesized as early as 1891, with first commercial epoxy resins, which are gener-
the first patent applications occurring in the ally mixtures of monomeric diglycidyl ether of
1930s and the first commercial production in bisphenol A (DGEBA), with a molecular weight
the 1940s (Potter 1975; Ellis 1993). Large- (MW) of 340 Da, and oligomers with a higher
scale production of epoxy resins began in the MW. The average number of repetitive parts in
early 1950s. By the end of the 1960s, at least the oligomers ranges from essentially 0 to
25 distinct types of epoxy resins were commer- approximately 25 (Fig. 1) (Bauer 1985). The
cially available (Lee and Neville 1967). Epoxy sensitizing capacity decreases with higher MW
resins have numerous desirable properties such (Thorgeirsson et al. 1978b). DGEBA epoxy
as easy curing, low shrinkage, high adhesive- resins account for 75–95% of epoxy resins used
ness, electrical insulation, high physical worldwide, while 1% of resins are based on
strength, and good chemical and mechanical diglycidyl ether of bisphenol F (DGEBF)
resistance. Their versatility enables wide use in (Pontén et al. 2002). DGEBA epoxy resins with
commercial applications (Jolanki 1994; Cao an average MW as high as 8000 Da are available
et al. 2009). Unfortunately, however, they are (Guin and Work 1995). When DGEBA epoxy
strong sensitizers. The first cases of epoxy der- resins are prepared, apart from DGEBA and
matitis were observed in the 1950s, shortly after higher oligomers, side reactions result in the
commercial epoxy resins were introduced formation of low levels of impurities that both
(Calnan 1958; Jolanki 1991). decrease the epoxide content from the theoretical
52 Epoxy Resins 759
amount of two per molecule and affect the resin 3.1.2 Reactive Diluents
properties, both before and after curing. DGEBA Reactive diluents are used to reduce the viscosity
epoxy resins with a low average MW of of the resin and improve polymerization (Angelini
350–400 Da are liquids with a relatively high et al. 1996). The reactive diluents are generally
viscosity, and they contain monomeric DGEBA glycidyl ethers and sometimes glycidyl esters;
up to more than 90%. Resins with an average structurally, they are aliphatic or aromatic, and
MW of more than 900 Da are solids (Muskopf they also contain epoxy groups in their molecules.
and McCollister 1987) but may contain Reactive diluents participate in the curing process
more than 15% DGEBA (Henriks-Eckerman via their epoxy groups and become chemically
and Laijoki 1986b). DGEBA epoxy resins linked to cured epoxy resins (Muskopf and
are relatively expensive but have a unique McCollister 1987). A list of chemical names and
combination of properties such as electrical CAS numbers of representative examples of avail-
insulation, good chemical and mechanical able reactive diluents is given in Table 2. The
resistance, and versatility (Jolanki 1994). chemical structures of some compounds are also
Non-DGEBA epoxy resins possess special prop- shown in Fig. 3. Reactive diluents based on diols,
erties that have made them competitive with such as l,4-butanediol diglycidyl ether (BDDGE)
DGEBA resins for certain applications. A list and l,6-hexanediol diglycidyl ether (HDDGE),
of chemical names and CAS numbers of avail- may also be used as low-MW epoxy resins
able epoxy resins is given in Table 1. The chem- (Muskopf and McCollister 1987). It has been
ical structures of some dermatologically estimated that more than half of epoxy resin prod-
interesting non-DGEBA epoxy resins are pre- ucts contained varying (0.1–20%) amounts of
sented in Fig. 2. The resin or mixture of resins reactive diluents (Henriks-Eckerman and Laijoki
chosen for a particular application depends on 1986b; Jolanki et al. 1987a).
the desired balance of properties. For example,
brominated epoxy resins are semisolids and 3.1.3 Hardeners
resistant to ignition, while epoxy novolacs A wide variety of hardeners or curing agents is
exhibit better high-temperature performance currently available. Tables 3, 4, 5, and 6 list repre-
and chemical resistance than DGEBA epoxy sentative examples of available hardeners with their
resins. CAS numbers. The chemical structures of some
Fig. 1 Diglycidyl ether of

bisphenol A (DGEBA)
epoxy resin
Table 1 Epoxy resins (Muskopf and McCollister 1987; Table 1 (continued)

Guin and Work 1995)
Fluorinated epoxy resins
Diglycidyl ether of bisphenol A-based epoxy resins Epoxidized cycloaliphatic olefins
Diglycidyl ether of bisphenol A (DGEBA) [CAS 30 ,40 -Epoxycyclohexylmethyl-3,4-
1675-54-3] epoxycyclohexanecarboxylate (cycloaliphatic epoxy
Brominated bisphenol A-based epoxy resins resin) [CAS 2386-87-0]
Diglycidyl ether of tetrabromo bisphenol A [CAS 4-Epoxyethyl-l,2-epoxycyclohexane (vinyl
68928-70-1, 26265–08-7, 40039-93-8] cyclohexene diepoxide) [CAS 25550-49-6]
Phenol and cresol epoxy novolacs Naphthalene epoxy resins
Cresol epoxy novolacs [CAS 37382-79-9] 1,6-Bis(2,3-epoxypropoxy)naphthalene [CAS 27610-
Diglycidyl ether of bisphenol F [CAS 54208-63-8] 48-6]
2,20 ,200 ,2000 -[1,2-ethanediylidenetetrabis
(4,1-phenyleneoxymethylene)]tetrabisoxiran [CAS
7328-97-4]
Phenol epoxy novolacs [CAS 9003-36-5] amine hardeners are also presented in Fig. 4. When
Resorcinol diglycidyl ether [CAS 101-90-6] epoxy resins are used in two-component products,
Trisphenol novolac epoxy resin [CAS 66072-38-6] the hardeners are added to the resins immediately
Glycidyl ethers of phenol-aldehyde adducts
before the application, and the subsequent cross-
1,1,2,2-Tetrakis[4-(2,3-epoxypropyl)phenyl]ethane
[CAS 27043-37-4]
linking occurs at either an ambient or an elevated
Tris[4-(2,3-epoxypropoxy)phenyl]methane [CAS temperature. Aliphatic and cycloaliphatic poly-
66072-39-7] amines are low-viscosity liquids which react read-
Glycidyl ethers of phenol-hydrocarbon novolacs ily with epoxy resins at ambient temperatures; less
2,5-Bis[(2,3-epoxypropoxy)phenyl]octahydro-4,7- reactive aromatic polyamines require an elevated
methano-5 H-indene [CAS 13446-85-0] curing temperature (Muskopf and McCollister
Glycidyl ethers of aliphatic diols 1987). 3-Dimethylaminopropylamine (DMAPA)
Ethylene glycol diglycidyl ether [CAS 2224-15-9] is an aliphatic alkyl polyamine hardener (Fig. 4)
Diglycidyl and triglycidyl ether of glycerol and is also an intermediary in cocamidopropyl
Diglycidyl ether of polypropyleneglycol [CAS 16096-
betaine synthesis and exists as an impurity of
30-3]
Diglycidyl ether of hydrogenated bisphenol A [CAS
cocamidopropyl betaines (Angelini et al. 1995).
30583-72-3] Polyamines are often troublesome to work with
Sorbitol polyglycidyl ether [CAS 68412-01-1] because of their reactivity and volatility and also
Aromatic glycidyl amines because of their irritating and sensitizing properties
4-Glycidyloxy-N,N-diglycidylaniline to the skin and respiratory tract. To overcome these
N,N0 -tetraglycidyl-4,40 -methylenedianiline (TGMDA) problems, less volatile, less reactive, and less irri-
[CAS 28768-32-3] tating and sensitizing polyamides, and amine-
Triglycidyl-p-aminophenol (TGPAP) [CAS 5026- epoxy adducts, have been developed. Polyamides
74-7]
are prepared by combining aliphatic polyamines,
Heterocyclic glycidyl imides
e.g., diethylenetriamine (DETA) or tri-
1,3-Bis(2,3-epoxypropyl)-5,5-
dimethylhydantoin; dimethylhydantoin epoxy resin ethylenetetramine (TETA), with fatty acids.
[CAS 15336-81-9] Amine-epoxy adducts are formed in a reaction
3-(2-glycidyloxypropy1)-1-glycidyl-5,5- between epoxy resin and an excess of polyamine,
dimethylhydantoin [CAS 32568-89-l] mostly DETA, TETA, or isophoronediamine
Triglycidyl isocyanurate (TGIC) [CAS 2451-62-9] (IPDA) (Bauer 1985). The content of free amine
Glycidyl esters
is about 5% in the amine-epoxy adduct hardeners
Diglycidyl ester of hexahydrophthalic acid [CAS
5493-45-8]
used in metal paints, but for those used in floor and
Diglycidyl ester of phthalic acid [CAS 7195-45-1]
concrete coatings, the corresponding figure is about
Glycidyl ester of dimerized linoleic acid and 20% (Back and Saarinen 1986). Free DGEBA is
epichlorohydrin not found in amine-epoxy adducts (Henriks-
(continued) Eckerman and Laijoki 1986b).
52 Epoxy Resins 761
Fig. 2 Non-diglycidyl ether of bisphenol A (DGEBA) epoxy resin
When DGEBA epoxy resins are cured by and Laijoki 1986a). Exposure to uncured resin
polyamine-bearing hardeners at room tempera- may be the cause of unexplained epoxy resin
ture, the amounts of unreacted DGEBA and sensitization. A patient was reported to react to
polyamine diminish rapidly within 1–2 days, DGEBA in a mop handle at a concentration of
but thereafter the decrease is slow. Nevertheless, 0.015% and on patch testing to dilutions was
after 1-week cure, 0.02–12% of free DGEBA positive down to 0.00032% (Kanerva et al.
and 0.01–1% of free DETA were found when 2000a). The use of an elevated curing tempera-
six different epoxy resin products were experi- ture is more effective in reducing the DGEBA
mentally cured by DETA (Henriks-Eckerman concentration than simply waiting until the next
Table 2 Reactive diluents (Muskopf and McCollister phthalic anhydride (PA) and PA derivatives
1987; Angelini et al. 1996; Jolanki 1991) (Muskopf and McCollister 1987; Jolanki et al.
Aliphatic glycidyl ethers 1997b). The typical latent curing agents in pow-
Allyl glycidyl ether (AGE) [CAS 106-92-31] der epoxy paints are composed of about 4%
1,4-Butanediol diglycidyl ether (BDDGE) [CAS hardeners, such as dicyandiamide or
2425-79-8]
pyromellitic anhydride. Triglycidyl isocyanurate
n-Butyl glycidyl ether (n-BGE) [CAS 2426-08-6]
(TGIC) is used to cure powder polyester paints.
tert-Butyl glycidyl ether (tert-BGE) [CAS 7665-72-7]
Blocked isocyanates are latent curing agents
Diethyleneglycol diglycidyl ether (DEGDGE)
used in waterborne coatings (Muskopf and
Diglycidyl ether of pentaerythritol
2-Ethyl hexyl glycidyl ether
McCollister 1987). Polysulfides and hexavalent
Glycidyl ether of aliphatic alcohols (epoxide 8) [CAS chromate are constituents found especially in
68609-97-2] the curing agents of epoxy sealants used in
Glycidyl ether of polypropyleneglycol [CAS 9072-62-2] the aircraft industry (Handley and Burrows
1,6-Hexanediol diglycidyl ether (HDDGE) [CAS 1994; Bruze et al. 1996). Polyamine and organic
16096-31-4] acid anhydride hardeners serve as co-reactive
Neopentyl glycol diglycidyl ether (NPGDGE) [CAS hardeners, which become incorporated into
17557-23-2]
the epoxy resin, whereas tertiary amines,
Cycloaliphatic glycidyl ethers
such as 2,4,6-tris-(dimethylaminomethyl)phenol
Cyclohexanedimethanol diglycidyl ether
(tris-DMP) and N,N-dimethylbenzylamine,
Aromatic glycidyl ethers
p-tert-Butylphenyl glycidyl ether (PTBPGE) [CAS
imidazoles, and boron trihalide-amine com-
3101-60-8] plexes are catalyst-type curing agents, which
Cresyl glycidyl ether (CGE) [CAS 26447-14-3] may not be chemically bound to the resin mole-
p-Fluorophenyl glycidyl ether cules during epoxy curing reactions (Guin and
Alpha-naphthyl glycidyl ether Work 1995; Muskopf and McCollister 1987).
Phenyl glycidyl ether (PGE) [CAS 122-60-1]
Glycidyl esters 3.1.4 Epoxy Di(Meth)Acrylates
Castor oil glycidyl ether [CAS 74398-71-3] Epoxy di(meth)acrylates (also called vinyl esters)
Glycidyl ester of neodecanoic acids (Cardura E 10) are another name for β-hydroxyester acrylates,
[CAS 26761-45-5]
because they are usually obtained by reacting
Glycidyl methacrylate [CAS 106-91-2]
epoxy resins of glycidyl derivatives with (meth)
Glycidyl neodecanoate [CAS 26761-45-5]
acrylic acid. They can also be manufactured from
bisphenol A and glycidyl (meth)acrylates.
day (Hansson 1994). One-component products Although prepared from compounds containing
contain curing agents which are inactive at stor- reactive epoxy groups, completed epoxy di(meth)
age temperatures but which initiate a curing pro- acrylate molecules do not contain these groups.
cess when heated. Typical latent curing agents Both aromatic and aliphatic epoxy di(meth)-
include organic acid anhydrides (Table 4, Fig. 5), acrylates are available, as well as acrylated
which are used mainly in the electrical industry epoxydized oils (Jolanki 1991; Jolanki et al.
when good electrical properties are required. 1995). The first epoxy di(meth)acrylate, known as
Other examples of one-component epoxy prod- bis-GMA (2,2-bis(4-(2-hydroxy-3-methacrylox-
ucts include powder epoxy or epoxy-polyester ypropoxy)phenyl)propane) [CAS 1565-94-2]
paints, polyester paints (Peltonen 1986), (Fig. 6), was developed by Bowen in 1956. bis-
one-pack glues (Dahlquist et al. 1979), and pre- GMA is manufactured from DGEBA and
preg laminates (Mathias 1987). With the anhy- methacrylic acid or bisphenol A and glycidyl meth-
drides, the cross-linking reaction is achieved acrylate (Bowen 1962; Jolanki et al. 1995). Ana-
using tertiary amines (Table 6) as catalysts and lyses have shown that epoxy di(meth)acrylate
an elevated curing temperature (50–200 C). The products may contain DGEBA as an impurity
anhydrides used as epoxy hardeners include (Kanerva et al. 1989; Henriks-Eckerman
52 Epoxy Resins 763
Fig. 3 Reactive diluents
and Kanerva 1997). bis-GA (2,2-bis[4-(2-hydroxy- acrylate based on bisphenol A (Fig. 6). bis-EMA
3-acryloxypropoxy) phenyl]propane) [CAS 1565- (2,2-bis[4-(2-methacryloxyethoxy)phenyl] pro-
94-2] is another example of an epoxy di(meth) pane) [CAS 24448-20-2] (Fig. 6) was developed
Table 3 Polyamine hardeners (Muskopf and McCollister Table 4 Organic acid anhydride hardeners (Guin and
1987; Guin and Work 1995; Kanerva et al. 1996) Work 1995; Jolanki et al. 1997b)
Aliphatic polyamines Chlorendic anhydride [CAS 115-27-5]
N0 -(3-aminopropyl)-N,N-dimethyl-l,3- Cis-cyclohexane-l,2-dicarboxylic anhydride [CAS
propanediamine [CAS 10563-29-8] 13149-00-3]
Diethylenetriamine (DETA) [CAS 111-40-0] Dodecenylsuccinic anhydride (DDS) [CAS 25377-73-5]
Diethylamino propylamine (DEAPA) [CAS 104-78-9] Hexahydrophthalic anhydride (HHPA) [CAS 85-42-7]
3-dimethylaminopropylamine (DMAPA) [CAS Maleic anhydride (MA) [CAS 108-31-6]
109-55-7] Methyl endo-methylene-tetrahydrophthalic anhydride
Dipropylene triamine (DPTA) [CAS 56-18-8] Methylhexahydrophthalic anhydride (MHHPA) [CAS
Ethylene diamine (EDA) [CAS 107-15-3] 19438-60-9]
p-Menthane-I,8-diamine [CAS 80-52-4] Methyl nadic anhydride [CAS 25134-21-8]
Poly(oxypropylenediamine) [CAS 9046-10-0] Methyltetrahydrophthalic anhydride (MTHPA) [CAS
Poly(oxypropylenetriamine) [CAS 39423-51-3] 26590-20-5]
Tetraethylene pentamine (TEPA) [CAS 112-57-2] Phthalic anhydride (PA) [CAS 85-449]
Triethylenetetramine (TETA) [CAS 112-24-3] Polyazelaic polyanhydride
2,2,4-Trimethylhexamethylene 1,6-diamine [CAS Polysebacic polyanhydride [CAS 26776-29-4]
3236-53-1] Pyromellitic dianhydride (PMDA) [CAS 89-32-7]
2,4,4-Trimethylhexamethylene 1,6-diamine [CAS Succinic anhydride [CAS 108-30-5]
3236-53-2] Tetrahydrophthalic anhydride (THPA) [CAS 85-43-8]
Cycloaliphatic polyamines Trimellitic anhydride (TMA) [CAS 552-30-7]
1,2-Cyclohexanediamine [CAS 694-83-7]
3-Cyclohexylaminopropylamine [CAS 3312-60-5]
Table 5 Miscellaneous curing agents (Muskopf and
1,4-Diaminocyclohexane [CAS 3114-70-3]
McCollister 1987; Guin and Work 1995; Kanerva et al.
Isophoronediamine (IPDA) [CAS 2855-13-2] 1996)
2,20 -Dimethyl-4,40 -methylene-bis(cyclohexylamine)
[CAS 6864-37-5] N-Aminoethylpiperazine [CAS 140-31-8]
Aromatic polyamines Cyanoethyl modified aliphatic amine
4,40 -Diaminodiphenylmethane (DDM) [CAS 101-77-9] 2,4-Diamino-6-(20 -alkylimidazol-l-yl)ethyl-5-triazine
4,40 -Diaminodiphenyl sulfone (DDS) [CAS 80-08-0] Dicyandiamide [CAS 461-58-5]
Diethyltoluenediamine [CAS 75389-89-8] Di- and polyisocyanates
m-Phenylenediamine (MPDA) [CAS 108-45-2] Diethylene glycol diaminopropyl ether
o-Tolyl biguanide [CAS 93-69-6] Hexavalent chromate
m-Xylene diamine [CAS 1477-55-0] Melamineformaldehyde resins [CAS 9003-08-1]
Polyamide diamines Phenolformaldehyde resins [CAS 9003-35-4]
Polymeric amido-amine alkoxylated triethylene Polycarboxylic acid polyesters
tetramine Ureaformaldehyde resins [CAS 9011-05-6]
Adducts of aliphatic amines with mono- and
diepoxides and ketones (i.e., amine-epoxy adducts)
Diethylenetriamine-ethylene oxide adduct tertiary amines. Chemically cured dental restor-
Ethylene diamine adduct to solid epoxy ative composite material is usually available in
Triethylenetetramine-propylene oxide adduct two bis-GMA-based components. The tooth-
colored base paste contains a tertiary amine
(1–2%), and the catalyst paste contains dibenzoyl
as a substitute for bis-GMA and is a component of peroxide (1–1.5%). The light-cured composite
some anaerobic glues, gelcoats, and dental com- material consists of only one component (Ander-
pounds (Kanerva and Zwanenburg 2000; Aalto- son and Messick 1985; Janda 1987). Epoxy di
Korte et al. 2013). (meth)acrylates have the desirable properties of
Epoxy di(meth)acrylates can be polymerized, both epoxy resins and poly(meth)acrylates,
not only by exposure to an electron beam, ultra- including relatively low volumetric shrinkage
violet (UV) light, or even visible light but also during the curing process (epoxy resins) and an
chemically activated using various peroxides and adequate polymerization rate (2–5 min at 37 C)
52 Epoxy Resins 765
Table 6 Catalyst-curing agents (Guin and Work 1995; many chemicals, corrosion, heat, and abrasion
Kanerva et al. 1996) and to form tough, high-strength adhesive bonds
Aliphatic thioester on metal and many other surfaces (including
Boron trichloride-amine complex plastics, rubber, wood, glass, and ceramics).
Boron trifluoride-benzylamine complex [CAS 696-99-1] Epoxy resins are also used to insulate or encap-
Boron trifluoride/monomethylamine sulate, and they are used in the assembly of a
l-Cyanoethyl-2-(alkyl or phenyl)imidazoles wide variety of electrical and electronic devices,
l-Cyanoethyl-2-(alkyl or phenyl)imidazole-trimellitates in the manufacture of glass fibers as sizing agents
1-Cyanoethyl-2-phenyl-4,5-di(cyanoethoxymethyl)
(Toffoletto et al. 1994) and in the manufacture of
imidazole
Dimethylaminomethylphenol [CAS 25338-55-0]
sporting goods or other plastic items. They can
2,4,6-Tris-(dimethylaminomethyl)phenol (tris-DMP) also be used as injection resins to repair cracks in
[CAS 90-72-2] concrete, in flooring materials (Conde-Salazar
Tris(dimethylaminomethyl)phenol-tri(2-ethylhexoate) et al. 1994), and stone work (Angelini et al.
N,N-Dimethylbenzylamine [CAS 103-83-3] 1996). Powder paints (Peltonen 1986) and even
Imidazolinealkyl imidazoles nail polishes (Jolanki et al. 1996a) may contain
Ketimine epoxy resin compounds. Epoxy resins were
2-(methyl or phenyl)imidazole-isocyanuric acid adduct introduced in 1956 in the preparation of samples
4,40 -methylene-bis(2-ethyl-5-methylimidazole) for electron microscopy (Jolanki et al. 1988;
Morpholine salt of p-toluenesulfonic acid Sommer et al. 1997) and are still widely used.
2-Phenylimidazole [CAS 670-96-2] More recent uses include in the manufacture of
Thioether
wind turbines (Ponten et al. 2004a) and in the
N-Oleyl-1,3-propanediamine [CAS 7173-62-8]
pipe relining trade (Anveden Berglind et al.
Trifunctional mercaptan terminated polymer
2012). In the manufacture of epoxy composite
products, for example, by lamination, glass
(methacrylates of low MW) (Vanherle and Smith fibers, woven cloth, and matting are impregnated
1985; Janda 1987). with an epoxy resin/curing agent matrix. Glass
fibers usually form composites with a DGEBA
3.1.5 Other Epoxy Compounds epoxy resin/diamine matrix. Epoxy composites
Apart from epoxy resins, reactive diluents, and epi- are used in the manufacture of pipes and vessels;
chlorohydrin, other compounds containing at least in sporting goods, such as tennis racquets,
one epoxy group in their molecules are also poten- skis, ski poles, bowling balls, and fishing rods;
tial causes of contact allergy. Examples of these in the automotive, boatbuilding, and aircraft
epoxy compounds include glycidyl methacrylate industries; in military and aerospace applica-
[CAS 98104-93-9] (Matura et al. 1995, Fig. 6), tions; and in electrical applications in articles
epoxy propane [CAS 75-56-91] (Steinkraus and such as electronic circuit boards (Fregert
Hausen 1994; Morris et al. 1998), 2.3-epoxypropyl 1981b; Burrows et al. 1984; Muskopf and
trimethyl ammonium chloride (EPTMAC) [CAS McCollister 1987; Tarvainen et al. 1995b;
3033-77-01] (Estlander et al. 1986), and trans-3- Amado and Taylor 2008). Most epoxy surface
(4-methoxyphenyl) glycidate (Buisson et al. 1991). coatings are based on DGEBA epoxy resins,
but epoxy resins based on DGEBF and phenolic
novolac resins have also been increasingly used.
3.2 Use Liquid epoxy resins are used in two-component
solventless coatings. Waterborne epoxy coatings
3.2.1 Epoxy Resin Compounds are prepared by the dispersion of epoxy resins
The scope of epoxy resin application is broad. modified with water-soluble functional groups
Epoxy resins are used mostly in two-component or by the emulsification of DGEBA epoxy
paints and other protective coatings and resins with surfactants. Both solventless and
two-component adhesives. Epoxy resins are solvent-borne epoxy coatings have been
used to provide good resistance against water, employed mainly as anticorrosion protection
Fig. 4 Polyamine hardeners and catalyst-curing agents
for metals (marine and maintenance coatings), as Epoxy adhesives range from those used as
waterproof protection for concrete, and as two-pack, ambient-cure, general adhesives in
chemical-resistant protection for floors and domestic applications to high-performance,
walls (Muskopf and McCollister 1987). one-component sheet adhesives for aircraft
Two-component coatings can be cured at ambi- assembly (Gardiner et al. 1992). Araldite™ is a
ent temperatures with polyamines, polyamides, registered trademark of Huntsman Advanced
and amine-epoxy adducts. Tertiary amines, e.g., Materials (previously part of Ciba Geigy) used
tris-DMP, are frequently used to accelerate the for consumer epoxy adhesives. Liquid DGEBA
curing rates (Lee and Neville 1967). epoxy resins are used in most of the one- and
52 Epoxy Resins 767
Fig. 5 Organic acid

anhydride hardeners
two-component epoxy adhesives. The curing Anhydride-cured cycloaliphatic epoxy resins

agent generally consists of polyamides or ali- are commonly used when durability is required,
phatic polyamines, e.g., DETA and TETA. Cast- such as in outdoor electrical insulators (Muskopf
ing resins are liquid and solventless mixtures of and McCollister 1987; Jolanki et al. 1989).
low-MW epoxy resin, a curing agent, and addi- Epoxy molding compounds are solid mixtures
tives, e.g., fillers, reinforcements, and catalysts. of epoxy resin (epoxy novolac), a curing agent
The mixture is poured into molds and cured to and catalyst, mold-release compounds, fillers,
solid structures. The casting resins are used and other additives. The molding compounds
mainly as electrical insulating material in the become liquid at relatively low temperatures
manufacture of transformers, switching gear, cir- (200 C) (Muskopf and McCollister 1987).
cuit breakers, conductors, and insulators. Epoxy molding compounds are used, for
Fig. 6 Methacrylated epoxy compounds
example, in the manufacture of models and in the aircraft and military industries (Burrows
engine covers and in the encapsulation of elec- et al. 1984; Pesonen et al. 2015).
trical components (Fregert 1981b). TGIC is one
of the non-DGEBA epoxy resins (Table 1) and is 3.2.2 Epoxy Di(Meth)Acrylates
mainly used in thermosetting one-component bis-GMA is used in dental restoration work, in
powder polyester paints as a hardener (Muskopf dental filling and coating materials, in dentin
and McCollister 1987). TGMDA, an aniline primers, and also when fissures in posterior
non-DGEBA epoxy resin, is used in pre- teeth are sealed to protect them from caries
impregnated composite materials and adhesives (Vanherle and Smith 1985; Janda 1987). Several
52 Epoxy Resins 769
similar epoxy di(meth)acrylate compounds have caused by epoxy chemicals (Jolanki 1991). In
appeared as substitutes for bis-GMA or in addi- patients diagnosed from 1974 to 1995 at the Finn-
tion to bis-GMA in dental resins. ish Institute of Occupational Health, 80% of
Epoxy di(meth)acrylates also have many indus- 182 patients who had occupational ACD from
trial applications. They are used in UV-curable epoxy chemicals were sensitized to DGEBA
printing processes (Emmett and Kominsky 1977; epoxy resins. Polyamine hardeners (23%) were
Björkner 1984), in corrosion-resistant equipment, the second most common sensitizer, followed by
land transportation equipment, electrical insulation reactive diluents (16%) and non-DGEBA epoxy
for heavy electrical equipment, in anaerobic seal- resins (9%); six patients had ACD from TGIC and
ants and glues, and in marine applications. In the one from phthalic anhydride hardener (Jolanki
manufacture of composite plastic products, epoxy et al. 2001). Simultaneous allergy to different
di(meth)acrylates are used after being dissolved epoxy chemicals was found in 29% of the
in styrene (Anderson and Messick 1985; Janda patients. More recent data from the same institute
1987). Solventless epoxy acrylate coatings are from 1991 to 2014 showed that in patients diag-
cured by initiation with UV light (Bauer 1985). nosed with occupational contact allergy to epoxy
Glycidyl methacrylate, which contains an epoxy chemicals, 82% of 209 patients were sensitized to
group (Fig. 6), is used in emulsions for impregnat- DGEBA resins, 26% to at least one epoxy hard-
ing paper and textile materials (Matura et al. 1995). ener, and 30% to reactive diluents (Aalto-Korte
et al. 2015b). The Information Network of Depart-
3.2.3 Other Epoxy Compounds ments of Dermatology (IVDK) demonstrated that
EPTMAC is used in the manufacture of cationic of all patch-tested patients who were sensitized to
starch as a cationizing chemical, in the manu- DGEBA, 19% also reacted to at least one hardener
facture of ion-exchange resins, and in many and 43% to at least one diluent (Geier et al.
other applications (Bergquist-Karlsson 1985). 2015a). It is known that concomitant sensitization
Other epoxy compounds are used in drug syn- to DBEGA and reactive diluents is quite common
thesis (Rudzki and Rebandel 1990) or found (Jolanki et al. 2001).
among the oxidation products of abietic and High rates of contact allergy from exposure
related acids (Hausen et al. 1990). to epoxy chemicals have been reported in
studies emanating from workplaces, such as 56%
in aircraft manufacturing workers (Burrows et al.
3.3 Allergic Contact Dermatitis 1984), 45% in marble workers (Angelini et al.
to Epoxy Chemicals 1996), 27% in ski-factory workers (Jolanki
et al. 1996b), and 12.1% in workers exposed to
3.3.1 Epoxy Resin Compounds epoxy chemicals from Australia (Nixon and
The first reports of sensitization to epoxy Frowen 1991). In Germany, the frequency of
chemicals were published in the 1950s in Swit- ACD to epoxy chemicals was reported to be
zerland, the Netherlands, the United States, and 18.2% in tile setters and terrazzo workers, 9.7%
Great Britain, where most of the epoxy resin in construction and cement workers, 10.2% in
development had taken place (Calnan 1958; electronics industry workers, and 8.2% in painters
Jolanki 1991). By the beginning of the 1970s, (Dickel et al. 2002). The incidence rate of ACD to
epoxy chemicals began to cause increasing num- epoxy chemicals in industrial painters in the Nor-
bers of occupational dermatoses. During wegian oil industry was calculated to be 4.5/1000
1990–1995, epoxy chemicals were clearly more person years (Rømyhr et al. 2006). In a retrospec-
frequent causes than other plastic chemicals. They tive study of patients in Oregon, USA, evaluated
caused 11.7–12.5% of the cases of occupational for workers’ compensation payments, epoxy
ACD (Jolanki 1991; Holness and Nethercott resins were the third most frequent work-related
1992), and roughly 1% of the exposed workers allergen (10%) in those diagnosed with occupa-
annually developed an occupational dermatosis tional ACD (Coman et al. 2015). Among Danish
painters patch tested between 2001 and 2010, 8% because of contamination from hands (Nixon
were sensitized to epoxy resin, second only to 1997). Reactive diluents and hardeners have
methylchloroisothiazolinone/methylisothiazolin- been considered the most probable causes of air-
one (Mose et al. 2012). In building trade workers borne epoxy ACD, because these substances are
diagnosed with occupational skin disease in Ger- more volatile than DGEBA epoxy resins
many, there was a rise in sensitization to epoxy (Dahlquist and Fregert 1979). In another study,
resin from 8.4 to 12.4% between the periods facial dermatitis was found in 60% of patients, but
1994–1996 and 2006–2008. Workers who started it was not especially common among patients
in the building trade after 1999 had a significantly allergic to reactive diluents or hardeners (Jolanki
increased risk of sensitization to epoxy resin et al. 1990). IVDK data from 1994 to 2013
(odds ratio 2.79) compared with those who showed that among 421 patients with occupa-
started before 1994 (Geier et al. 2011). In an tional airborne contact dermatitis, 18% were sen-
Italian patch test cohort, prevalence of sensitiza- sitized to DGEBA resin (Breuer et al. 2015).
tion to epoxy resin in construction workers The prognosis of ACD from epoxy resins
increased from 1.4% in 1996–1998 to 14.8% in appears to be variable and is dependent on a
2008–2010 (Prodi et al. 2015). number of factors, both individual and environ-
Crucial factors for the development of derma- mental (Cahill et al. 2005). While some authors
titis from epoxy chemicals include the type of have reported that ACD from epoxy chemicals
exposure, frequency of skin contact with the caus- has a better outcome than from other allergens,
ative agent, the concentration of the epoxy chem- due to epoxies being less ubiquitous in the envi-
ical used, the size of the contaminated skin area, ronment, other studies have shown poorer out-
and the use of protective gloves (Jolanki 1991). In comes (Krajewska and Rudzki 1976; Cahill et al.
some instances, the latent period before onset of 2005). Factors that may be associated with a poor
ACD to epoxy chemicals may be quite short, prognosis, and possible development of persistent
ranging from less than 1 month to several years post-occupational dermatitis, include age, atopy,
(Suhonen 1983; Holness 1992). Even a single duration of symptoms, and severity at diagnosis
accidental exposure may induce primary sensiti- (Cahill et al. 2005). There are rare case reports
zation to epoxy resin (Kanerva et al. 1994). In which may demonstrate an association between
German construction workers, there was a mono- persistent photosensitivity and ACD to epoxy
tonic increasing risk of developing epoxy allergy resins (Kwok et al. 2013).
with increasing exposure hours per week. Years
working with epoxy products were inversely asso- 3.3.2 Diglycidyl Ether of Bisphenol A
ciated with epoxy allergy, which the authors (DGEBA) Epoxy Resins
attributed to a healthy worker survivor effect Thorgeirsson and Fregert (1977) confirmed that
(Spee et al. 2016). Most of the patients developing the main sensitizer in epoxy resin systems was
dermatitis to epoxy chemicals are men (Fregert DGEBA, with a MW of 340 Da. In the guinea-
1975; Jolanki 1991; Nethercott et al. 1994). The pig maximization test, the oligomer with a MW of
difference in the frequency between the two gen- 624 Da was also a sensitizer but with minor sen-
ders probably represents differences in exposure. sitizing capacity, whereas oligomers with a MW
Epoxy chemicals can induce direct or airborne of more than 900 Da did not induce sensitivity
contact dermatitis. The skin symptoms are located (Thorgeirsson et al. 1978). Until 1964, 1.6% of
mainly on the patients’ hands or arms and, to a 1690 patients who were not employed in the
lesser extent, face and neck. The fingers and epoxy resin industry developed allergic patch
interdigital spaces, forearms and wrists, and the test reactions to DGEBA epoxy resin at the
eyelids are the most typical locations of the skin Department of Dermatology, University of Lund
disease caused by epoxy chemicals (Jolanki et al. (Fregert and Rorsman 1964). Thus, the DGEBA
1990; Geier et al. 2004; Aalto-Korte et al. 2015b). epoxy resin, as one of the top 20 contact allergens,
In addition, genital involvement may occur was included in the European standard patch test
52 Epoxy Resins 771
series in 1966 (Jolanki 1991). In the beginning of nonoccupational exposure in North America
the 1990s, the rate of sensitization from the North (Rietschel et al. 2002). Paints, varnishes, and
American Contact Dermatitis Group (NACDG) other surface coatings as well as exposure in the
was 1.8% among 3500 patients studied (Marks electronics industry are common causes of
et al. 1995). This rate remained stable at 1.8% DGEBA epoxy resin sensitization (Jolanki
among 4454 patients patch tested by the 1991). Epoxy sensitization is also often caused
NACDG from 2005 to 2006, with 30.8% of reac- by exposure to two-component glues and bonding
tions thought to be definitely or probably relevant agents (Conde-Salazar et al. 1993; Jolanki et al.
(Zug et al. 2009). Edman (1988) found a lower 1994b). Several reports describe workers sensi-
frequency of 1% among 3562 patients patch tested tized to epoxy resins used as binders in carbon- or
during 1982–1987 at the Malmo General Hospi- glass fiber-reinforced plastic products (Suhonen
tal, Sweden. Similarly, in Denmark, 0.8% of 1983; Holness and Nethercott 1989; Tarvainen
10,423 patients (Veien et al. 1992) and, in China, et al. 1995b). Epoxy resin used as a sizing agent
0.7% of 1135 patients were found to be patch test in glass fibers has also induced contact allergy
positive to DGEBA epoxy resin (Liu et al. 1997). during production (Toffoletto et al. 1994). Rarer
However, the positive rates from specialized occupational exposures causing ACD include the
occupational dermatology clinics in Helsinki and use of DGEBA epoxy resin in bowling ball plug-
Toronto were as high as 3.7% (Jolanki 1991; ging (Amado and Taylor 2008), golf club repair
Holness and Nethercott 1992). (Isaksson et al. 2008), and solder mask coating on
More recently, the IVDK in Germany reported printed circuit boards (Wenk and Ehrlich 2010).
sensitization rates to DGEBA epoxy resin of A relatively recent source of exposure to epoxy
0.9–1.4% from 1992 to 2000 (Geier et al. 2004) chemicals was in the production of wind turbines,
and 1.6% among 93,406 patients patch tested where 10.9% of 603 workers studied had ACD
from 2002 to 2011 (Geier et al. 2015a). The Dan- caused by epoxy chemicals (Pontén et al. 2004a).
ish Contact Dermatitis Group reported similar DGEBA was the causative factor in approxi-
rates of 1.3% (1.9% in males; 1.0% in females) mately 50% of cases: the remaining cases were
among 20,808 patients patch tested from 2005 to caused by amine hardeners and catalysts. Epoxy
2009 (Bangsgaard et al. 2012). In Portugal, the pipe relining, a method to repair old and worn
rate over 10 years in 2440 patients was 0.9% waterpipes, has emerged as a new cause of occu-
(Canelas et al. 2010). Majasuo et al. (2012) pational ACD from epoxy resin systems, with the
found a sensitization rate of 0.9% to DGEBA majority of cases sensitized to both DGEBA and
epoxy resin among 6042 Finnish patients patch DGEBF (Anveden Berglind et al. 2012;
tested over a 10-year period; 35% of cases were Fillenheim et al. 2012).
due to nonoccupational exposure and 65% due to Well-recognized sources of nonoccupational
occupational epoxy exposure. A northeastern Ital- ACD from DGEBA epoxy resin include paints
ian group showed a sensitization rate of 0.9% to and adhesives used in domestic renovation and
DGEBA epoxy resin in 19,088 patients patch in hobbies such as model building, art and craft,
tested from 1996 to 2010 (Prodi et al. 2015). and boat repair, in addition to nail art/hardeners
From 2013 to 2014, the European Surveillance (Majasuo et al. 2012; Lolatgis and Nixon 2015).
System on Contact Allergies (ESSCA) found a Nonoccupationally induced ACD has also been
sensitization rate of 1.1% in 28,577 consecutively reported from epoxy resin in various medical
patch tested patients across 46 departments in 12 - devices, such as hemodialysis catheters, polyvinyl
European countries (Uter et al. 2017). This rate ostomy bags, infusion sets of an insulin pump,
rose to 1.9% when patients from specialized occu- nasal cannulae, pacemakers, amputation prosthe-
pational dermatology departments only were ses, and a hearing aid (Mann et al. 1983; Boom
considered. and van Driel 1985; Requena et al. 1986; Toome
Epoxy resin was the only allergen more often 1989; Skoet et al. 2003; Haussmann et al. 2005;
associated with occupational exposure than Word et al. 2011).
Furthermore, there are numerous case reports of 3.3.3 Non-diglycidyl Ether

epoxy ACD from hidden sources of epoxy resin, of Bisphenol A
such as oil painting (Conde-Salazar et al. 1982), Since the 1980s, ACD has also been reported from
lamination of glass products (Heskel 1988), adhe- non-DGEBA epoxy resins, for example, the aniline
sive plaster (Dooms-Goossens et al. 1993), lawn epoxy resins (also called aromatic glycidyl amines).
bowls polish (Lyon et al. 1998), a billiard cue These include N-N-tetraglycidyl-4,40 -methylene
(Gonçalo et al. 1992), microscopy immersion oils dianiline (TGMDA) (Burrows et al. 1984; Ayala
(Sommer et al. 1997), a bus pass (Sasseville et al. et al. 1990; Tarvainen et al. 1995b; Kanerva et al.
2002), and a car seat covering (Wurpts and Merk 2000b; Jolanki et al. 2001; Pesonen et al. 2015),
2010). Solid, completely polymerized resins rarely triglycidyl derivative of p-aminophenol (TGPAP)
cause dermatitis, but traces of unhardened mono- (Ayala et al. 1990; Tarvainen et al. 1995b; Bruze
meric DGEBA epoxy resin have been identified on et al. 1996; Kanerva et al. 2000b; Jolanki et al.
sign boards, bottle caps, film cassettes, metal pack- 2001; Jappe et al. 2005), and 4-glycidyloxy-N,N-
ages, and brass doorknobs (Fregert 1981a). Tooling, diglycidylaniline (Burrows et al. 1984; Mathias
including sawing and drilling of epoxy resin in cured 1987). ACD has also been reported from
state, promotes the release of epoxy allergens (Hans- diglycidyl ester of phthalic acid (o-diglycidyl
son 1994). ACD has also been induced by phthalate) (Burrows et al. 1984), diglycidyl ether
unhardened epoxy resin in several finished products of polypropylene glycol (Yung and Wilkinson
(Taylor et al. 1983; Malanin and Kalimo 1985; 2003), vinyl cyclohexene dioxide (Dannaker
Fischer et al. 1987; Goulden and Wikinson 1996). 1988), and 1,6-bis (2,3-epoxypropoxy) naphtha-
In addition, a few cases of ACD from DGEBA lene (Yokota and Michitsuji 2004). In addition,
epoxy resins with a high average MW have been cycloaliphatic epoxy resins based on diglycidyl
reported (Jolanki et al. 1987b; Suhonen 1983), even ester of hexahydrophthalic acid, heterocyclic
though the amount of DGEBA has been as low as dimethylhydantoin epoxy resins, phenol novolac
0.2% in the causative products (Jolanki et al. 1987b). epoxy resins, and brominated epoxy resins have
Epoxy resins used as stabilizers and plasticizers for been found to be causes of ACD (Jolanki et al.
polyvinyl chloride have also been shown to be sen- 1987b, 1989, 2001; Kanerva et al. 1991b; Bruze
sitizers (Ancona-Alayon et al. 1976; Toome 1989). et al. 1996). Many of the patients sensitized to
Airborne ACD caused by epoxy resin systems these non-DGEBA epoxy resins are not allergic to
has been reported in multiple occupational and non- DGEBA resin.
occupational settings. However, it is more fre- Cycloaliphatic epoxy resins have been found
quently attributed to hardeners or diluents, which in jet aviation hydraulic fluid (Maibach and
are more volatile than DGEBA (Dahlquist and Mathias 2001) and in neat oil when added as a
Fregert 1979). Unusual cases of DGEBA resin caus- stabilizer (Jensen and Andersen 2003). Tri-
ing airborne ACD include “neighborial allergy” glycidyl isocyanurate (TGIC) is a known skin
caused by transmission of volatile resin from a irritant (Nishioka et al. 1988) but has also been
two-part glue via a ventilation system from the shown to be an allergen. Workers may become
downstairs furniture repair shop (Özkaya 2012), sensitized to TGIC from short-term exposure to
application of epoxy resin to canvas in recreational the chemical during its production, in the manu-
painting (Lolatgis and Nixon 2015), and an occupa- facture and use of TGIC-containing powder
tional case of airborne contact conjunctivitis, which polyester paints, and from silk-screen printing
occurred in the absence of eyelid dermatitis, from coatings in the manufacture of circuit boards
resin used in the assembly of aircraft components (Nishioka et al. 1988; Munro and Lawrence
(Goodson and Powell 2014). Both Swedish and 1992; Jolanki et al. 1994a).
Danish groups have reported associations between There have been an increasing number of
contact allergy to DGEBA resin and fragrance mix reports of ACD to diglycidyl ether of bisphenol
1, of unclear relevance (Pontén et al. 2004b; Ander- F (DGEBF) (Pontén and Bruze 2001; Pontén
sen et al. 2009). et al. 2004c; Sakata et al. 2005). The addition
52 Epoxy Resins 773
of DGEBF prevents DGEBA from crystallizing, of PGE analogues, slight changes in chemical
as DGEBF epoxy resin is less viscous, and it is structure are associated with appreciable differ-
also used when greater resistance is needed ences in sensitizing capacity (Niklasson et al.
(Pontén and Bruze 2001). Epoxy resin based on 2009). In most cases, it is considered likely that
DGEBF may be manufactured by methods sim- positive patch test reactions to PGE are the result
ilar to epoxy resin based on DGEBA or may be of immunological cross-reactions in patients pri-
produced from novolac resins based on phoneol marily sensitized to DGEBA resin (Pontén et al.
and formaldehyde (Pontén et al. 2002). DGEBF 2004d). Contamination of epoxy resins with low
has three isomers, and there is immunological levels of PGE has also been reported (Pontén
cross-reactivity between DGEBA and two of et al. 2008).
these isomers: p,p0 -DGEBF and o,p0 -DGEBF Reactive diluents are more volatile than
(Pontén et al. 2002). Concomitant reactions DGEBA epoxy resin and may cause an airborne
to DGEBA and DGEBF are common, based dermatitis pattern (Dahlquist and Fregert 1979;
on both cross-sensitization and co-exposure Tosti et al. 1988; Angelini et al. 1996; Geier
(Geier et al. 2004). A recent study by the et al. 2009). Most patients sensitized to reactive
Finnish Institute of Occupational Health, where diluents are allergic to PGE, cresyl glycidyl
DGEBF has been included in the baseline ether (CGE), 1,6-hexanediol diglycidyl ether
patch test series since 1999, found that indepen- (HDDGE), 1,4-butanediol diglycidyl ether
dent sensitization to DGEBF was rare. Of 1972 (BDDGE), or p-tert-butylphenyl glycidyl
patients patch tested over 11.5 years, 66 (3.3%) ether (PTBPGE), and cross-sensitization bet-
were sensitized to DGEBF; of these, 61 were ween reactive diluents is common (Jolanki et al.
also sensitized to DGEBA (Aalto-Korte et al. 1987a; Jolanki 1991; Tosti et al. 1992; Conde-
2014). This is in accordance with German find- Salazar et al. 1994; Angelini et al. 1996; Geier
ings (Geier et al. 2004), although Swedish et al. 2004; Geier et al. 2009; Geier et al. 2015a;
researchers have reported independent DGEBF Aalto-Korte et al. 2015a).
contact allergy in higher numbers (Pontén and A recent analysis by the IVDK found that
Bruze 2001). among patients sensitized to DGEBA epoxy
resin, the most common diluent causing contact
3.3.4 Reactive Diluents allergy was HDDGE (42%), followed by BDDGE
Fregert and Rorsman (1964) described contact (34%), PGE (29%), and PTBPGE (27%) (Geier
allergy to reactive diluents. Epoxy reactive dilu- et al. 2015a). Fifteen to twenty-two percent of
ents have been revealed to be strong sensitizers patients sensitized to reactive diluents did not
in guinea pigs, especially phenylglycidyl ether react to DGEBA. A 13-year review by the Finnish
(PGE) (Thorgeirsson 1978a), and in humans, Institute of Occupational Health found the most
reactive diluents have caused allergy in exposed common diluent allergen, in absolute numbers, to
workers (Jolanki 1991; Tosti et al. 1992; be PGE, followed by BDDGE, PTBPGE, and
Angelini et al. 1996). Sensitization to reactive CGE (Aalto-Korte et al. 2015a). The four major
diluents is commonly associated with concomi- diluents causing contact allergy were identical to
tant sensitization to DGEBA epoxy resin; iso- those in the earlier EPOX 2002 study, although in
lated contact allergy to reactive diluents is also a different order (Geier et al. 2004). The authors
possible but rarer (Jolanki et al. 1987a; Jolanki did highlight the difficulty in comparing fre-
1991; Angelini et al. 1996; Geier et al. 2015a; quency of reactions as the number of patients
Aalto-Korte et al. 2015a). It has been shown in tested with each reactive diluent varied consider-
guinea pigs that induction of sensitization with ably. Ten percent of patients had isolated sensiti-
DGEBA is associated with allergy to PGE, while zation to diluents without concomitant DGEBA
induction of sensitization to PGE is not associ- allergy, and 70% were sensitized to more than one
ated with allergy to DGEBA (Pontén et al. 2009). diluent. BDDGE was considered the most clini-
In addition, when considering the allergenicity cally relevant compound; as in the majority of
patients sensitized to PGE or PTBPGE, no signif- MXDA, followed by tris-DMP, IPDA, and
icant exposure history could be identified, DETA (Aalto-Korte et al. 2014). The IVDK
although this could be due to incorrect labeling found MXDA and IPDA to be the most common
of products or material data safety sheets. sensitizers among epoxy hardeners (Geier et al.
Rare reactive diluent contact allergens include 2015a), although sensitization rates for tris-DMP
allyl glycidyl ether (Jolanki 1991; Angelini et al. were not included in the data as it was not
1996), n-butyl glycidyl ether (n-BGE) (Aalto- routinely tested for. The first case report of
Korte et al. 2015a), cyclohexanedimethanol ACD caused by 2-methylpentane-1,5-diamine
glycidyl ether (Angelini et al. 1996), neopentyl (MPMD), an aliphatic amine hardener, was
glycol diglycidyl ether (NPGDGE) (Jolanki 1991; recently reported in a German painter and var-
Aalto-Korte et al. 2015a), Cardura E10 (Lovell nisher (Darr-Foit et al. 2016). In the same year,
et al. 1984), Epoxide 8 (Björkner et al. 1980), Pesonen et al. (2016) reported the first six cases of
diethyleneglycol diglycidyl ether (DEGDGE) ACD from N-(2-phenylethyl) derivatives of
(Jolanki et al. 1996b; Aalto-Korte et al. 2015a), 1,3-benzenedimethanamine (a synonym for
trimethylolpropane triglycidyl ether (TMPTGE) MXDA) [CAS no. 404362-22-7], used as a curing
(Aalto-Korte et al. 2015a), alpha-naphthyl agent in epoxy paints and coatings. Despite the
glycidyl ether, and p-fluorphenyl glycidyl ether close structural similarity between MXDA and
(De Groot 1994). Allyl glycidyl ether has also derivatives of 1,3-benzenedimethanamine, only
caused ACD in the plastics industry from the use three patients also reacted positively to MXDA.
of epoxy silane in a single-component sealant Concomitant contact allergy to DGEBA resin
(Dooms-Goossens et al. 1995). was seen in two of the six patients (Pesonen
et al. 2016).
3.3.5 Hardeners Cross-reactivity between polyamine hardeners
In the guinea-pig maximization test, polyamine may be possible (Rudzki and Krajewska 1976;
hardeners with a low MW were found to be strong Kirkup et al. 2001), although both the FIOH and
sensitizers (Thorgeirsson 1978b). Most of the IVDK found no evidence for immunological cross-
patients with contact allergy to epoxy hardeners reactions in their most recent analyses (Aalto-Korte
have reacted to 4,40 -diaminodiphenyl methane et al. 2014; Geier et al. 2015b). Isolated contact
(DDM), DETA, and TETA (Jolanki 1991; Tosti allergy to epoxy hardeners was previously thought
et al. 1992). In addition, cases of contact allergy to uncommon (Tosti et al. 1992; Kanerva et al. 1991a,
IPDA (Lachapelle et al. 1978; Camarasa and 1996); however, the IVDK found that a consider-
Serra-Baldrich 1989; Kanerva et al. 1998), tri- able proportion of patients were sensitized to hard-
methyl hexamethylene diamine (Kanerva et al. eners without being sensitized to DGEBA resin
1991a, 1998), tetraethylenepentamine (TEPA) (Geier et al. 2015a). This was particularly pro-
(Kanerva et al. 1998), m-xylylene diamine nounced for hardeners such as TMHDA, DETA,
(MXDA) (Kanerva et al. 1991a, 1998; Rømyhr and TETA, with around 60% of the sensitized
et al. 2006), diaminocyclohexane (Kirkup et al. patients not reacting to DGEBA resin.
2001), or other cyclohexylamines (Gordon and Epoxy hardeners are well known to cause air-
McLelland 1998) have been reported. More recent borne ACD due to their volatility (Dahlquist and
reports have emphasized reactions occurring to Fregert 1979). There are recent reports of occupa-
MXDA, as well as IPDA and DDM (Geier et al. tional airborne ACD to tris-DMP in epoxy adhe-
2004). 2,4,6-Tris-(dimethylaminomethyl)phenol sive used by a parquet tile installer (Geier et al.
(tris-DMP) has been reported to be probably a 2012) and a concrete repair worker (Geier et al.
more common allergen than expected (Kanerva 2009). Airborne ACD has also been reported from
et al. 1991a, 1996; Brooke and Beck 1998; IPDA in epoxy resin-based grout used to lay
Rømyhr et al. 2006). A recent 12-year Finnish swimming pool tiles (Foti et al. 2010).
review of contact allergy to epoxy hardeners Positive patch test reactions to DDM or ethylene
found the highest rates of sensitization were to diamine (EDA) are not necessarily an indication of
52 Epoxy Resins 775
sensitivity from exposure to epoxy hardeners. The to epoxy resin by patch testing bisphenol A at a
relevance of DDM allergy is sometimes difficult to concentration of 2% in water, but they did not men-
determine. For example, a positive patch test reaction how the positive reactions were scored. Addi-
tion to DDM may represent allergy to para-amino tional data on the high incidence of bisphenol A
compounds, such as p-phenylene diamine allergy among those sensitized to epoxy resin are
(Gailhofer and Ludvan 1989), or exposure to lacking. The Dutch research group of van Joost
diphenyl methane diisocyanate (Jolanki et al. found very few cases of bisphenol A allergy in
1990). EDA allergy may be caused by exposure, workers at epoxy resin manufacturing plants,
for example, to rubber, synthetic coolants, or topi- although several patients had been sensitized to
cal creams (Rietschel and Fowler 2008). Another epichlorohydrin (van Joost 1988; van Joost et al.
aliphatic amine hardener, DMAPA, is an impurity 1990). Cases of allergy to bisphenol A have been
responsible for cocamidopropylbetaine allergy reported from fiberglass made of epoxy resin (Gaul
from cosmetics (Speight et al. 1993; Angelini 1960), bis-GMA-based dental composite resins
et al. 1995; Kanerva et al. 1996). A few reports of containing 0.014–0.015% bisphenol A (Jolanki
contact allergy to non-amine hardeners have et al. 1995), semisynthetic waxes (Freeman and
been published in the case of dicyandiamide Warin 1984), plastic footwear (Srinivas et al.
(Senff et al. 1988), dodecenyl succinic anhydride 1989), PVC gloves (Aalto-Korte et al. 2003), and
(Göransson 1977), methylhexahydrophthalic anhy- in shoemaking glue (Koch 2002). Contact allergy to
dride (Kanerva et al. 1997), hexavalent chromate, bisphenol A may also be a cross-reaction with com-
an accelerator additive (Handley and Burrows pounds responsible for phenolformaldehyde resin
1994; Bruze et al. 1996), polysulfides (Bruze et al. allergy, such as dihydroxydiphenyl methanes
1996), and a polymercaptan hardener (Guin 2005). (bisphenol F) (Bruze and Zimerson 1985; Jolanki
1991).
3.3.6 Bisphenol A and Epichlorohydrin
Occupational contact dermatitis caused by epichlo- 3.3.7 Epoxy Di(Meth)Acrylates
rohydrin and bisphenol A is uncommon (Jolanki The guinea-pig maximization test has shown that
1991). In the finished DGEBA epoxy resin, the epoxy di(meth)acrylates range from being weak to
proportion of free epichlorohydrin is less than extreme sensitizers (Björkner 1984). Despite the
0.001%. The proportion of bisphenol A is even increasing use of epoxy di(meth)acrylates in dental
smaller because, in the manufacturing process, epi- care and in industry, relatively few reports of con-
chlorohydrin is always present in excess to ensure tact allergy caused by these compounds have been
that the molecules terminate in epoxy groups. In published (Emmett and Kominsky 1977; Kanerva
epoxy resin plants, despite closed manufacturing and Alanko 1998; Aalto-Korte et al. 2009). Non-
systems, workers may have a higher risk of becom- occupational allergy is even rarer (Kanerva and
ing sensitized to epichlorohydrin, but they do not Alanko 1998). Sensitized subjects have mainly
generally become sensitized to bisphenol A (van been workers in the UV light printing industry
Joost et al. 1990). Allergy to epichlorohydrin has (Emmett and Kominsky 1977; Björkner 1984) or
also been reported from a solvent cement (Beck and the dental industry (Kanerva et al. 1989; Aalto-
King 1983) and from drug synthesis of propranolol Korte et al. 2009). In addition, the manufacture of
hydrochloride and oxprenolol hydrochloride UV-curable epoxy diacrylate paints (Jolanki et al.
(Rebandel and Rudzki 1990). One patient with 1995), UV-curable coating varnish containing
ACD from exposure to epoxy propane reacted also epoxy acrylate oligomers (Guimaraens et al.
to epichlorohydrin and to diglycidyl ester of hexa- 1994), and UV-curable inks (Kanerva et al.
hydrophthalic acid (Morris et al. 1998). Reports of 2000c; Aalto-Korte et al. 2009) is associated with
bisphenol A sensitization have been rather contro- occupational allergy. ACD from epoxy di(meth)
versial (van Joost et al. 1990). Krajewska and acrylates commonly presents as hand and forearm
Rudzki (1976) described positive patch tests to dermatitis and sometimes facial dermatitis from
bisphenol A in 13 of 17 Polish workers sensitized transfer via the hands. In dental patients, it may
manifest as gingivostomatitis or perioral dermatitis dimethacrylate may also have contact allergy to
(Kanerva and Alanko 1998; Koch 2003). bisphenol A from handling products containing
Patients who acquire their epoxy di(meth)acry- dental composite resin (Jolanki et al. 1995).
late allergy from products that contain bis-GMA Cross-reactivity among epoxy acrylates, together
as the main monomer are, in general, concomi- with DGEBF and DGEBA allergy, was also
tantly allergic to both bis-GMA and DGEBA reported in North America (Lee et al. 2002).
epoxy resin (Kanerva et al. 1989; Kanerva and
Alanko 1998; Aalto-Korte et al. 2009). Bis-GMA 3.3.8 Other Epoxy Compounds
is the reaction product of DGEBA and methyl 2.3-epoxypropyl trimethyl ammonium chloride
methacrylate (Lee et al. 2002). It has been (EPTMAC) has been shown to be a moderate
shown that bis-GMA-borne dental materials may sensitizer in guinea pigs and to cause ACD in
contain minute amounts of DGEBA, enough to humans (Bergquist-Karlsson 1985; Estlander
induce sensitization (Niinimäki et al. 1983; et al. 1986; Jolanki 1991). An intermediate
Kanerva et al. 1989). Patch test results by several product in the synthesis of the drug diltiazem
groups suggest the possibility of true immunolog- hydrochloride, 2,3-epoxy-3-(4-methoxyphenyl)
ical cross-reactions between DGEBA and propionate, has induced contact allergy in two
bis-GMA (Kanerva and Zwanenburg 2000; Lee cases (Rudzki and Rebandel 1990; Buisson et al.
et al. 2002; Geier et al. 2007). Contact allergy to 1991). Another epoxy compound, 13,14(p)-
epoxy di(meth)acrylates has been found in epoxyabietic acid, is an isolated allergen of
patients who have been exposed to DGEBA unmodified colophony (Hausen et al. 1990;
epoxy resins but with no known exposure to the Karlberg and Gafvert 1996). Epoxy propane (pro-
epoxy di(meth)acrylates (Jolanki et al. 1990; pylene oxide) used as a solvent in histology has
Kanerva et al. 1991c). also been shown to be a contact allergen
bis-EMA is used as a substitute for bis-GMA (Steinkraus and Hausen 1994; Morris et al. 1998).
in anaerobic sealants and dental compounds
(Kanerva and Zwanenburg 2000). Although
bis-EMA is considered a strong sensitizer 3.4 Contact Urticaria
(Björkner 1981), only rare cases of contact
allergy have been described, and subjects often Relatively few cases of immediate-type contact
have concomitant sensitization to DGEBA urticaria (CU) caused by epoxy chemicals have
epoxy resin and bis-GMA (Kanerva and been reported. Both epoxy resins (Jolanki et al.
Zwanenburg 2000; Geukens and Goossens 1997a) and organic acid anhydride hardeners
2001; Aalto-Korte et al. 2009). Recently, a case (Jolanki et al. 1997b) should be regarded as poten-
of occupational ACD to bis-EMA in an anaero- tial causes of the CU syndrome. In 1974, a patch
bic glue, without cross-allergy to DGEBA epoxy test with an epoxy resin was reported to induce
resin, was reported in a factory machinist (Aalto- generalized urticaria and an asthmatic reaction
Korte et al. 2013). The structurally similar com- (Woyton et al. 1974). In 1983, Subonen reported
pound bis-GA is also a strong sensitizer on two patients who, in a patch test, showed imme-
(Björkner 1981) but accounts for only seldom diate urticarial reactions, probably caused by an
reports of ACD in workers exposed to impure DGEBA epoxy resin used in a ski pole
UV-cured inks and anaerobic sealants (Kanerva factory. Kanerva et al. (1991c) described two
et al. 2000c; Aalto-Korte et al. 2009). patients with both delayed allergy to DGEBA
Matura et al. (1995) described a chemist who epoxy resin and specific immunoglobulin E
had developed ACD to glycidyl methacrylate (IgE)-mediated immediate sensitization from
from compounding emulsions used to impregnate DGEBA with a MW of 340 Da. Nixon and Frowen
paper and textile materials to make them oil- and (1991) reported eight cases of CU in 198 workers
water-resistant. The role of glycidyl methacrylates exposed to epoxy chemicals. Sasseville (1998)
in bis-GMA contact allergy is unknown. Patients reported a case of CU from an aircraft factory. On
with ACD from products containing epoxy patch testing after 30 minutes, the worker
52 Epoxy Resins 777
experienced urticarial reactions to epoxy resin (1% epichlorohydrin, and glass or carbon fiber-based
pet), PGE (0.25% pet), and CGE (0.25% pet). No epoxy composites (Jolanki 1991; Jolanki et al.
delayed reactions were seen. Similarly, Miyamoto 1990, 1996b). Additionally, irritating, low-MW
and Okumura (1998) reported CU confirmed by a degradation products may be produced in the
15-minute open test and a 15-minute closed patch tooling of epoxy products and in heating pro-
test for epoxy resin at 1% in petrolatum. Anaphy- cesses (Engstrom and Henriks-Eckerman 1988).
laxis was reported to epoxy resin in a root canal Amine and anhydride hardeners and epichlorohy-
sealer after a patient became unconscious when drin irritate the skin and conjunctivae. In addition
visiting the dentist (Stutz et al. 2008). to causing irritant contact dermatitis, epichlorohy-
Occupational asthma was reported by Kanerva drin, as a highly reactive compound, and aliphatic
et al. (2000d) and Hannu et al. (2009). In another polyamines, as highly alkaline compounds
case, the CU test reaction was augmented when (pH 13–14), can cause corrosive burns on the
the allergen was wiped off with an alcohol skin (Ippen and Mathies 1970; Rietschel and
swab, presumably because the alcohol enhanced Fowler 2008). Ippen and Mathies (1970)
skin penetration of the allergen (Kanerva et al. described protracted chemical burns after the
2002). Urticarial reactions have been reported exposure of five patients to epichlorohydrin. Lea
in workers involved in the manufacture of et al. (1958) found that an epoxy reactive diluent,
phthalic anhydride (Menschik 1955). Other butyl glycidyl ether, also caused irritation in
case reports describe patients who human volunteers. Eedy (1996) described a
developed CU from hexahydrophthalic anh- worker with airborne irritant contact dermatitis
ydride (HHPA), methylhexahydrophthalic anhy- from grinding carbon fiber-based epoxy compos-
dride (MHHPA), or methyltetrahydrophthalic ites. Curing agents in powder paints, such as
anhydride (MTHPA) epoxy hardeners from the dicyandiamide and organic anhydrides, are also
manufacture of condensers (Jolanki et al. 1987b, potentially irritant (Peltonen 1986; Jolanki et al.
1990), electrical machines (Tarvainen et al. 1997b). When cold, organic anhydrides are not
1995a; Kanerva et al. 1997, 1999a), integrated very harmful to dry skin, but hot compounds may
circuits for electronic appliances (Yokota et al. cause severe chemical burns. On sweating skin,
2001), or ski poles (Tarvainen et al. 1995a). anhydrides are hydrated to the corresponding
Appreciable respiratory symptoms from MTHPA acids and can cause caustic dermatitis and burns
were reported in a worker from a plant producing (Menschik 1955; Malten and Zielhuis 1964).
rocket gun barrels from an epoxy resin (Nielsen Generally, DGEBA epoxy resins are not strong
et al. 1992). Acid anhydrides may induce specific irritants, and their irritancy decreases with the
IgE-mediated sensitization (Jolanki et al. 1990; increasing MW of the oligomer (Hine et al.
Tarvainen et al. 1995a; Kanerva et al. 1997), 1958). However, four patients developed irritant
resulting in CU and allergic respiratory and con- contact dermatitis from paints or paint raw mate-
junctival symptoms. The Finnish experience of rials containing DGEBA epoxy resins with a high
occupational CU from cyclic acid anhydrides average MW and one patient from a mixture of a
(21 cases) was recently reviewed (Helaskoski et al. DGEBA epoxy resin with a low average MW and
2009). In addition, CU can be caused by aliphatic its anhydride hardener, used in electrical insula-
polyamine hardeners (Rietschel and Fowler 2008) tion (Jolanki et al. 1987b, 1990).
and possibly by other amines (Savonius et al. 1994).
3.5.1 Active Sensitization
Patch testing has occasionally produced sensitiza-
3.5 Irritant Contact Dermatitis from tion to patch test allergens (active sensitization).
Epoxy Compounds Active sensitization is especially common when
acrylics are tested (Kanerva et al. 1992) but has
Irritant contact dermatitis from epoxy resin sys- also complicated testing with epoxy chemicals
tems has occasionally been reported with high- (Fregert and Rorsman 1964; Calnan 1967, 1975;
MW DGEBA epoxy resins, hardeners, Lachapelle et al. 1978; Jolanki 1991; Kanerva and
Estlander 1998). At the Finnish Institute of Occu- diluents, and non-DGEBA epoxy resins without
pational Health, the test concentration of epichlo- simultaneous contact allergy to the standard
rohydrin was lowered to 0.1% in petrolatum epoxy resin are relatively common among
because of active sensitization (Kanerva et al. workers exposed to epoxy chemicals (Jolanki
1999b). It has not been established whether false 1991; Tosti et al. 1992; Geier et al. 2015a). It is
negative tests occur. PGE at 0.25% in petrolatum therefore recommended that patients suspected of
has also been reported to cause active sensitiza- contact dermatitis from epoxy chemicals should
tion (Kanerva and Estlander 1998). also be tested with the individual allergenic com-
pounds, hardeners, reactive diluents, and
non-DGEBA epoxy resins to which they have
3.6 Other Skin Disorders Caused by been exposed.
Epoxy Chemicals Wherever there is suspiction of epoxy allergy,
patients should be tested with their own specific
Purpuric ACD, scleroderma-like disorders, atypi- materials, especially if there is no response to the
cal psoriasis, and erythema multiforme have all standard epoxy resin (Holness and Nethercott
been reported to be caused by exposure to epoxy 1993). Houle et al. (2012) found that among
chemicals (Holness and Nethercott 1989). 24 patients investigated for epoxy resin ACD,
Bachurzewska and Borucka (1986) reported find- there was an additive value of testing own aller-
ings similar to Raynaud’s disease. Rycroft (1980) gens in 13 (54%) patients; of these, 6 reacted to
reported on a patient whose epoxy resin sensitiza- only their own materials; thus the standard epoxy
tion was followed by atypical psoriasis, while series alone would not have diagnosed their ACD.
Lichter et al. (1992) described a patient whose It should be borne in mind that testing only with
sensitization to epoxy resin and hardener was the patients’ own materials is not always
followed by lichenoid contact dermatitis. The completely reliable, because the allergens may
development of vitiligo in the sites of positive become too diluted and thus give negative patch
patch tests to TGPAP has been reported (Jappe test results (Jolanki 1991).
et al. 2005), together with contact vitiligo follow- Based on the positivity ratio and reaction
ing ACD to DGEBA resin or reactive diluents index, Warshaw et al. (2010) found DGEBA
(Kumar and Freeman 1999; Silvestre et al. epoxy resin 1% to be one of the most “acceptable”
2004). Photosensitivity has been reported in rela- patch test preparations, i.e., most likely to produce
tion to the heating of DGEBA epoxy resin and the strong (þþ or þþþ) reactions as opposed to
use of epoxy powder paints (Allen and Kaidbey weak, questionable, or irritant reactions. A patch
1979; Göransson et al. 1984). It is thought to be test concentration of 0.5% in petrolatum for
caused by bisphenol A contained in the resin non-DGEBA epoxy resins is probably preferable
(Maguire 1988). to 1% when low-viscosity resins are being tested,
because 1% non-DGEBA resins may irritate
(Jolanki et al. 1989). Aalto-Korte et al. (2015b)
3.7 Skin Testing and Chemical recommend that DGEBF-R be tested at a concen-
Investigations tration of 0.25% in pet. (0.1 mg/cm2). Aniline
epoxy resins, especially TGMDA, are useful for
No single chemical can be used alone to screen for investigating workers in the aircraft industry
sensitization to the different epoxy chemical con- (Aalto-Korte et al. 2015b).
tact allergens. Approximately 30% of patients Patch testing with the resinous part alone does
with contact allergy to epoxy chemicals have not exclude contact allergy to reactive diluents.
been found to be sensitive to more than one of A test concentration of 0.25% in petrolatum
the three main epoxy chemical groups: resins, was found to be suitable for testing reactive
hardeners, and reactive diluents. In addition, indi- diluents (Jolanki 1991; Jolanki et al. 1996b;
vidual contact allergies to hardeners, reactive Geier et al. 2004; Aalto-Korte et al. 2015b). On
52 Epoxy Resins 779
patch testing, cross-reactivity has been found and this possibility should be clarified by
between compounds that are chemically closely additional patch tests (Kanerva et al. 1989;
related, especially between reactive diluents. Jolanki 1991).
With the exception of PGE, reactive diluents In general, petrolatum seems to be a good
rarely produce cross-reactions with DGEBA vehicle for testing epoxy chemicals. For solid
epoxy resins, and contact allergy to reactive materials containing uncured epoxy resins, it is
diluents is not revealed by testing with the preferable to use acetone instead of water for
standard epoxy resin. However, patients who ultrasonic cleaning bath extractions or to soften
are allergic to cycloaliphatic epoxy resins often the material in the patch test chamber (Jolanki
react to reactive diluents and vice versa et al. 1990; Bruze et al. 1992).
(Jolanki 1991). A study by Hillen et al. (2006) found that late
In a study by Jolanki et al. (2001), most patch test reactions to epoxy resin, at or after day
patients who were sensitized to reactive diluents 7, occurred in 0.3% of 1428 cases. It is necessary
were allergic to PGE. BDDGE was found to to combine chemical and dermatological experi-
screen contact allergy to aliphatic reactive dilu- ence for the optimal investigation of occupational
ents. Thus PGE and BDDGE have often been skin diseases induced by epoxy chemicals. The
considered sufficient to screen for contact allergy methods include clarification of the causative
to other related compounds (Jolanki 1991). How- agents through patch testing and planning of pre-
ever, Aalto-Korte et al. (2015a) suggest that CGE ventive measures for both the patient and, impor-
patch tested at a concentration of 0.25% in petro- tantly, unaffected fellow workers. In problematic
latum may have more clinical value as an inde- cases, skin prick testing with epoxy chemicals,
pendent allergen than PGE. The same group consultations with industrial hygienists, visits to
found HDGGE to be the more clinically signifi- the patients’ work sites, and analyses of the mate-
cant aliphatic reactive diluent, due to lack of expo- rials handled by the patients are also important
sure information for other diluents (Aalto-Korte (Estlander 1990; Jolanki 1991). In suspected con-
et al. 2015b). tact urticaria from epoxies, an open test may be of
When allergy to polyamine hardeners is value. It is also important to note that safety data
suspected, patch testing with MXDA, tris- sheets are incorrect relatively often and epoxy
DMP, IPDA, and DETA should be performed, chemicals have sometimes not been listed
in addition to TETA and DDM (Aalto-Korte (Nixon 1997). Thin-layer chromatography and
et al. 2015b). All but tris-DMP are available other chromatographic methods (gas chromatog-
from the test substance suppliers. The raphy and high-performance liquid chromatogra-
recommended test concentration for tris-DMP phy) can be used to demonstrate the presence or
is 0.5–1% in petrolatum (Kanerva et al. 1996; absence of particular allergens (Fregert 1988;
Brooke and Beck 1998; Aalto-Korte et al. Jolanki et al. 1988; Ayala et al. 1990; Kanerva
2015b). Because of the vast variety of hardeners et al. 1991a).
used, it is highly recommended to test patients
with the hardeners that they have been exposed
to. Test concentrations of up to 10% should 3.8 Prevention of Epoxy Chemical
be used for the amine-epoxy adducts. A test Dermatitis
concentration of about 1% is the most suitable
for polyamine-type hardeners, e.g., DETA Complete avoidance of contact with the causative
(Jolanki 1991). allergens is always necessary. In a patient highly
bis-GMA and bis-GA should be tested for sensitive to epoxy compounds, even a minimal
the detection of contact allergy caused by amount of an allergen may be enough to evoke
epoxy di(meth)acrylates. An allergic reaction the symptoms on the exposed skin. Most patients
induced by the standard epoxy resin may indi- with occupational dermatitis caused by epoxy
cate contact allergy to epoxy di(meth)acrylates, chemicals have to leave their work. This may
also be beneficial for the prevention of possible The use of less sensitizing products may reduce
respiratory allergy following skin sensitization the possibility of developing allergy to epoxy, as
(Kanerva et al. 1991c). ACD to epoxy chemicals high-MW epoxies do not sensitize readily. The
has generally been thought to have a good prog- use of one-bag epoxies, which mix in the package
nosis, predominantly because it is easier to avoid (Van Putten et al. 1984), may reduce the possibil-
contact with these chemicals than to avoid contact ity of skin contact. Work by the dermatochemistry
with more ubiquitous allergens, such as nickel group at the University of Gothenburg has dem-
or chromate (Rosen and Freeman 1993). How- onstrated that minor changes to the structure of
ever, recent work suggests that this may not PGE are associated with less allergenicity
always be the case, and in some cases, workers (Niklasson et al. 2009). More recently, the same
develop persistent post-occupational dermatitis research group has shown the contact allergenic
(Sajjachareonpong et al. 2004). This may relate effects of DGEBA/DGEBF monomers to be
to the initial severity of the dermatosis (Cahill largely determined by their terminal reactive
et al. 2005). epoxide groups (O’Boyle et al. 2012). Changes
Those working with epoxy compounds to the structure of DGEBA, through extension of
should be made aware of the risk of sensitization. chain length, removal of aromaticity, and removal
Gloves made of laminated, multilayered plastic of an oxygen atom, result in monomers that are
(Silver Shield ®/4H ® Gloves, Honeywell Safety less sensitizing and which show little or no cross-
Products), containing ethylene-vinyl alcohol reactivity with DGEBA epoxy resin (O’Boyle
copolymer, developed especially for the han- et al. 2014; Hagvall et al. 2016).
dling of epoxy chemicals, give the best protec- The airways should also be protected from expo-
tion and are considered the gold standard for sure to the epoxy compounds, because these com-
protection (Henriksen and Petersen 1986; pounds may cause asthma. Even use of an automated
Roed-Petersen 1989; McClain and Storrs process does not guarantee protection against skin
1992). However, these are underutilized due to contact and exposure of the respiratory tract, because
their high cost and inconvenience (Henricks- of the possibility of exposure during maintenance,
Eckerman et al. 2015). Using a newly developed machine repair, or sampling (Jolanki 1991).
glove penetration testing method, the FIOH An “Epoxy Code” was developed for use in the
demonstrated that thick chemical protective construction industry, involving Denmark, Ger-
gloves composed of nitrile rubber, polyvinyl many, the Netherlands, and the UK (Spee et al.
chloride (PVC), and butyl rubber showed no 2006). In Denmark, although a low prevalence of
detectable penetration of DGEBA or diamine sensitization to epoxy monomer (DGEBA) is
hardeners after 30 minutes (Henricks-Eckerman observed, a recent survey of sensitized patients
and Mäkelä 2015; Henricks-Eckerman et al. reported that of 95 patients with occupational
2015). The cheaper disposable nitrile rubber, exposure to epoxies, only 51% had participated
rubber blend, and vinyl gloves were found to be in the legislated educational program prior to
suitable for short-contact work, with the caveat commencing work, and 37% did not use gloves
that at least two layers are used and the top glove (Bangsgaard et al. 2012).
is removed 15 minutes after contamination has Finally, once a case of ACD to epoxy
occurred. Two suitable clothing materials, e.g., chemicals has been diagnosed, it is worth
for use in coveralls, were identified which had no reflecting on the factors that led to sensitization
detectable DGEBA penetration. and the risks to other workers, who have not (yet)
Another complicating factor is concurrent developed dermatitis. As Boris Lushniak said
solvent use, which may adversely affect glove “By its nature, occupational dermatology is
function. The suitability of gloves with other also related to occupational preventive medicine.
chemicals may be obtained from websites The ideal role of the medical practitioner
such as https://www.ansellpro.com/download/ involved in occupational dermatology is not
Ansell_8thEditionChemicalResistanceGuide.pdf. only to diagnose and treat patients, but also to
52 Epoxy Resins 781
determine the etiology of the occupational skin Bachurzewska B, Borucka I (1986) Gefãssläsionen bei
disease and to make recommendations for its Eisenbahnarbeiterinnen, die mit Epoxidharzen in
Berührung kommen. Dermatosen 34:77–79
prevention” (Lushniak 2004). Back B, Saarinen L (1986) Free amines in epoxy hardeners
and in workplace air (in Finnish with English sum-
mary). Työterveyslaitoksen tutkimuksia 1:31–36
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Contact Allergy
to Phenol-Formaldehyde Resins 53
Erik Zimerson and Magnus Bruze
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
3 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
4 Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
5 Contact Dermatitis and Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
6 Connections to Other Sensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
7 Treatment and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796

Allergic contact dermatitis · Bakelite · Delayed
hypersensitivity · Novolac resin · Resol resin · • The raw materials, phenols and aldehydes, are
Hydroxymethyl groups · Sensitizing not important allergens in phenol-formaldehyde
monomers and dimers resins.
• The strongest allergens are found among
monomers and dimers with reactive
hydroxymethyl groups, the hydroxymethyl
phenols.
E. Zimerson (*) • Resins produced with a deficit of formaldehyde
Department of Occupational and Environmental (novolac resins) show low allergenicity
Dermatology, Lund University/Skåne, University
Hospital, Malmö, Sweden
because they contain very low concentrations
e-mail: Erik.Zimerson@med.lu.se of hydroxymethyl phenols. Addition of form-
M. Bruze
aldehyde needs to be done before curing.
Department of Dermatology, University of California Novolac resins should not be used for patch
Medical School, San Francisco, CA, USA testing.
Department of Occupational and Environmental • The concentrations of allergens usually drop
Dermatology, Skåne University Hospital Malmö, Lund significantly when the resins are cured (e.g.,
University, Malmö, Sweden phenol-formaldehyde resin), while some
e-mail: magnus.bruze@med.lu.se

https://doi.org/10.1007/978-3-319-68617-2_52
790 E. Zimerson and M. Bruze
resins more or less retain their levels of Modified phenol-formaldehyde resins are, for
allergens regardless of treatment (e.g., p-tert- example, used for surface coatings and impregna-
butylphenol-formaldehyde resin). tion. In these cases, the phenol-formaldehyde
• Phenol-formaldehyde resins made from dif- resin can be mixed with colophony, terpenes,
ferent phenols and/or aldehydes will contain fatty acids, amines, or epoxy resins.
different allergens and cross-reactions Formaldehyde reacts with phenols giving
between different resins should not be methylol-substituted phenols. Another word for
expected. methylol phenol is hydroxymethyl phenol. These
• Patch testing should be performed with the substances are the monomers in the resin. Form-
specific phenol-formaldehyde resin the patient aldehyde also creates chemical bonds between the
is exposed to. monomers. This bond can be either of the methy-
• p-tert-Butylcatechol is a strong sensitizer used lene type (–CH2–) or of the methylene-ether type
as a stabilizer in plastic monomers (e.g., sty- (–CH2–O–CH2–) thus forming dimers, trimers,
rene) and is also found in p-tert-butylphenol- tetramers, and so on. Phenol-formaldehyde resin
formaldehyde resin. In case of a positive patch can be produced in two principal ways, either as
test reaction to p-tert-butylphenol-formalde- resol or novolac resins.
hyde resin with no clinically relevant exposure Resol resins are produced by the reaction of
to this resin, p-tert-butylcatechol should be phenol with a molecular excess of formaldehyde
patch tested and exposure to this substance under alkaline conditions. The monomers form
investigated. dimers, trimers, and other oligomers in which
the monomers are mainly connected by methylene
groups. The excess of formaldehyde in the reac-
2 Introduction tion makes all the constituents of the resin rich in
reactive methylol groups. The methylol groups in
The first successful commercial exploitation of o- or p-position to the hydroxy group of the phe-
phenol-formaldehyde resin was made in 1909 nol make the resol substances reactive by giving
under the name of Bakelite. This was the first them the possibility to split off a water molecule
wholly synthetic polymer ever made, but in spite and become extremely reactive quinonmethides.
of this, it is still used in many applications and This is the mechanism behind formation of
products. Fillers and other additives are used to dimers, trimers, and other oligomers. This reac-
improve the product. From the first resins, other tivity also means that the substances can react
varieties have been developed so that phenol- with proteins in the skin and act as type IV aller-
formaldehyde resins now designate a group of gens. The resol resins are viscous dark reins,
resins with varying properties made from differ- which often are used, dissolved in a solvent
ent phenols and aldehydes. (such as methanol) before being applied to differ-
ent materials such as paper. Stabile products are
then created by curing (polymerization) of the
3 Chemistry resins by application of pressure and heat. Curing
transforms the resins into rigid network polymers.
The most used phenol-formaldehyde resins are Novolac resins are produced when formalde-
based on phenol or p-tert-butylphenol and form- hyde reacts with a molecular excess of phenol
aldehyde. However, other phenols can be used under acidic conditions. Almost all of the added
such as resorcinol, cresols, guayacol (2-methoxy formaldehyde is consumed producing methylene
phenol), p-phenylphenol, xylenols, amylphenol, groups, which create bonds between the mono-
octylphenol, nonylphenol, and bisphenol A. In mers. As there are few or no methylol groups in
some resins, a mixture of phenols is used. Alde- the molecules, these resins show very low reac-
hydes other than formaldehyde are occasionally tivity and more aldehyde must be added in the
used, for example, furfural. process before curing. This is often done by the
53 Contact Allergy to Phenol-Formaldehyde Resins 791
addition of a formaldehyde releaser such as para- in building, construction, car, leather, shoe, mold-
formaldehyde or hexamethylenetetramine. ing, and electric industries.
p-tert-Butylphenol-formaldehyde resin is pro- Resins based on phenol and formaldehyde or a
duced as a resol resin in a similar way as resins combination of phenol, resorcinol, and formalde-
based on phenol but has several different proper- hyde are used in many glues and adhesives. The
ties. The constituents of the resin are more lipo- resins are used for decorative boards, laminated
philic and thus more fat soluble. The bonds boards for floors, plywood, water-resistant
between the monomers are mostly of the methy- boards, glass and mineral fibers for insulating,
lene-ether-type, which are more unstable than the brake and clutch linings, abrasive cloth and
methylene bonds in phenol-formaldehyde resin. paper, grinding wheels, and molds for casting
The methylene-ether bonds can, for example, be metal and plastic. Phenol-formaldehyde resins
split by reaction with water (hydrolysis) or light- are developed for new applications, which include
catalyzed reaction with oxygen (oxidation). The being a base for nanoparticles and for use in the
resins cannot create a network polymer when production of foaming boards from wastepapers.
cured due to blocking of one position on the p-tert-Butylphenol-formaldehyde resin is used
aromatic ring of the phenol by the tert-butyl in adhesives based on neoprene and other rubbers.
group. As a consequence, the resin will often These glues are used when flexibility of the joint
contain relatively high levels of monomers, or when extra water resistance is needed. The
dimers, and trimers. If the resin is more condensed resin is frequently used in glues for shoes and
and thus contains larger molecules, these can still other leather products such as watch straps.
be converted back to smaller ones by spontaneous Other uses include glues for automobile uphol-
hydrolysis and/or oxidation. If the resin is heavily stery, furniture, hobbies, artificial fingernails, and
condensed at high temperatures, a part of the adhesive labels. Other products reported to con-
methylene-ether bonds will be converted into tain the resin include athletic tapes, glue in hearing
methylene bonds, and this will make the polymer aid, and ink in marking pens.
more stable to degradation but it will still be a Modified resins or resins based on p-tert-
thermoplastic polymer. butylphenol or other alkyl-substituted phenols
All the phenol-formaldehyde resins are pro- are used for surface coatings as protective and
duced with different degrees of condensation (cur- isolating varnishes for packing due to their
ing). In this way, resins with different viscosity or water-repellent properties. Modified resins can
tackiness can be achieved. Resins with a low be used as binders in inks, typewriter correction
degree of condensation are rich in low molecular papers, and different laminates.
weight compounds such as monomers and dimers.
These resins consist of hundreds or thousands of
substances of which the vast majority is not chem- 5 Contact Dermatitis and Allergy
ically identified. However, efforts to identify the
main sensitizers in resins based on phenol and Phenol-formaldehyde resins can cause several
p-tert-butylphenol have been made. types of damage to the skin. The most frequently
reported effects are different types of contact der-
matitis such as irritant contact dermatitis and aller-
4 Use gic contact dermatitis. Depigmentation and
contact urticaria have also been described. Reac-
Phenol-formaldehyde resins were earlier much tion products such as monomers and dimers, or
used as casting compounds for products such as remaining raw material such as phenols and alde-
knobs, electrical switches, ashtrays, and many hydes, are causative agents.
others. This use has diminished and, nowadays, Phenol-formaldehyde resins can cause irritant
the resins are mainly used as binders in different contact dermatitis (Fregert 1980) and chemical
products. Large quantities are used, for example, burns (Fisher 1973). Many phenols are known to
be irritating and can cause chemical burns and the investigation, 17 cases of occupational allergic
level of remaining or free phenol can vary in the contact dermatitis due to phenol-formaldehyde
resins. The reaction products, methylol phenols, resin are reported. Their occupations were friction
generally seem to be less irritating to the skin than material production, fiberglass manufacture,
the phenols. Low or high pH of the resin can foundry work, aircraft construction, joinery, and
contribute to irritant contact dermatitis. The pH adhesives processing (Owen and Beck 2001).
of a resin mainly depends on remaining or added Occupational allergic contact dermatitis from
catalyst which can be an acid or a base. In a case cured and used casting sand containing phenol
report, a life-threatening condition involving formaldehyde has been reported (Isaksson
necrotic lesions of the skin and renal functional 2002). Also occupational airborne allergic contact
impairment is reported of a patient who had dermatitis from medium-density fiberboard
spilled phenol-formaldehyde resin over a large (MDF-board) has been reported (Ezughah et al.
area of the skin (Cohen et al. 1989). 2001). Phenol-formaldehyde resin has also been
Depigmentation can be caused by certain reported to cause palmoplantar dermatitis (Downs
resins and are likely due to remaining phenols and Sansome 1998). One factor that can contrib-
such as p-tert-butylphenol (Malten et al. 1971; ute to the relatively few reported cases is that
Stevenson 1981). resins of this type usually are not used in baseline
Contact urticaria has been ascribed to p-tert- patch test series. However, a resol resin based on
butylphenol-formaldehyde resin in a case report phenol and formaldehyde (PFR-2) is included in
due to handling of glass fiber insulation (Kalimo the Swedish baseline series since a few years
et al. 1980). (Isaksson et al. 2011), and it is a candidate to be
Most reports about adverse effects from included in the baseline patch test series of the
phenol-formaldehyde resins describe allergic con- International Contact Dermatitis Research Group
tact dermatitis. Although free formaldehyde can (Isaksson et al. 2015). The usefulness of this resol
be found in many phenol-formaldehyde resins, it resin (PFR-2) to detect occupational allergic con-
is not a major sensitizer in these resins (Hjort and tact dermatitis from phenol-formaldehyde resins
Fregert 1967; Bruze et al. 1985). Free phenols also was demonstrated in a Finnish study (Aalto-Korte
seem to be of little or no significance concerning et al. 2017).
allergic reactions to the resins (Fregert and Hjort It has been shown that resol resins based on
1969; Bruze et al. 1985), although p-tert- phenol contain highly sensitizing substances.
butylphenol once was considered the main sensi- Fourteen sensitizers from this type of resin have
tizer in resins based on this phenol (Malten 1958). been isolated and described. Some of the allergens
There are relatively few reports on contact are shown in Fig. 1. Both monomers and dimers
allergy to resins based on phenol. In some inves- were shown to be sensitizers. Patch testing with
tigations of workers in laminate productions, high serial dilutions showed that some of the sensi-
frequencies of allergies have been reported (Bruze tizers, for example, the dimer 4,40 -dihydroxy-
and Almgren 1988; Isaksson et al. 1999). Reports 3,30 -dimethylol-diphenylmethane, could elicit an
on occupational sensitization have also concerned allergic reaction down to a concentration of about
a secretary handling typewriter correction paper 0.01 ppm in patients with a high sensitivity. The
(Jordan and Bourlas 1975), a newspaper dealer presence of these sensitizers in resins and prod-
(Castelain et al. 1980), painters (Hjort and Fregert ucts based on phenol and formaldehyde has been
1967), a worker in a rubber factory (van der investigated. Concentrations of allergens in cured
Willingen et al. 1987), bricklayers (Sonneck products were reduced by a factor of 100–1000
1964), workers producing abrasive paper when compared to the contents of the uncured
(Bompart and Smagge 1959), a worker resins (Bruze 1985; Bruze et al. 1986).
manufacturing gasoline filters (Gaul 1967), and p-tert-Butylphenol-formaldehyde resin is the
workers sawing masonite or using grinding most frequently reported sensitizer among the
wheels (Fregert and Tegner 1972). In one phenol-formaldehyde resins. As this resin is used
Fig. 1 Chemical structures a OH OH b OH

of some of the identified
sensitizers in resins based
e
on phenol and
formaldehyde.
(a) 2-methylol phenol;
(b) 4-methylol phenol; HO OH
(c) o-cresol; (d) 2,4,6-
trimethylol phenol; c OH
(e) 4,40 -dihydroxy
diphenylmethane;
f
(f) 4,40 -dihydroxy-3- OH
hydroxymethyl-
diphenylmethane (a main
allergen); (g) HO OH
4,40 -dihydroxy-
3,30 -dihydroxymethyl- d
diphenylmethane (a main OH OH OH
g
allergen)
HO OH
HO OH
OH
both in industries and in personal products, sensi- 250 dermatitis patients were shown to be allergic
tization can be of occupational origin or caused by to p-tert-butylphenol-formaldehyde resin
contact with the resin in ordinary daily life. In (Kashani et al. 2005). Also among workers in a
1958, contact allergy was described among cob- car factory (Calnan and Harman 1959; Engel and
blers (Malten 1958). Since then, more patients Calnan 1966), painters (Högberg and Wahlberg
working with shoe manufacturing or shoe 1980), and glue users (Moran and Martin-Pascual
repairing have been reported (Mancuso et al. 1978; Cronin 1980), contact allergy has been
1996) as well as patients with shoe dermatitis reported. Other causes of mainly nonoccupational
(Malten et al. 1983; Freeman 1997) and still a sensitization and/or allergic contact dermatitis can
major problem facing sensitized persons is to be leather watch straps (Foussereau et al. 1968;
find shoes that they can tolerate. Among Mobacken and Hersle 1976), use of certain plastic
140 patients with suspected shoe dermatitis in finger nail adhesives (Rycroft et al. 1980), athletic
Israel, 8.7% showed an allergic reaction to p- tape (Shono et al. 1991), an hearing aid
tert-butylphenol-formaldehyde resin (Trattner (Matrolonardo et al. 1993), a lip liner (Angelini
et al. 2003), while a retrospective study et al. 1993), a knee guard (Vincenzi et al. 1992),
(1998–2004) showed a frequency of 1.3% detoration brace after an orthopedic operation and
among dermatitis patients also in Israel (Lazarow a rain coat (Hayakawa et al. 1994), a waist support
2006). There seems to be a tendency that allergy for treatment of scoliosis and leather glues
frequencies to p-tert-butylphenol-formaldehyde (Tarvainen 1995), marking pens (Hagdrup et al.
resin are declining in European countries but are 1994), prosthesis (Romaguera et al. 1985), and
increasing in other countries. In a study in electrocardiograph-monitoring electrodes (Avenel-
England (1994–2003), 0.5% out of 230 patients Audran et al. 2003).
with foot dermatitis were allergic to p-tert- The first allergen reported in p-tert-
butylphenol-formaldehyde resin (Holden and butylphenol-formaldehyde resin was p-tert-
Gawcrodger 2005), but in Iran 8.0% of butylphenol (Malten 1958). Formaldehyde is a
known allergen, which is present in the resin. the patients’ own resin/material can therefore be
However, most individuals sensitized to p-tert- indicated (Bruze 1985, 1988; Isaksson et al.
butylphenol-formaldehyde resin are not sensitive 2011, 2015).
to p-tert-butylphenol or formaldehyde (Malten Active sensitization has been reported when
1987). The two monomers 2-hydroxymethyl-p- patch testing with 1.0% p-tert-butylphenol-form-
tert-butylphenol and 2,6-dimethylol-p-tert- aldehyde resin. However, the authors point out
butylphenol have been shown to be allergens in that the benefits of patch testing with this sub-
the resin, the latter being the stronger sensitizer of stance outweighs the risks for sensitization, as
the two (Zimerson and Bruze 2002d). Some the- this seems to happen very seldom (Arpa et al.
oretical constituents and theoretical degradation 2002; Stenberg et al. 2015).
products have been synthesized, and among
these a linear tetramer has been reported as an
allergen (Agatha and Schubert 1979; Schubert 6 Connections to Other
and Agatha 1979). Present investigations in our Sensitizers
department regarding isolation of allergens directly
from the resin has shown the presence of many In 1967, a possible relation between contact
other allergens and some of which have a potency allergy to phenol-formaldehyde resin and coal
comparable to the strongest allergens in resins tar was noted (Hjort and Fregert 1967). Some
based on phenol (Zimerson et al. 1999; Zimerson simple phenols have been shown to be probable
and Bruze 1998, 2000a, b, 2002a, b, c). The pres- cross-reacting substances in patients hypersensi-
ence of two allergenic dimers varied a lot when tive to phenol-formaldehyde resin, for example,
investigated chemically in test preparations with p- o-cresol (Bruze and Zimerson 1997). o-Cresol is
tert-butylphenol-formaldehyde resin and commer- also a known component in coal and wood tar
cial samples of this resin from various manufac- (Snell and Ettre 1973; Richardson 1993), and it
turers (Hamann et al. 2012). Chemical structures of has been identified as an allergen in phenol-
some allergens in p-tert-butylphenol-formaldehyde formaldehyde resin (Bruze and Zimerson 2002).
resin are shown in Fig. 2. This could explain the connection to coal tar. It
p-tert-Butylphenol-formaldehyde resin is also indicates a possible connection to other
included in the baseline patch test series of both sources of o-cresol, for example, tobacco smoke
the International Contact Dermatitis Research (Jeanty et al. 1984).
Group (ICDRG) and the European Society of In patients hypersensitive to phenol-
Contact Dermatitis. Positive patch test reactions formaldehyde resin (resol), simultaneous patch
have varied between 0.3% and 2.6% among der- test reactions to formaldehyde, colophony,
matological patients (Tarvainen 1995; Handley hydroabietyl alcohol, balsam of Peru, perfume
et al. 1993). In Portugal, positive reactions var- mixture, and p-tert-butylphenol-formaldehyde
ied between 1.4% (1984) and 3.8% (1992), with resin have been reported. In patients hypersensitive
an increasing tendency mainly in woman to p-tert-butylphenol-formaldehyde resin (resol),
(Marques et al. 1994). This resin was one of the simultaneous patch test reactions to hydroabietyl
top ten contact sensitizers (prevalence 1.3%) alcohol, balsam of Peru, and phenol-formaldehyde
when more than 3000 individuals from samples resin have been reported (Bruze 1986).
of the general population in five European coun- Simultaneous patch test reactions to p-tert-
tries were patch tested with the European base- butylphenol-formaldehyde resin and p-tert-
line series (Diepgen et al. 2016). A slightly lower butylcatechol have been reported (Estlander
prevalence rate (0.9%) was noted in approxi- et al. 1998), and p-tert-butylcatechol has been
mately 1000 Swedish youths from the general shown to be a component in at least some
population (Stenberg et al. 2015). However, resins based on p-tert-butylphenol-formaldehyde
patch testing with this resin is not sufficient to (Zimerson and Bruze 1999). This can indicate
detect allergies to phenol-formaldehyde resins a connection to other sources of p-tert-
based on other phenols, and patch testing with butylcatechol, which is used as an antioxidant
Fig. 2 Chemical structures a b c

of some of the identified OH OH OH OH OH OH OH O
sensitizers in resins based
on p-tert-butylphenol and
formaldehyde. (a) 4-tert-
butyl-2-hydroxymethyl-
phenol; (b) 4- tert-butyl-
2,6-bis-hydroxymethyl-
phenol; (c) 4- tert-butyl-2-
hydroxymethyl-6-
methoxymethyl-phenol;
(d) p-tert-butylcatechol
(PTBC); (e) 5-tert-butyl-2- OH OH OH
hydroxy-3-hydroxymethyl-
d OH f
benzaldehyde; (f) 4-tert-
OH
butyl-2-(5-tert-butyl-2-
O
hydroxy-
benzyloxymethyl)-6-
hydroxymethyl-phenol
(a main allergen); (g) 4-tert-
butyl-2-(5-tert-butyl-2-
hydroxy-3-hydroxymethyl-
benzyloxymethyl)-6-
hydroxymethyl-phenol e g
(a main allergen); (h) 4-tert- OH OH OH OH OH OH
butyl-2,6-bis-(5-tert-butyl-
2-hydroxy-3- CHO
hydroxymethyl- O
benzyloxymethyl)-phenol
h
OH OH OH OH OH
O O
(Gellin et al. 1970) and as a stabilizer in different irritating resin. In many cases of occupationally
plastic monomers (Macfarlane et al. 1990). related allergic dermatitis caused by phenol-
formaldehyde resin, the person cannot continue
the job. However, the prognosis is usually good
7 Treatment and Prevention when they can change job. Work including han-
dling of cured products can be tolerated if the
Dermatitis caused by phenol-formaldehyde resins sensitivity is not too high.
is treated in the same way as other contact derma- For patients hypersensitive to p-tert-
titis. Irritant dermatitis can usually be successfully butylphenol-formaldehyde resin and for whom no
treated if it is possible to reduce exposure to the clinically relevant contact to this resin can be found,
patch testing with p-tert-butyl catechol can be indi- Bruze M, Zimerson E (1997) Cross-reaction patterns in
cated. Patch testing with p-tert-butylphenol-formal- patients with contact allergy to simple methylol phe-
nols. Contact Dermatitis 37:82–86
dehyde resin is not sufficient to detect Bruze M, Zimerson E (2002) Contact allergy to o-cresol – a
hypersensitivity to phenol-formaldehyde resins sensitizer in phenol-formaldehyde resin. Am J Contact
based on other phenols. A more complete patch Dermat 13:198–200
testing for allergies to this group of resins should Bruze M, Fregert S, Zimerson E (1985) Contact allergy to
phenol-formaldehyde resins. Contact Dermatitis 12:81–86
include testing with phenol-formaldehyde resin and Bruze M, Persson L, Trulsson L, Zimerson E (1986) Dem-
the patients’ own resins/materials. Extracts of fin- onstration of contact sensitizers in resins and products
ished products can be useful for patch testing. based on phenol and formaldehyde. Contact Dermatitis
Resins based on phenol and p-tert-butylphenol can 14:146–154
Calnan CD, Harman RRM (1959) Studies in contact der-
be tested as a mix (Bruze 1985, 1988). matitis. X. Sensitivity to para-tertiary butylphenol.
Phenol-formaldehyde resin included in stan- Trans St John’s Hosp Derm Soc 43:27–32
dard or supplementary test series should be of Castelain PY, Pirious A, Raulot-Lapointe H, Rabaglia JL
the resol type, as this type of resin contains higher (1980) Sensitization to abieto-formo-phenolic resin in
printing ink. Contact Dermatitis 6:145
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phenol-formaldehyde intoxication. A life threatening
occupational hazard. Hum Toxicol 8:247–250
Cronin E (1980) Contact dermatitis. Churchill Livingstone,
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Polyurethane Resins
54
Kristiina Aalto-Korte, Malin Engfeldt, Tuula Estlander, and
Riita Jolanki
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
3 Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
4 Skin Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
5 Skin Problems Caused by PU Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
5.1 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
5.2 Irritant Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
5.3 Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
6 Examination of Dermatoses Caused by PU Chemicals . . . . . . . . . . . . . . . . . . . . . . . 804
7 Prevention of Dermatoses Caused by PU Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . 805
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Keywords
Isocyanates · Diphenylmethane diisocyanate
K. Aalto-Korte (*)
(MDI) · Diaminodiphenylmethane (MDA) ·
Occupational Medicine, Finnish Institute of Occupational Paints · Surface coatings · Glues · Adhesives ·
Health, Helsinki, Finland Foams · Contact urticaria · Toluene
e-mail: kristiina.aalto-korte@ttl.fi diisocyanate (TDI) · Isophorone diisocyanate
M. Engfeldt (*) (IPDI) · Hexamethylene diisocyanate (HDI) ·
Department of Occupational and Environmental Polymeric MDI (PMDI) ·
Dermatology, Skåne University Hospital (SUS), Lund
University, Malmö, Sweden
Dicyclohexylmethane diisocyanate (DMDI) ·
e-mail: malin.engfeldt@med.lu.se Car painters · Paint industry · Casts
T. Estlander
Terveystalo Healthcare Oyj, Helsinki, Finland
e-mail: tuula.estlander@pp.inet.fi
R. Jolanki
Section of Dermatology/Control of Hypersensitivity
Diseases, Finnish Institute of Occupational Health (FIOH),
Helsinki, Finland
e-mail: riitta.jolanki@hiy.fi

https://doi.org/10.1007/978-3-319-68617-2_53
800 K. Aalto-Korte et al.
1 Core Messages 1989; Estlander et al. 1992; Mancuso et al. 1996;

Schroder et al. 1999; Goossens et al. 2002; Frick
• Polyurethane (PU) products are formed by et al. 2003a, b; Valks et al. 2003; Morgan and
reacting a di- or polyfunctional isocyanate Haworth 2003; Liippo and Lammintausta 2008;
with a polyol in the presence of suitable cata- Stingeni et al. 2008). Allergic contact dermatitis
lysts and additives. from isocyanates is not necessarily extremely rare,
• The most feared PU-associated occupational as for example in Finland, occupational allergic
disease is isocyanate-induced asthma, and pre- contact dermatitis due to isocyanates is nowadays
ventive measures in work places have been almost twice as common as occupational isocya-
focused to decrease respiratory exposure to nate asthma.
isocyanates.
• Isocyanates in PU hardeners are also a relatively
important cause of occupational allergic contact 3 Composition
dermatitis, at least in some countries. The typi-
cal location is hands and face. Occupational PUs are formed as a result of a condensation or an
allergic contact dermatitis is most commonly adduction reaction between isocyanates and
induced by diphenylmethane diisocyanate multifunctional alcohols (polyols). Isocyanates
(MDI)-based products. Chemicals in PU resins can be classified based on the number of –NCO
are also skin irritants. Isocyanate-induced con- groups in the molecule (i.e., monoisocyanates
tact urticaria is a very rare disease. contain one –NCO, diisocyanate contains two
• When patch testing workers exposed to poly- –NCO, and polyisocyanates contain multiple
urethane chemicals, it is advisable to test with –NCO groups). The chemical structures of the
their own work material in addition to the most common diisocyanate monomers and their
commercially available patch-test preparations technical grade counterparts are shown in Fig. 1.
of diisocyanates. A second reading on day Di- and polyisocyanates form thermosetting end
seven is advisable since positive reactions products when reacting with polyols. Generally
may appear late. Positive reactions to the polyols are polyesters or polyethers with ter-
methylenedianiline (MDA) (also known as minal hydroxyl groups, or castor oil or tall oil with
diaminodiphenylmethane) should be taken secondary hydroxyl groups, but other compounds
into account as it is an important marker for containing active hydrogen atoms such as water
MDI sensitivity. and amines can also serve as polyols. Isocyanates
can also be classified as either aromatic
(containing one or more aromatic rings) or ali-
2 Introduction phatic. The aromatic isocyanates dominate the
market. The most commonly used aromatic
Poluyurethanes (PUs) are used in a wide range of diisocyanate is diphenylmethane diisocyanate
products including paints, glues, castings, surface (MDI) followed by toluene diisocyanate (TDI).
coatings, adhesives, and soft and rigid foam. The They are frequently used in the production of
main occupationally hazard associated with PU rigid and flexible foam but also in coatings, adhe-
chemicals are isocyanates, which are known to sives, binders, and elastomers. Aliphatic isocya-
affect the airways and eyes and can cause rhinitis, nates such as isophorone diisocyanate (IPDI) and
asthma, hypersensitive pneumonitis or alveolitis, hexamethylene diisocyanate (HDI) are generally
conjunctivitis, and chronic obstructive lung dis- more expensive to produce, but they are used
ease (Baur et al. 1994; Klees and Ott 1999). when the performance of aromatic isocyanates is
Exposure to isocyanates and auxiliary inadequate, mainly because of their tendency to
chemicals may also result in both allergic and undergo oxidative discolouration upon exposure
irritant contact dermatitis, as well as contact urti- to light and moisture (Ulrich 2001). Due to their
caria (Rothe 1976; Malten 1984; Kanerva et al. light and weather resistance, the aliphatic
54 Polyurethane Resins 801
Aromatic isocyanates
Monomers Technical grade products
NCO
OCN NCO OCN

NCO n=0-4
Diphenylmethane-4,4⬘-diisocyanate (4,4⬘-MDI)
Polymeric MDI (PMDI)
NCO OCN NCO
+
NCO
Toluene diisocyanate (2,4- & 2,6-TDI)
Aliphatic isocyanates
Monomers Technical grade products

R\s1
NCO
OCN O N O R1 represents either
HDI or IPDI
1,6-Hexamethylene diisocyanate (1,6-HDI) N N
R1 R\s1 R2 represents HDI
NCO O
Isocyanurate/trimer
NCO
O R2
Isophorone diisocyanate (IPDI) O NH
R2 N N R2 H
N N
R2 R2
O
O
OCN NCO Uretdione/dimer Biuret
Dicyclohexylmethane-4,4⬘-diisocyanate (4,4⬘-DMDI)
Fig. 1 Chemical formulae of various isocyanates used in the production of polyurethane plastics
isocyanates are commonly used in lacquers, coat- molecular weight molecules with more than two
ings and paints. The production of both aromatic –NCO groups), and they are often referred to as
and aliphatic diisocyanates is mainly based on polyisocyanates of the diisocyanate monomer.
synthesizing the corresponding molecular struc- TDI is industrially available as mixtures of the
ture with primary amine groups. The amino 2,4- and 2,6-TDI isomers at ratios of 80:20 or
groups are then transformed into isocyanate 65:35 (2,4:2,6) or as pure 2,4-TDI (Fig. 1). Com-
groups by treatment with phosgene (Thorpe mercial MDI products generally contain a com-
2002). plex mixture of 25–80% monomeric 4,40 -MDI as
In industry, technical grade isocyanate prod- well as oligomers containing predominately 3–6
ucts are mainly used. They often consist of a aromatic rings, but also smaller amounts of olig-
mixture of isomers of monomers (i.e., omers containing a higher number of rings
diisocyanates) and oligomers (i.e., higher (Fig. 1). They also contain low amounts of the
monomeric isomers 2,20 -MDI and 2,40 -MDI which has led to strict regulations regarding occu-
(Anonymous 2001). These MDI mixtures are usu- pational exposure limits for airborne isocyanates
ally referred to as polymeric MDI (PMDI), but the in order to avoid adverse health effects on the
synonyms crude MDI and polymethylene poly- respiratory tract. Monomeric diisocyanates with
phenyl isocyanate (PAPI or PMPPI) are some- high vapor pressures, such as TDI, IPDI, and HDI,
times also used. Phenyl isocyanate has been cause airborne exposure already at room tempera-
reported as a trace constituent in commercial ture. MDI and most prepolymers, on the other
MDI products (Karol and Kramarik 1996). Tech- hand, have low vapor pressures and are only vola-
nical products of HDI and IPDI are often produced tile at elevated temperatures. Isocyanate exposure
by reacting the monomeric isocyanates either with has also been reported in spraying applications, in
themselves (di- or trimerization) forming which exposure to isocyanates with low vapor
uretdiones, biurets, and isocyanurates or with urea pressures becomes significant even at room tem-
or urethane compounds to form higher molecular perature (Crespo and Galan 1999).
weight polyisocyanates (Thorpe 2002) (Fig. 1). Direct skin contact while handling uncured
The monomer content in the technical products of isocyanate-containing PUR hardeners is probably
IPDI and HDI is generally low (Marand et al. the exposure that leads to skin sensitization.
2004). Completely hardened polyurethane products usu-
Several auxiliary substances are also used in ally do not cause skin problems. Unreacted isocy-
the manufacturer of PU products. The hardening anate monomer may, however, remain in excess
process can be modified by heat or with a catalyst, inside polyurethane foams even after curing. This
usually tertiary amines and/or organometallics can create a health hazard due to isocyanate expo-
(primarily tin compounds) (Zimmerman 2002). sure when polyurethane dust is produced during
Other additives, e.g., fire retardants, fillers, color- machining or cutting (Emmett 1976; Kanerva
ing agents, and cross-linking agents can be added et al. 1997). Additionally, processing of PUR
to modify the polyurethane reaction as well as the materials at temperatures above 150 C causes
properties of the final product. In the production thermal degradation, which leads to dissociation
of foamed plastics, blowing agents, e.g., pentane, of the PUR into a complex mixture of isocyanates,
carbon dioxide, or water, are also added (Anony- amines, and aminoisocyanates (Karlsson et al.
mous 1996). When used as activators or hard- 2001). The possibility of airborne symptoms
eners, diisocyanates are often dissolved in must be taken into account in patients with contact
aliphatic or aromatic hydrocarbon solvents or a allergy to isocyanates.
mixture of different organic solvents, e.g., ali- Concerns have been raised about the role of
phatic hydrocarbon solvents, petroleum, and skin exposure from isocyanates in the develop-
butyl acetate. Adhesives, varnishes, and paints ment of occupational asthma (Bello et al. 2008),
may also contain solvents. and animal studies have shown that animals sen-
sitized by dermal contact alone exhibit respiratory
response upon inhalation of isocyanates (Rattray
4 Skin Exposure et al. 1994). Thus, protection against direct skin
contact might even prevent isocyanate-induced
Exposure to isocyanates is mainly an occupational asthma.
problem that occurs in work places where isocy-
anates or PUR are manufactured and processed.
However, there have recently been reports 5 Skin Problems Caused by PU
describing isocyanate exposure in domestic set- Chemicals
tings (Militello et al. 2004; Morgan and Haworth
2003). Exposure to isocyanates may result in both aller-
The most hazardous occupational exposure has gic and irritant contact dermatitis, as well as con-
been considered to occur through inhalation, tact urticaria (Larsen et al. 2001; Goossens et al.
2002; Valks et al. 2003; Stingeni et al. 2008), and et al. attributed this to cross-sensitivity, referring
the typical location of allergic contact dermatitis is to Thorne et al. who investigated MDI, TDI, HDI,
hands and face. and DMDI and showed cross-reactions between
all isocyanates, regardless of whether they were
aromatic or aliphatic, in animal experiments based
5.1 Allergic Contact Dermatitis on the mouse-ear swelling test (Thorne et al.
1987; Militello et al. 2004). In the same study, it
Diisocyanates are strong contact sensitizers, was postulated that HDI was the most potent
judged by the results of animal studies (Tanaka sensitizer, followed by DMDI, MDI, and TDI in
et al. 1987; Thorne et al. 1987; Hamada et al. declining order of potency (Thorne et al. 1987).
2017a). Animal experiments have also shown MDI-positive patients may also react to the
that polyisocyanate prepolymers are capable of corresponding amine methylenedianiline (MDA)
causing skin sensitization in guinea pigs (Zissu (also known as diaminodiphenylmethane)
et al. 1998). (Fregert 1967; Rothe 1976; Estlander et al. 1992;
Heavy exposure to diisocyanates may result in Goossens et al. 2002; Frick et al. 2003b; Liippo
a rapid sensitization after accidental spillage or and Lammintausta 2008; Aalto-Korte et al. 2012).
other heavy exposure (Estlander et al. 1992; In 1967, Fregert was the first to report these
Frick et al. 2003b; Donovan et al. 2009; Engfeldt simultaneous reactions (Fregert 1967). He attrib-
and Pontén 2013; Aalto-Korte et al. 2010). uted this to cross-reactivity. In 1976, Rothe
Contact allergy to MDI, TDI, IPDI, HDI, suggested that MDA might be the actual allergen
dicyclohexylmethane diisocyanate (DMDI), and that it is formed from hydrolysis of MDI
naphthalene diisocyanate (NDI), and trimethyl when MDI comes into contact with the skin
hexamethylene diiosocyanate (TMDI) has been (Rothe 1976). Several reports describe workers
reported (Kanerva et al. 1989; Estlander et al. exposed to MDI with positive patch-test
1992; Rothe 1976; Malten 1984; Schroder et al. reactions to MDA but negative reactions to MDI
1999; Frick et al. 2003a, b; Thompson and Belsito (Estlander et al. 1992; Tait and Delaney 1999;
1997; Belsito 2003; Morgan and Haworth 2003; Goossens et al. 2002; Frick et al. 2003b). In a
Goossens et al. 2002; Mancuso et al. 1996; Liippo recent study where Hamada et al. used the guinea-
and Lammintausta 2008; Aalto-Korte et al. 2012). pig maximization test, animals sensitized to
Most recorded cases were sensitized to MDI or 4,40 -MDI showed cross-reactivity to 4,40 -MDA
DMDI. HDI trimers are novel occupational con- and also to 4,40 -DMDI (Hamada et al. 2017a).
tact allergens (Aalto-Korte et al. 2010). Nowadays MDA is considered an important marker
DMDI has been reported as a very potent der- for MDI hypersensitivity (Estlander et al. 1992;
mal sensitizer (Emmett 1976; White et al. 1983; Goossens et al. 2002; Frick et al. 2003b; Aalto-
Frick et al. 2003a; Donovan et al. 2009). In a Korte et al. 2012). It has been proposed that allergic
company manufacturing medical equipment, reactions to MDA may also represent cross-allergy
13 out of 100 workers were sensitized to DMDI, to p-phenylenediamine (Rothe 1976; Uter et al.
which was used in a glue (Frick et al. 2003a). At a 2002; Engfeldt et al. 2013b; Aalto-Korte et al.
factory making car badges, two out of seven 2012). Recently this was supported in animal testing
workers showed positive patch-test reactions to where guinea-pigs sensitized to PPD showed cross-
DMDI. A case describing allergic contact reactions to 4,40 -MDA (Hamada et al. 2017b).
dermatitis to DMDI in an office environment Other examples of products and tasks or
where DMDI-charged cartridges were used was manufacturing processes which have caused sensi-
described (Kerre 2008). DMDI exposed patients tization and allergic eczema to PU chemicals are
have been reported to show positive reactions to workers exposed to PU chemicals and prepolymers
TDI, HDI, and IPDI without any previously in laboratories (Rothe 1976; Kanerva et al. 1989;
known contact with the substances in question Estlander et al. 1992; Aalto-Korte et al. 2010), in
(Frick et al. 2003a; Militello et al. 2004). Militello paint industry (Aalto-Korte et al. 2010), and in the
manufacture of PUs, car spray painters, adhesive et al. 1999; Valks et al. 2003; Stingeni et al. 2008;
workers, such as those exposed to two-part glues Helaskoski et al. 2015). Prick tests and specific
used by floor layers (Lodi et al. 1993), consolida- IgE have been positive in these patients (Kanerva
tion of brittle ground (Bertrand et al. 1984), in the et al. 1999; Valks et al. 2003; Stingeni et al. 2008;
manufacture of heat exchangers (Engfeldt et al. Helaskoski et al. 2015).
2013a), sealants used to repair cracks in concrete
buildings (Rothe 1995), PU foams in the manufac-
ture of vehicle equipment (Kieć-Świerczyńska 6 Examination of Dermatoses
et al. 2014), and the making of PU casts (Vaichere Caused by PU Chemicals
et al. 1986; Isaksson et al. 2013).
Polyols are not considered to be sensitizers. Examinations should include clinical follow-up of
the symptoms and exploration of the exposing
chemicals, as well as patch testing. Patch testing
5.2 Irritant Contact Dermatitis is necessary to distinguish between sensitization
and irritation caused by PU chemicals. In com-
Isocyanates are described as mild to strong skin mercially available isocyanate series, the patch-
irritants and are listed in material safety data test preparations of TDI and MDI only contain
sheets as skin irritating substances. Liquid mono- one isomer of the respective monomers. There-
mer coming into contact with the skin has been fore, patients are generally tested with the isomers
reported to cause edema and redness if it is not 4,40 -MDI and 2,4-TDI. Patch-test preparations of
immediately washed away (Fisher 1986). Small DMDI is not commercially available but is nor-
epidemics have occurred in certain plants using mally tested as the 4,40 -DMDI isomer. Most
isocyanates. Itchy rash-like eruptions on exposed reports found in literature refer to contact allergy
skin areas in the factory workers who coat car to these specific isomers. However, when previ-
badges with the resin have been reported within ously described, the general abbreviations MDI,
1 week to 6 months of exposure to DMDI (White TDI, and DMDI have often been used. The sig-
et al. 1983). The same was reported in workers of nificance of the various subtypes (i.e., biuret, iso-
a glass-bottle factory, where DMDI was used to cyanurate, and asymmetric) of HDI trimers is still
coat the bottles (Israeli et al. 1981), as well as in the unknown and commercially available test sub-
workers of a PU-molding plant (Emmett 1976). stances are lacking. Allergic reactions to HDI tri-
Irritant dermatitis appearing in a laboratory techni- mers cannot be explained by sensitization to HDI
cian within a few hours of contact with TDI and in a monomer as it has been shown that HDI trimer
repair man have also been described (Rothe 1976). allergic patients are negative in patch-testing to
Irritant dermatitis, in addition to allergic dermatitis the HDI monomer (Aalto-Korte et al. 2010).
from HDI, occurred in the workers of two clothing Isocyanates are highly reactive and their stabil-
mills handling cloths previously coated with an ity in patch-test preparations has been discussed.
antipill finish containing HDI. The eruption was Chemical analysis on commercially available
located typically on the hands and face (Wilkinson patch-test preparations has shown that prepara-
et al. 1991). In Poland, MDI-containing polyure- tions of 2,4-TDI, 1,6-HDI, and IPDI seem to be
thane foam induced irritant contact dermatitis in stable but that the concentration of 4,40 -MDI
10 workers in a vehicle equipment factory declines rapidly in patch-test preparations (Frick
(Kieć-Świerczyńska et al. 2014). et al. 2004; Frick-Engfeldt et al. 2005). The inves-
tigators concluded that patch testing with com-
mercial preparations of 4,40 -MDI could not be
5.3 Urticaria considered reliable and therefore recommended
additional patch testing with the patients’ own
Contact urticaria from isocyanate exposure has fresh work material (Frick et al. 2004). The same
seldom been reported (Israeli et al. 1981; Kanerva recommendation was given by Goossens et al.
(Goossens et al. 2002) when reporting 13 patients performance of protective gloves and clothing are
with positive patch-test reactions to isocyanate- limited, and although nitrile gloves (thickness >
based products and where only one of these 0.3 mm) have been suggested as preferable to latex,
patients reacted to any commercially available studies have shown that isocyanates can be
patch-test preparation of diisocyanates. In the detected underneath both types of glove (Bello
case of MDI, it has been suggested that patch et al. 2007). Thus, Silver Shield® gloves made of
test preparations of PMDI with a monomer con- a multilayer of polyethylene/ethylene vinyl alco-
tent of at least 35% are used instead of prepara- hol/polyethylene give the best protection against
tions of 4,40 -MDI. Additionally, preparations polyurethane chemicals (Forsberg and Mansdorf
should be stored in a freezer, for no longer than 2007). A recent study using a novel penetration
1 year in order to ensure stability (Frick-Engfeldt test method found affordable glove and clothing
et al. 2007). A commercial PMDI patch test prep- materials (natural rubber and nitrile rubber) that
aration is now available. provide adequate protection during short contact
Patch testing workers exposed to polyure- with MDI (Henriks-Eckerman and Mäkelä 2015).
thane chemicals should include relatively fresh Good ventilation, local exhausts, and general
preparations of the most common diisocyanates cleanliness are also essential.
MDI, TDI, HDI, and IPDI as well as MDA,
PMDI, and the actual chemicals to which the
workers have been exposed. It has been pro-
posed that positive reactions to isocyanates References
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Polyester Resins
55
Rosemary Nixon
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
3 Skin Problems from Polyester Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811
4 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
4.1 Unsaturated Polyester (UP) Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
4.2 Saturated Polyester (SP) Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
4.3 Nonoccupational Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
5 Irritant Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
5.1 Skin Testing and Chemical Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 816
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817
Abstract from ancillary components of the resin system,

Polyester resins are one of the largest classes of such as accelerators, catalysts, and inhibitors,
synthetic resins and are used extensively in the than the resins themselves. The small amount
reinforced plastics industry, in water-based of allergic contact dermatitis that does occur
paints, powder coatings, lacquers, automotive from polyester resins is mostly due to unsatu-
cements, and glues. Allergic contact dermatitis rated polyester resins and extremely rarely
from polyester resins is rare. When allergic from saturated polyester resins. Occasionally,
contact dermatitis does occur, it is more often allergic contact dermatitis may occur from
monomers liberated from the hardened resin
or its dust. Irritant contact dermatitis from
C. Higgins · J. Cahill · R. Nixon (*)
Occupational Dermatology Research and Education
polyester resin systems occurs more frequently
Centre, Skin and Cancer Foundation, Melbourne, VIC, than allergic contact dermatitis. Irritant contact
Australia dermatitis and chemical burns may occur from
e-mail: clairelhiggins@gmail.com; additives such as organic peroxides, styrene,
jencahill@hotmail.com; rnixon@occderm.asn.au
and acetone. Contact urticaria is well known to
R. Jolanki occur from acid anhydrides.
Section of Dermatology/Control of Hypersensitivity
Diseases, Finnish Institute of Occupational Health (FIOH),
Helsinki, Finland
e-mail: riitta.jolanki@hiy.fi

https://doi.org/10.1007/978-3-319-68617-2_54
Keywords reaction between polybasic dicarboxylic acids

Polyester resin · Unsaturated polyester · or their anhydrides (mainly phthalic anhydride,
Saturated polyester · Alkyd · Catalyst · maleic anhydride, or fumaric acid) with polyal-
Inhibitor · Cross linker · Hardener · cohols (such as glycerol, propylene glycol,
Plasticizer · Powder · Anhydride · Cobalt · diethylene glycol, neopentyl glycol, or tri-
Organic peroxide · Benzoyl peroxide · Phthalic methylolpropane). They may be modified by
acid · Styrene · Triglycidyl isocyanurate · Para- oil-containing fatty acids or chemically cross-
tertiary butyl catechol occupational · Allergic linked with curing agents such as isocyanates to
contact dermatitis · Contact allergy · improve thermal and chemical stability (Kanerva
Sensitization · Irritant contact dermatitis · et al. 1996a; Björkner 2006). Saturated polyester
Contact urticaria · Patch test · Airborne resins are commonly used as plasticizers, in
paints and powder coatings, adhesives, and sur-
face coatings. They are used in optical equipment
1 Core Messages for their clarity and color stability (Elliot 1993).
Polyethylene terephthalate (PET) is one of the
• Allergic contact dermatitis from polyester best known members of the saturated polyester
resins is rare. resin family and is used in plastic water bottles,
• Irritant contact dermatitis from polyester resin containers for liquids and foods, and in synthetic
systems occurs more frequently than allergic textile fibers, where it is simply called
contact dermatitis. “polyester.”
• Allergic reactions are more likely to occur Unsaturated polyester (UP) resins are pro-
from ancillary components of the resin system, duced through an esterification reaction of poly-
such as cobalt octoate and benzoyl peroxide, basic dicarboxylic acids or their anhydrides with a
than the resins themselves. diol, such as diethylene glycol or 1,2-propylene
• When allergic contact dermatitis occurs from glycol (Fig. 1). They are versatile materials and
polyester resins, it is mostly due to unsaturated are used extensively in the reinforced plastics
polyester resin monomers and extremely rarely industry in the manufacture of products for trans-
from saturated polyester resins. portation, construction, and marine applications.
• Irritant contact dermatitis and chemical burns They are also used for coatings, finishes, lacquers,
may occur from additives such as organic per- cements, and glues (Kanerva et al. 1996a;
oxides, styrene, and acetone. Björkner 2006).
• Contact urticaria may occur from acid UP resins are thermoset resins, meaning they are
anhydrides. converted from liquid to solid through the process of
polymerization and once cured cannot be converted
back to their liquid form (Updegraff 1982). The
2 Introduction cross-linking or polymerization process occurs
when the double bond of unsaturated polyesters
Polyesters are one of the largest classes of syn- reacts with a vinyl monomer, resulting in a three-
thetic resins and have widely varying properties dimensional cross-linked structure. Styrene is the
depending on their composition. Polyester resins most commonly used monomer for the cross-linking
are polycondensates which are prepared in two of UP resins. Other cross-linking agents include
different forms: saturated and unsaturated resins. vinyl toluene and methyl methacrylate. The cross-
They are cost-effective to produce and have many linking reaction is initiated through a catalyst
desirable properties such as stiffness, toughness, (or hardener), which is usually an organic peroxide
heat resistance, and stability (Elliot 1993). such as benzoyl peroxide or methyl ethyl ketone
Saturated polyester (SP) resins, also termed peroxides, ultraviolet (UV) light, or a combination
alkyd or unmodified alkyd resins, are thermo- of the two. An inhibitor such as hydroquinone or
plastic resins manufactured by a condensation para-tertiary butyl catechol is added in small
55 Polyester Resins 811
Fig. 1 Unsaturated O
polyester resin is made by O
CH3 CH C C
condensing
1,2-propanediol, maleic O O
HO CH CH2 OH + +
anhdyride, and phthalic CH C C
anhydrides. Styrene is used O
O
as a cross-linking monomer
1,2-propanediol maleic anhydride phthalic anhydride
− H2O
CH3
O O CH3 O O
O CH CH2 O C CH CH C O CH CH2 O C C
n
unsaturated polyester resin

CH CH2
+
styrene
CH3 O O CH3 O O
n
HC
CH3 O CH2 O CH3 O O

n
cured polyester resin
quantities to prevent premature polymerization,

improve resin stability, prolong shelf life, and mod- 3 Skin Problems from Polyester
ify cure rate to prevent cracking of thick moulded Resins
sections (Cassis and Talbot 1998). Accelerators,
such as cobalt naphthenate or octoate, or tertiary The vast majority of skin problems from polyes-
amines such as dimethyl aniline, diethyl aniline, ter resins occurs in the occupational setting and
and dimethyl-p-toluidine, is also necessary for the may occur via direct contact or airborne expo-
curing of plastics at room temperature. sure (Tarvainen et al. 1995b). The incidence of
The UV-curable polyester system is used in ACD from polyester resins is low, with the most
the furniture industry as a top coating and for common sensitizers being ancillary chemicals
orthopedic casts and contains vinyl toluene as such as the organic peroxides and cobalt
the cross-linking agent and a benzoin-ether mol- naphthenate/octoate (Rietschel et al. 2008). Indi-
ecule as a photo-initiator (Kanerva et al. 1996a; vidual components of polyester resin systems
Björkner 2006). A plasticizer such as dibutyl/ reported to have caused ACD are summarized
dioctyl phthalate or tricresyl phosphate may be in Table 1. Most cases of occupational dermato-
added to alter the mechanical properties of the ses from polyester resins are of the irritant type
UP resin and make it more flexible. Other ancil- (Rietschel et al. 2008). ICD may occur from
lary components in UP resin systems include cyclic acid anhydrides, propylene glycol, sty-
pigments, stabilizers, fillers, flame retardants, rene, acetone, fiberglass, and the polyester resin
and UV-protecting agents. dust itself.
Table 1 Reported causative allergens in polyester resins Table 1 (continued)

Actual allergen in resin Cobalt salts Bhushan et al. (1998),
Maleic acid Malten and Zielhuis Minamoto et al. (2002a),
(1964) and Aalto-Korte and
Fumaric acid Malten and Zielhuis Suuronen (2016)
(1964) Cobalt naphthenate Key et al. (1961), Bourne
Adipic acid Malten and Zielhuis and Milner (1963), Malten
(1964) and Guin (2001) and Zielhuis (1964),
Kadlec et al. (1974),
Adipic polyester Sowa et al. (2005)
Schena et al. (1995),
Phthalic anhydride Malten and Zielhuis Tarvainen et al. (1995b),
(1964), Lidén et al. (1984), and Tarvainen (1996)
and Tarvainen et al.
Cobalt octoate (cobalt-2- Kanerva et al. (1996b),
(1995b)
ethylhexanoate) Anavekar and Nixon
Maleic anhydride Minamoto et al. (2002b) (2006), and Cahill and
Methyl tetrahydrophthalic Kanerva et al. (1997) Andersen (2010)
anhydridea Dimethyl aniline Wehle (1966)
Polyethylene Lung et al. (2009) Dimethyl-p-toluidine Haddad et al. (1996)
terephthalatea
Terephthalic acid Geier et al. (2001)
Maleic esters Minamoto et al. (2002b) diglycidylestera
and Malten (1984)
Inhibitors
Polyester methacrylate Bjlyeste (1982)
Hydroquinone Wehle (1966) and Torres
Methyl methacrylate Wehle (1966) et al. (1993)
Diethylene glycol maleate Tarvainen et al. (1993a), Para-tertiary butyl Freeman (1986),
Kanerva et al. (1999b), catechol MacFarlane et al. (1990),
and Pfäffli et al. (2002) Estlander et al. (1998), and
Cross-linking monomers Minamoto et al. (2002a)
Styrene Key et al. (1961), Bourne Plasticizers
and Milner (1963), Sjöborg Pthalates (dibutyl/ Malten and Zielhuis
et al. (1982), and Conde- dimethyl/dioctyl (1964) and Malten (1984)
Salazar et al. (1989) phthalate)
Vinyltoluene Sjöborg et al. (1982) Tricresyl phosphate Key et al. (1961)
Triglycidyl isocyanuratea Nishioka et al. (1988), Other
Mathias (1988), Dooms-
Phthalic anhydride/ Moffit and Sansom
Goossens et al. (1989),
trimellitic anhydride/ (2002), Gach et al. (2005),
Munro and Lawrence
ethylene glycol/ neopentyl and Nassif et al. (2007)
(1992); Foulds and Koh
glycol monomers (PTGC)
(1992), McFadden and a
Rycroft (1993), and Aalto- Saturated polyester (SP) resin allergens
Korte and Suuronen (2016)
Hardening catalysts
Benzoyl peroxide Bourne and Milner (1963), Although saturated polyester resins are not
Malten and Zielhuis generally considered to be sensitizing, cyclic
(1964), Vincenzi et al.
(1991), Minamoto et al.
acid anhydrides, particularly phthalic anhydrides,
(2002a), and Tsovilis et al. have been reported to cause irritant contact der-
(2005) matitis (ICD) (Malten and Zielhuis 1964) and are
Cyclohexanone Malten (1964) a well-known cause of immediate IgE-mediated
hydroperoxide hypersensitivity manifesting as asthma, allergic
Methyl ethyl ketone Bourne and Milner (1963), rhinitis, and contact urticaria (Jolanki et al. 1987,
peroxide Malten and Zielhuis
(1964), Stewart and Beck 1997; Tarvainen et al. 1995a; Kanerva et al.
(1992), Bhushan et al. 1999a, 2000). A recent case series from the Finn-
(1998), and Minamoto ish Institute of Occupational Health (FIOH)
et al. (2002a) described 21 patients with contact urticaria from
(continued) cyclic acid anhydrides, including one case caused
by maleic acid anhydride in the production of poly- less sensitizing than epoxy resins (Malten and
ester resins (Helaskoski et al. 2009). In one case of Zielhuis 1964).
contact urticaria caused by methyl hexa- ACD was first reported from UP resins in 1955
hydrophthalic anhydride, the reaction was (Lieber 1955). Five patients with ACD and posi-
enhanced by wiping off the substance with an alco- tive patch tests to UP resins were reported from a
hol disinfectant, which was presumed to enhance group of 30 workers in an airplane factory (Malten
penetration of the allergen (Kanerva et al. 1999a). 1956). Most cases of ACD from UP resins have
There are only rare reports of cyclic acid anhydrides been reported in lamination workers (Malten
causing ACD (Kanerva et al. 1997). 1956; Bourne and Milner 1963; Lidén et al.
Various inhibitors of UP-resin systems are 1984), painters (Kadlec et al. 1974), and in those
known to induce contact leukoderma/vitiligo. working with UV light-cured inks (Björkner
Horio et al. (1977) described occupational 1982). Other common occupational causes of
leukoderma from para-tertiary butyl catechol ACD from UP resins include in automotive repair
(PTBC) in a polyester resin plant worker. Moroni putties (Aalto-Korte and Suuronen 2016), in the
and Tomasini (1992) reported a case of contact manufacture of UP cement and resin moulds
leukoderma likely resulting from hydroquinone, (Tarvainen et al. 1993a; Kanerva et al. 1999b)
parabenzoquinone, and PTBC used as inhibitors and in workers in the fiberglass-reinforced plastics
in fiberglass-reinforced polyester resin for boat industry (Tarvainen et al. 1993b, Minamoto et al.
building. 2002a, b).
Most reports of skin problems from polyester Guin (2001) reported a machine repairman
resins involve workers in the reinforced plastics who had developed ACD from adipic acid while
and plastic composites industries, for example, working in the synthesis of polyester resins.
workers involved in lamination and moulding of Adipic polyester, produced from adipic acid and
boat and airplane components (Tarvainen et al. propylene glycol, is a thermoplastic polyester
1995b; Minamoto et al. 2002a). Other at-risk occu- used as a plasticizer in vinyl gloves and has also
pations include automotive repair workers using caused ACD (Sowa et al. 2005).
UP-resin based car putties and cements and those The FIOH previously described eight cases of
working with powder paints (Kanerva et al. 1999b; occupational contact allergy caused by UP-resin
Aalto-Korte and Suuronen 2016). In the fiberglass- car putties/cements (Tarvainen et al. 1993a;
reinforced plastics (FRP) industry, occupational der- Kanerva et al. 1999b), in several of whom, the
matoses may be due to a number of causative causative allergen was identified as diethylene
agents, including UP resin, ancillary resin glycol maleate (DEGM). The FIOH has recently
chemicals, glass fiber, and dust comprising glass published a case series of 11 new patients with
fiber and UP-resin particles (Minamoto et al. occupational contact allergy to components of
2002a). polyester resin systems (Aalto-Korte and
Suuronen 2016). Of these, five reacted to
UP-resin car putties (although chemical analysis
4 Allergic Contact Dermatitis was not performed to identify the causative aller-
gen), three to cobalt salts used as catalysts, and
4.1 Unsaturated Polyester three to triglycidyl isocyanurate (TGIC) used a
(UP) Resins curing agent in polyester powder spray paints.
Although rates of ACD from polyester resins
Despite UP resins being used extensively in the remain low, automotive body repair workers
reinforced plastics industry and in applications appear to be one of the at-risk populations.
such as surface coatings, paints, cements, automo-
tive putties, and glue, there are only infrequent 4.1.1 Hardened Resin
cases of ACD from UP resin described in the Although for some years it was believed that
literature. Unsaturated polyester resins are far hardened resin contained no reactive monomers,
several authors have demonstrated otherwise. In Bourne and Milner 1963; Malten and Zielhuis
a chemical analysis of polyester resin dust, 1964; Kadlec et al. 1974; Tarvainen et al. 1995b;
dibutyl phthalate was shown to comprise 3.5% Tarvainen 1996). Lymphomatoid-like allergic
of the cured resin (Bourne and Milner 1963). contact dermatitis in a marble worker was
Small amounts of unreacted DEGM were identi- reported from cobalt naphthenate (Schena et al.
fied in UP-resin car putties (Tarvainen et al. 1995).
1993a; Pfaffli et al. 2002). Free phthalic anhy-
dride causing ACD has been identified in the dust Organic Peroxides
from a hardened UP-resin glue (Tarvainen et al. ACD from organic peroxides used as polyester
1995b). resin catalysts was first described in the 1960s.
ACD has been reported from the dust of UP Early case reports include ACD caused by ben-
resin in reinforced plastic products (Bourne and zoyl peroxide (Bourne and Milner 1963; Malten
Milner 1963; Tarvainen et al. 1993b, 1995b) and and Zielhuis 1964), cyclohexanone hydroperox-
car repair putty (Tarvainen et al. 1993a; Kanerva ide (Malten 1964), and methyl ethyl ketone
et al. 1999b; Dooms-Goossens and De Jonge hydroperoxide (Bourne and Milner 1963; Malten
1985). Grinding the resin can give airborne and Zielhuis 1964). More recently, ACD has been
allergic reactions many years after it has been reported from benzoyl peroxide in a prosthetic
hardened (Kanerva et al. 1999b; Pfäffli et al. limb (Vincenzi et al. 1991) and in a marble glue
2002). (Tsovilis et al. 2005) and from methyl ethyl
ketone peroxide in a polyester spray paint (Stew-
4.1.2 Ancillary Chemicals art and Beck 1992). In one report, a worker pro-
ducing moulded children’s rides from fiberglass-
Vinyl Monomers reinforced plastic was found to have occupational
ACD has been reported from styrene, which is the ACD caused by both methyl ethyl ketone perox-
most commonly used cross-linking monomer in ide and cobalt but not by the UP resin itself
the production of UP resins (Key et al. 1961; (Bhushan et al. 1998).
Bourne and Milner 1963; Sjoborg et al. 1982;
Conde-Salazar et al. 1989). Inhibitors
Para-tertiary butyl catechol (PTBC), which is
Cobalt used as an inhibitor for polyester resin systems,
Cobalt salts including cobalt naphthenate and is a rare occupational allergen. There are a few
cobalt octoate (cobalt-2-ethylhexanoate) are used case reports of ACD caused by PTBC in the
as hardening catalysts for polyester resins. Cobalt literature (Estlander et al. 1998; Minamoto et al.
octoate is a metal salt of carboxylic acid. When 2002a), notably several from prosthetic limbs
combined with a catalyst such as benzoyl perox- (Freeman 1986; MacFarlane et al. 1990). How-
ide, cobalt octoate enables the curing of unsatu- ever, the FIOH was found PTBC to be one of the
rated polyester resins at room temperature most common causes of active sensitization,
(Foussereau et al. 1982; Anavekar and Nixon alongside acrylates and para-phenylenediamine
2006). Occupational ACD has been reported (Estlander 1998). As a result, in the late 1990s,
from cobalt octoate used as a paint drying com- they lowered their patch test concentration from
ponent in a paint/ink used by an offset printer 1% to 0.25%.
(Kanerva et al. 1996b) and as an accelerator in
polyester resin used by a spa bath laminator Plasticizers
(Anavekar and Nixon 2006) and a boat builder ACD has been reported from dibutyl phthalate,
(Cahill and Andersen 2010). Occupational ACD dimethyl phthalate, and dioctyl phthalate (Malten
from cobalt naphthenate used as an accelerator in and Zielhuis 1964), in addition to tricresyl phos-
unsaturated polyester resins has also been phate, which are used as plasticizing agents
reported by multiple authors (Key et al. 1961; (Key et al. 1961).
4.2 Saturated Polyester (SP) Resins More recently, several authors have described
a case series of ACD from an original polyester
4.2.1 Resin Allergens resin compound comprising phthalic anhydride,
The phthalic anhydrides have been reported to trimellitic anhydride, ethylene glycol, and neo-
cause IgE-mediated respiratory diseases and con- pentyl glycol monomers (termed PTGC), which
tact urticaria but rarely ACD. Kanerva et al. is used as an alternative to toluene sulfonamide
(1997) reported the case of a boring machine formaldehyde resin in some nail polishes (Moffit
worker who developed ACD, in addition to aller- and Sansom 2002; Gach et al. 2005; Nassif et al.
gic rhinitis and an immediate contact skin reac- 2007).
tion, from methyl tetrahydrophthalic anhydride.
Lung et al. (2009) described a 4-year old boy
with ACD caused by a polyethylene terephthalate 5 Irritant Contact Dermatitis
(PET) mesh in a cochlear implant.
Multiple chemicals used in the production of
4.2.2 Cross-Linking Agents polyester resins, and the resins themselves,
Triglycidyl isocyanurate (TGIC) is a tri- have been reported to cause ICD. In one work-
functional epoxy compound used as a cross- place study, ICD was reported from both
linking agent in saturated polyester resin-based chemicals and mechanical irritants such as glass
powder spray paints and automotive coatings. fiber and dust created in the production of
There are reports of occupational ACD to TGIC fiberglass-reinforced polyester resin (Minamoto
in factory workers producing the raw chemical et al. 2002a). In a study of 43 workers with
(Nishioka et al. 1988), in workers manufacturing occupational dermatoses employed in the plas-
polyester powder paints (Munro and Lawrence tics composite industry, 21 were diagnosed with
1992; Foulds and Koh 1992), and in spray pain- ICD; in 2 cases this was due to dust from ground
ters using polyester powder paints (Mathias UP resin, in 1 case due to solvent, and in 18 cases
1988; Dooms-Goossens et al. 1989; McFadden due to glass fiber used in fiberglass-reinforced
and Rycroft 1993; Aalto-Korte and Suuronen polyester resin (Tarvainen et al. 1995b).
2016). ICD has been reported from the cross-
Geier and colleagues (2001) described the case linking styrene monomer (Rietschel and Fowler
of a factory worker with airborne ACD to 2008) or, in earlier times, diallylphthalate
terephthalic acid diglycidylester used as a hard- (Fregert 1971). Styrene is classified as a mild
ener in a polyester resin-based powder spray irritant, although it has been reported to cause
coating. blisters (Bourne and Milner 1963) and even
chemical burns (Bruze et al. 2000). Prolonged
exposure to styrene has caused a case of skin
4.3 Nonoccupational Sources atrophy, neurogenic muscular atrophy, and anx-
iety reaction (Araki et al. 1971). Levels of
Nonoccupational ACD from UP resin is infre- styrene vapor exceeding 300 ppm (1260
quent but has been reported from “hypoaller- mg/m3) have been reported to induce erythema
genic” nail varnish (Shaw 1989), UP glue used of the skin (Stewart et al. 1968). Even at levels
domestically (Sjoborg et al. 1982), and limb pros- of 50 ppm (215 mg/m3), styrene vapor may
theses. Several authors have described ACD from irritate conjunctival and nasal mucous mem-
components of polyester resin-based limb pros- branes (Gotell et al. 1972). It is thought that
theses, including to the UP resin itself the vinyl group in styrene is responsible for
(MacFarlane et al. 1986), to the inhibitor PTBC causing the mucous membrane irritation (Alarie
(Freeman 1986; MacFarlane et al. 1990), to ben- 1973). However, workers may develop a toler-
zoyl peroxide (Vincenzi et al. 1991), and to ance to the irritation after prolonged exposure
dimethyl-p-toluidine (Haddad et al. 1996). (Gotell et al. 1972).
Phthalic anhydride used in the manufacture of 5% (Kanerva et al. 1999b); however it is not
polyester resins can cause ICD, and even caustic clear at what concentration active sensitization
blisters especially on moist skin, where the anhy- occurs. Aalto-Korte and Suuronen (2016)
dride is transformed into the corresponding acid recommended that the UP-resin component of
(Malten and Zielhuis 1964). polyester car putties and lamination resins be
Organic peroxides such as hydrogen peroxide tested at 5% in petrolatum, that polyester powder
and benzoyl peroxide are used as 3–10% solutions paint be tested at 10% and cured polyester putty/
to catalyze the hardening reactions of UP resins. dust at 20%.
They are weak sensitizers but strong irritants Benzoyl peroxide is traditionally tested at
(Haustein et al. 1985; Mora Morillas et al. 1987; 1% in petrolatum. Patch testing with benzoyl
Aguirre et al. 1994; Kanerva et al. 1998). In the peroxide can be problematic as it can be chal-
plastic composite industry, organic peroxides have lenging to discriminate irritant reactions from
caused severe ICD (Bourne and Milner 1963). weak positive allergic reactions (Ockenfels
Reactive organic peroxide molecules in et al. 2009). The IVDK trialed parallel patch
unhardened resin dust may cause stinging on testing benzoyl peroxide at 1% and 0.5% for a
uncovered areas of the skin during spray lamina- 6-month period from 1993 to 1994. The results
tion (Schumes 1990). Patients with atopic derma- showed that decreasing the concentration
titis are particularly prone to irritant reactions from halved the proportion of positive reactions but
benzoyl peroxide (Ockenfels et al. 2009). Hydro- did not improve the reaction index or positivity
gen peroxide is also an irritant but very rarely an ratio; thus interpretation was not made easier.
allergen (Aguirre et al. 1994; Kanerva et al. 1998). As such, the German Contact Dermatitis
In addition to chemicals included in the resin Research Group (DKG) has maintained the
system, mould-release agents (chemicals which higher patch test concentration in their test
produce a slip effect between the resin and the series (Ockenfels et al. 2009). A similar phe-
mould) have also caused ICD (Bourne and Milner nomenon was observed by Geier et al. (2003)
1963). Acetone dissolves liquid UP resin and is when testing with the rubber chemical
used to clean equipment and spills in UP-resin N-(cyclohexylthio)phthalimide.
industries. With repeated contact, acetone may Erikstam and colleagues (2001) conducted
defat the skin and disrupt the epidermal barrier chemical analyses showing that degradation of
(Fartasch 1997), and it has been reported to be a TGIC used in their patch test preparation was
contributing factor for ICD in the moulded poly- the cause of a false-negative patch test reaction.
ester resin industry (Bourne and Milner 1963; Retesting with a new preparation of fresh TGIC
Tarvainen et al. 1993b, 1994). Chlorinated hydro- powder yielded a positive result. They
carbon solvents such as methylene chloride and recommended that if a false-negative reaction
trichloroethane are often used for cleaning pur- occurs in the setting of high suspicion of an
poses and are also skin irritants (Midtgard and allergen, the patient should be retested with a
Knudsen 1994). new patch test preparation of fresh material, in
addition to their own materials.
When allergy to polyester resins is suspected, it
5.1 Skin Testing and Chemical is important to test with specialized patch test
Investigations series, in addition to the patient’s own products.
A retrospective review by Shmidt et al. (2010)
UP resins have been patch tested at concentra- found that of 193 patients with positive patch
tions of 0.5–10% (Tarvainen et al. 1993a; tests to plastics and glues, 162 of these were
Kanerva et al. 1999b) but also at 20% in acetone only identified using specialized test series and
(Foussereau et al. 1982). It has been suggested would have been missed using the baseline series
that the test concentration may need to be at least alone (Shmidt et al. 2010).
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glycidyl isocyanurate in polyester paint pigments. Con- allergy to styrene with cross reaction to vinyltoluene.
tact Dermatitis 19:67–68 Contact Dermatitis 8:207–208
McFadden JP, Rycroft RJ (1993) Occupational contact Sowa J, Kobayashi H, Tsuruta D et al (2005) Allergic
dermatitis from triglycidyl isocyanurate in a powder contact dermatitis due to adipic polyester in vinyl chlo-
paint sprayer. Contact Dermatitis 28:251 ride gloves. Contact Dermatitis 53:243–244
Stewart L, Beck MH (1992) Contact sensitivity to methyl due to airborne methylhexahydrophthalic and methyl
ethyl ketone peroxide in a paint sprayer. Contact Der- tetrahydrophthalic anhydrides. Contact Dermatitis
matitis 26:52–53 32:204–209
Stewart RD, Dodd HC, Baretta ED, Schaffer AW (1968) Tarvainen K, Kanerva L, Jolanki R, Estlander T (1995b)
Human exposure to styrene vapor. Arch Environ Health Occupational dermatoses from the manufacture of plas-
16:656–662 tic composite products. Am J Contact Dermat 6:95–104
Tarvainen K (1996) Occupational dermatoses from plastic Torres V, Mano-Azul AC, Correia T, Soares AP (1993)
composites based on polyester resins, epoxy resins and Allergic contact cheilitis and stomatitis from hydroqui-
vinyl ester resins. People and Work 11:1–66 none in an acrylic dental prosthesis. Contact Dermatitis
Tarvainen K, Jolanki R, Estlander T (1993a) Occupational 29:102–193
contact allergy to unsaturated polyester resin cements. Tsovilis E, Crépy MN, Jonathan AM, Ameille J (2005)
Contact Dermatitis 28:220–224 Occupational contact dermatitis due to a marbler’s
Tarvainen K, Jolanki R, Forsman-Gronholm L, exposure to benzoyl peroxide. Contact Dermatitis
Estlander T, Pfaffli P, Juntunen J, Kanerva L (1993b) 52:117–118
Exposure, skin protection and occupational skin dis- Updegraff IH (1982) Unsaturated polyester resins. In: Lubin
eases in the glass-fibre reinforced plastics industry. G (ed) Handbook of composites. Springer, Boston
Contact Dermatitis 29:119–127 Vincenzi C, Cameli N, Vassilopoulou A, Tosti A (1991)
Tarvainen K, Estlander T, Jolanki R, Kanerva L (1994) Allergic contact dermatitis due to benzoyl peroxide in
Occupational dermatoses caused by man-made mineral an arm prosthesis. Contact Dermatitis 24:66–67
fibers. Am J Contact Dermat 5:22–29 Wehle U (1966) Arbeitsbedingte Ekzeme durch Polyester.
Tarvainen K, Jolanki R, Estlander T, Tupasela O, Pfaffli P, Allerg Asthma (Leipz) 12:184–186
Kanerva L (1995a) Immunologic contact urticaria
Other Plastics
56
George-Sorin Ţiplica, Letiţia Bucur, Gheorghe Bucur, and
Carmen Maria Sălăvăstru
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822
3 Chemistry, Use, and Skin Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
3.1 Amino Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
3.2 Polyolefins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
4 Occupational Diseases Induced by Plastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
5 Primary and Secondary Prevention Measures in Exposure to Plastics . . . . . 837
5.1 Primary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
5.2 Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
Abstract
Plastics are usually nontoxic and stable in
ambient conditions. Occupational dermatoses
occur mostly during the technological pro-
Gheorghe Bucur: deceased. cesses for producing plastics. Amino-plastics
(e.g., urea-formaldehyde resin, melamine-
G.-S. Ţiplica (*) formaldehyde resin) are of low toxicity. Phe-
Colentina Clinical Hospital, “Carol Davila” University of
Medicine and Pharmacy, Dermatology 2, Bucharest, nol-formaldehyde resins can produce allergic
Romania contact dermatitis in 10% of exposed workers.
e-mail: george.tiplica@umfcd.ro Patch testing to formaldehyde resins gives
L. Bucur false negative results in many cases. Para-ter-
Department of Occupational Health, Belsana Grup LLC, tiary-butyl-phenol-formaldehyde resins are
Bucharest, Romania used mainly as adhesives. Severe allergic skin
e-mail: letitia.bucur@gmail.com
reactions with systemic involvement can occur
G. Bucur in occupational settings. Melamine-formalde-
Bucharest, Romania
hyde resins can be involved in contact dermati-
C. M. Sălăvăstru tis, formaldehyde being the primary irritant and
Colentina Clinical Hospital, “Carol Davila” University of
Medicine and Pharmacy, Pediatric Dermatology, sensitizer. Polycarbonates were reported in iso-
Bucharest, Romania lated cases of orthoergic or allergic contact

https://doi.org/10.1007/978-3-319-68617-2_55
822 G.-S. Ţiplica et al.
dermatitis. Polyamide resins rarely induce skin Polyethylene and polypropylene are the most
allergies or irritation, even in conditions of pro- widely used plastics in the world.
longed contact (e.g., compression stockings for • Amino plastics usually contain formaldehyde,
workers in standing position). Half of the which is both irritating and sensitizing. Contact
workers inadequately protected when exposed and airborne dermatitis were described. Para-
to polyester fibers develop allergic contact der- tertiary-butyl-phenol-formaldehyde resin can
matitis. Styrene acts as primary irritant by also produce occupational vitiligo.
destroying the protective lipid film of the skin • Polycarbonates and polyamide resins rarely
surface. Polyurethane resins are rarely involved induce skin allergies or irritation.
in skin conditions but the resins manufacture • Polystyrene is obtained from styrene – a mild
can cause allergic and irritative dermatitis. Diag- primary irritant. Styrene acts as sensitizer only
nostic skin tests need careful interpretation as in rare situations.
cross-reactivity was described between isocya- • Polyurethanes contain isocyanates known for
nates (components of polyurethane resins) and their sensitizing actions.
their corresponding amines. • Polyolefin resins can induce skin irritation and
Polyolefins (thermoplastic resins obtained allergy. Sicca syndrome and epidermal
by polyaddition of olefins) can be involved in necrolysis were described in workers in contact
occupational contact dermatitis mainly when with polyethylene. Exposure to polypropylene
incompletely cured or in hot conditions due to can modify color perception.
depolimerization. Sicca syndrome and epider- • Polytetrafluoroethylene is a skin irritant.
mal necrolysis were also described.
Primary prevention to occupational derma-
toses induced by plastics involves health and 2 Introduction
safety instruction of the workers and the use of
masks and gloves to avoid contact with the low Plastics are organic macromolecular substances
molecular weight reagents. It is important to made by chains of similar molecules (monomers).
constantly improve the technological process Polymers are plastics made from identical
by the replacement of harmful adjuvants with monomers (in the process of polymerization) and
less dangerous ones. Secondary prevention is polycondensated polymers contain different mono-
performed by the medical team that treats and mers (combined in the reaction of polycondensa-
makes recommendations to the affected tion). Plastics do not have the tendency to
workers. crystallize, are usually nontoxic, and are stable at
ambient conditions. Health risks, including derma-
Keywords toses, are mainly induced by monomers or
Amino plastics · Formaldehyde · Polyolefins · by-products used or produced during the chemical
Contact dermatitis · Anaphylaxis · Vitiligo reactions (hardeners, plasticizers, stabilizers, initia-
tors, accelerators, inhibitors, catalyzers, antioxidants,
coloring agents). Thermic disintegration can produce
1 Core Messages potentially dangerous substances (Rusu 2009).
The rapid development of plastic industry
• Health risks, including dermatoses, are mainly generated an immense number of different types of
induced by monomers or by-products used plastic materials with diverse properties and many
or produced during the polymerization process applications. By nature, polymers can be natural,
(hardeners, plasticizers, stabilizers, initiators, artificial, or synthetics (Table 1). Natural polymers
accelerators, inhibitors, catalyzers, antioxidants, can be found in this form in nature (rubber, cellu-
coloring agents). lose). Artificial polymers are produced using natural
• The general population uses only on rare occa- polymers (ebonite, viscose). Synthetic polymers are
sions incompletely polymerized plastic resins. generated entirely by chemical synthesis and are
56 Other Plastics 823
Table 1 Polymers (e.g., epoxy resins, phenol-formaldehyde resins,

Group of carbamid-formaldehyde resins, acrylic resins, poly-
polymers Examples ester resins); (b) technological processes rarely
1. Natural Rubber, cellulose harmful to the health of exposed workers (e.g.,
polymers polypropylene, polyurethane, polystyrene, siliconic
2. Artificial Rubber derivates: vulcanized rubber, resins, polyvinyl chloride, polycarbonates, polyeth-
polymers ebonite
ylene). Among adjuvants, the most notorious nox-
Cellulose derivates: viscose, cellulose
acetate (zyl), nitrocellulose (flash ious are phthalates (e.g.,dibutyl-, dioctyl-) and
paper) maleates, dimethylaniline, cobalt naphtenate, tolu-
Proteic derivates: casein (galalith) ene sulfonic acid, benzoyl peroxide,
3. Synthetic Thermoplastics: polyolefins, phenylenediamine group, mercaptobenzothiazole
polymers polystyrene, polyacryls and group, epoxy compounds, phenols, and naphthyl-
polymethacryls, polyamides,
polycarbonates, vinyl derivatives amines. Plastics in general are involved in 8% of
Thermostables: amino-plastics, pheno- skin allergies of which 45% are due to epoxy and
plastics, epoxy resin, alchidic resins, acrylic resins, 9% to methacrylic resins, 8% to
polyurethane resins phenol-formaldehyde resin, 4% to urea-
formaldehyde resins, 3% to polyester resin, and
1% to polyurethane resins (Rudzki 1978). The pro-
classified in thermoplastic resins and thermoset cess of plastic recycling can be also harmful for the
resins. Thermoplastic resins are malleable if heated exposed workers as it involves heating of the plastic
and on cooling they become hard and keep their new materials in the processes of heat compression, ther-
shape. Thermoplastic resins are made by linear mal depolymerization, or monomer recycling.
chains of monomers. Thermostable resins are also Recycling codes are used to identify the material
malleable when heated, but overheated they develop from which an item is made, to facilitate easier
a tri-dimensional network generating a rigid recycling or other reprocessing. Such symbols for
material. plastics have been developed by the Society of the
The polymerization or polycondensation pro- Plastics Industry in 1988 and are actually interna-
cess involves many types of adjuvants: curing tionally covered used by the international standard
agents, plasticizers, stabilizers, initiators, acceler- ASTM D7611 (Table 2).
ators and inhibitors, catalysts, antioxidants, color- The general population uses only on rare
ing agents, flavoring agents, etc. Mainly those occasions incompletely polymerized/poly-
adjuvants and not the plastics are responsible for condensed resins: nail varnish containing form-
the occurrence of the majority of occupational aldehyde resins or toluene sulfonamidic resin;
pathology in the plastics industry. The health acrylic artificial nails; dental and orthopedic
risks are generated by exposure during plastics prostheses from acrylic/methacrylic resins;
manufacturing (direct contact with monomer mol- cement and adhesives containing epoxy or form-
ecules and adjuvants). In the case of further pro- aldehyde resins.
cessing or alteration of plastics (grinding, melting, Patch testing of synthetic resins should be
burning, etc.), molecules with irritating or allergic done with caution in order to avoid side effects
potential can be released: phenols, aldehydes, or errors in results interpretation. Acetone is the
acrylonitrile, vinyl chloride, styrene, etc. For this preferred vehicle for urethane monomers and
reason, sensitization among persons working in prepolymers, polyester, and epoxy resins
the plastics industry is four times more common because it does not react with these substances.
than in other industries (Foussereau and Benezra Solutions must always be fresh as acetone is very
1970). volatile. Other vehicles are petroleum jelly, alco-
The technological processes for producing plas- hol, and methyl-ethyl-ketone. Patch testing for
tics can be divided into: (a) technological processes plastics uses PG-1000 Plastic and glues series
highly harmful to the health of exposed workers (Table 3).
Table 2 Plastic identification code (according to the Society of the Plastics Industry and the Plastics and Chemical
Industries Association)
Plastic identification
code Type of plastic polymer Common properties Applications
Polyethylene terephthalate Clarity, strength, Beverage bottles; textile fibers
(PET, PETE) toughness, barrier to
gas and moisture
High-density polyethylene Stiffness, strength, Shopping bags; water pipes;

(HDPE) toughness, resistance to buckets; milk, juice and water
moisture, permeability bottles
to gas
Polyvinyl chloride (PVC) Versatility, ease of Blister packaging for

blending, strength, non-food items; cling films for
toughness non-food use; blood bags;
electrical cable insulation;
rigid piping; vinyl records;
watch straps
Low-density polyethylene Ease of processing, Frozen food bags; squeezable

(LDPE) strength, toughness, bottles; cling films; flexible
flexibility, ease of container lids; garbage bags
sealing, barrier to
moisture
Polypropylene (PP) Strength, toughness, Reusable microwaveable

resistance to heat, ware; kitchenware; yogurt
chemicals, grease and containers; margarine tubs;
oil, versatile, barrier to carpet fiber; toys; caps
moisture
(continued)
Table 2 (continued)
Plastic identification
code Type of plastic polymer Common properties Applications
Polystyrene (PS) Versatility, clarity, Egg cartons; packing peanuts;
easily formed disposable cups, plates, trays
and cutlery; disposable take-
away containers; refrigerator
bins; medical disposables;
dairy containers
Other plastics, including Dependent on polymers Beverage bottles; baby milk

acrylic, acrylonitrile butadiene or combination of bottles. Non-packaging uses
styrene (ABS), fiberglass, polymers for polycarbonate; compact
nylon, polycarbonate, discs; “unbreakable” glazing;
polylactic acid electronic apparatus housings;
lenses; automotive headlamps,
riot shields, instrument panels
Table 3 PG-1000 plastic and glues series

Index Substance Concentration
PG-1 Hydroquinone 1.0 pet
PG-2 Dibutyl phthalate 5.0 pet
PG-3 Phenyl salicylate (Salol) 1.0 pet
PG-4 Diethylhexylphthalate (Dioctylphthalate) 2.0 pet
PG-5 BHT/(2,6-Di-tertiary-butyl-4-cresol) 2.0 pet
PG-6 Drometrizole/(2(2-Hydroxy-5-methyl-phenyl)benzotriazole) 1.0 pet
PG-7 Benzoyl peroxide 1.0 pet
PG-8 4-tertiary-Butyl-catechol (PTBC) 0.25 pet
PG-9 Azodiisobutyrodinitrile 1.0 pet
PG-10 Bisphenol A 1.0 pet
PG-11 Tricresyl phosphate 5.0 pet
PG-12 Phenol formaldehyde resin (P-F-R-2) 1.0 pet
PG-13 4-tertiary-Butyl-phenol formaldehyde resin 1.0 pet
PG-14 Triphenyl phosphate 5.0 pet
PG-15 Toluenesulfonamide formaldehyde resin 10.0 pet
PG-16 Resorcinol monobenzoate 1.0 pet
PG-17 2-Phenylindole 2.0 pet
PG-18 2-tertiary-Butyl-4-methoxyphenol (BHA) 2.0 pet
PG-19 Hydroabietyl alcohol/(Abitol) 10.0 pet
PG-20 4-tertiary-Butyl-phenol 1.0 pet
PG-21 2-Monomethylol phenol 1.0 pet
PG-22 Diphenylthiourea 1.0 pet
PG-23 2- n-Octyl-4-isothiazolin-3-one 0.1 pet
PG-24 Cyclohexanone resin 1.0 pet
PG-25 Triglycidyl isocyanurate 0.5 pet
3 Chemistry, Use, and Skin coatings, waterproof canvas and paper, phone
Problems manufacturing, etc. Phenol-formaldehyde resins
are also used as core in foundries, as stands for
3.1 Amino Plastics chemical laboratories, and as surface sealers.
The manufacturing process of phenol-
Amino plastics are produced by polycondensa- formaldehyde resins can be done with different
tion of aldehydes (such as formaldehyde) with catalysts. Novolac resins are produced in acidic
amines (urea, melamine, thiourea) using heat conditions, resol resins are obtained in alkalinic
curing and an inorganic acid as catalyst (hydro- conditions, and rezitole resins result when alco-
chloric acid, phosphoric acid, etc.). hols and acetone are used as catalysts.
Urea–formaldehyde resin accounts for more To diagnose allergic skin conditions, patch
than 80% of amino plastics; melamine–for- tests can be performed with:
maldehyde resin accounts for most of the rest
(Williams 2002). All amino plastic resins have Resin (whole finished product) 5–10% pet
an excess of formaldehyde that may be gradually Bakelite 10% pet
eliminated. Today amino plastics release much Novolac 5% pet or 20% in
lower quantities of formaldehyde by comparison ethanol
Resol 5% pet or 20% in
with amino plastics produced in the past decades
ethanol
(Belsito 1997). Amino plastics have excellent
Formaldehyde 1–2% aq
solvent resistance and resistance to abrasion and Hexamethylenetetramine 1–2% pet
heat. Their hardness is much appreciated and Furfural 5% aq
they are used in the wood and furniture industry Phenols 2% aq
as surface coatings and adhesives to make ply- PTBP 1% pet (Chemo,
wood, chipboard, and sawdust board. Amino Trolab)
plastics are often reinforced with silica, cloth, 2-MMP = mono-methylol-2- 1% pet
cotton fabric, and glass (Björkner 2000). Both phenol
urea- and melamine-formaldehyde resins are of 4-MMP = methylol- p-phenol 1% in ethanol
low toxicity. Melamine-formaldehyde resins
may be used in paper that contacts aqueous and Skin Problems
fatty foods (Williams 2002). Formaldehyde is both irritating and sensitizing.
Direct contact can produce contact dermatitis
or contact urticaria. Airborne dermatitis was
3.1.1 Phenol-Formaldehyde Resins also described. Many people sensitized to formal-
Phenol-formaldehyde resins are based on phe- dehyde resins do not have positive skin reactions
nols (alkyl phenols, bisphenol-A, cresols, p-ter- to formaldehyde.
tiary-phenyl-phenol, phenol, resorcinol, Allergic reactions to resol-type phenol formal-
xylenol, etc.) and formaldehyde (See also dehyde resin are relatively common with 1.2%
▶ Chap. 53, “Contact Allergy to Phenol- positive patch tests in more than 22,000 tested
Formaldehyde Resins”). There are four major patients (Isaksson et al. 2015). More than this, in
forms of these resins: solid resin (bakelite an occupational dermatology clinic, 70% of the
type); powder resin (that can be melted and phenol formaldehyde resin reactions were clini-
poured into various forms); semisolid resins cally relevant (Aalto-Korte and Suuronen 2017).
(used as adhesives); and liquid resins (used for A case of severe widespread occupational
paints, varnish, polish, etc.). Phenol- allergic dermatitis was caused by contact
formaldehyde resins are used as electrical insu- with formaldehyde textile resin from the hospital
lators, wood varnishes, footwear, flooring, tex- “greens” (“scrubs”). In this case, patch testing was
tile dressing, wood glues, leather glue, performed with formaldehyde and ethyleneurea/
metal–metal glue, metal-rubber glue, paints, melamine formaldehyde resin, not with the
suspected offending fabric, which gives most use is in insecticides and disinfectants. Patch tests
often a false negative result (Donovan and for diagnostic are using:
Skotnicki-Grant 2007).
Solid resins are irritants not only through p-tertiary-butyl-phenol = PTBP 1–10% pet
Resin (whole finished product) 1–10% pet
their phenol and formaldehyde derivatives
Formaldehyde 1–2% aq
(which have also sensitizing properties) but also
Follow-up for late reactions must be performed (Stenberg
through the fine traces of oil that remain from the
et al. 2016)
manufacturing process or through the highly alka-
line NaOH used to neutralize the uncured excess
Skin Problems
of phenol and formaldehyde.
P-tertiary-butyl-phenol is usually the sensitizer.
Airborne particles from phenol-formaldehyde
The pathogenic allergic mechanism includes type
resins in powder can produce allergic contact
I and type IV reactions. In occupational settings,
dermatitis in 10% of exposed workers during
there is an airborne allergic dermatitis involving the
the first year of work. Most affected areas are
exposed skin (head and neck) and manifesting with
the face (periorbital area, eyelids), neck, pre-
severe edema and blistering. Not only skin is
sternal area, and uncovered hands and feet. In
affected as there are cases reported with aphonia
80% of cases, the cause is formaldehyde or
and bronchospasm (Kalimo et al. 1980) and allergic
hexamethylene-tetramine, but some dyes or
asthma, contact with these resins can also produce
zinc stearate can also be involved. Respiratory
skin depigmentation (occupational vitiligo). PTBP
problems (including pharyngitis, bronchitis,
resins can also induce orthoergic contact dermatitis
asthma) were also described when working
(especially on hands) and conjunctival irritation.
with phenol-formaldehyde resins containing
Nonoccupational allergies can develop in persons
methylol-phenol.
using footwear containing PTBP resins.
Bakelite in powder can induce irritating or
allergic dermatitis (Fregert 1981). Phenols ini-
tially induce skin erythema and after prolonged 3.1.3 Resorcinol-Formaldehyde Resins
Resorcinol-formaldehyde resins are used in the
contact ulcers that heal with skin hyper-
pigmentation, usually located on the hands, preparation of glues and adhesive solutions.
nose, and ear pavilions. These resins can induce Resorcinol is a widely used chemical reagent
present in some drugs (antiacne topical treatment –
allergic cross-reactions with colophony (rosin)
and Peru balm. as keratolytic agent, antipruritic, and antiseptic solu-
tions; eye drops; suppositories), in synthetic resins
(with formaldehyde), in cosmetics (hair dyes, defo-
3.1.2 Para-Tertiary-Butyl-Phenol-
Formaldehyde Resins liants), explosives, photographic and photocopying
Para-tertiary-butyl-phenol-formaldehyde resins solutions, etc. Also used as endodontic therapy
(“Russian Red”), but few data are available on the
(other names: p-tert- butylphenol formaldehyde
resin; PTBP formaldehyde; Butylphen; 4 possible contact reactions (Schwandt and Gound
(1,1-dimethylethyl) phenol; 4-tert-Butylphenol- 2003).
formaldehyde resin) are widely used as adhesives Patch test can be done using:
(glues for footwear, leather, wood, wool, glass,
stickers, door of the car upholstery, dental cement, Resorcinol-formaldehyde resin (whole 20% in
brakes, textile starches, insulation) (See also finished product) ethanol
▶ Chap. 53, “Contact Allergy to Phenol- Formaldehyde 1–2% aq
Formaldehyde Resins”). The resin can be also Resorcinol 2% pet
present in construction settings being used in
fiberglass products, plywood, and in masonry Skin Problems
sealant. It is also incorporated in printing inks, Formaldehyde is the main sensitizer. Resorcinol
additives for motor oils, and varnishes. Another can give cross-reactions with phenol and may
induce allergic contact dermatitis. Resorcinol in excepting exposures that combines wet and
contact with varnished nails turns them into warm or the use of chlorine or alkali, conditions
brown-orange and in contact with hair gives it for the formation of allergic dimethyl or urea
darker shades. The resin is also used as endodon- compounds.
tic therapy (“Russian Red”) but few data are avail- Dermatitis (including contact urticaria) from
able on the possible contact reactions (Schwandt textiles on which urea-formaldehyde resin was
and Gound 2003). used as starches is usually due to formaldehyde
(Belsito 1997). Lesions are diffuse and occur in
3.1.4 Sulfonamide-Formaldehyde particular on the hands, face, neck, and torso.
Resins Irritant contact dermatitis was induced in
Sulfonamide-formaldehyde resins combines a patient by urea-formaldehyde fiber board
d-sulfonamide with formaldehyde resulting in containing resin (Vale and Rycroft 1988). Airborne
a liquid soluble in alcohol and acetone, much irritancy to dust from urea-formaldehyde insulation
used in paint and varnish industry. When cellulose was also reported (Dooms-Goossens et al. 1986).
nitrate is added, the resin can be used as adhesive Persistent perionixis was described when using
and gain in plasticity. These new properties artificial nails made of urea-formaldehyde resins.
expand the industrial uses to cosmetics (nail var-
nish) as toluene-sulfonamide-formaldehyde resin. 3.1.6 Melamine-Formaldehyde Resins
Patch test can be performed with: Melamine-formaldehyde resins are thermoset
Toluene-sulfonamide-formaldehyde resin 10% pet
resins obtained through polycondensation of
Formaldehyde 1–2% aq melamine (2,4,6-triamino-1,3,5-triazines) with
formaldehyde. Melamine-formaldehyde resins
are similar to urea-formaldehyde resins but
Skin Problems
have a higher resistance to water. Due to their
Allergic lesions in fingers and nails lesions may
resistance to water, heat, and because they do not
occur (Sainio et al. 1997).
stain, they are frequently used as coating for fur-
niture (particularly kitchen), plates, and cups.
3.1.5 Urea-Formaldehyde Resins
Other common uses are for orthopedic and dental
Urea-formaldehyde resins are thermoset-type
cement, as an aid in pulp paper, and synthetic
resins. The condensation of formaldehyde
textiles to make them waterproof.
(a major sensitizer) with urea (carbamide,
Patch tests can be performed with:
H2N▬CO▬NH2) produces a liquid that is treated
with pigments, zinc stearate, hexamethylenetetra- Melamine-formaldehyde resin 50% in
mine 10.5%, etc., for the finished product. ethanol
Urea-formaldehyde powder can be molded Ethylene-urea + melamine- 5% pet
formaldehyde
into containers for cosmetics, electrical fittings,
Formaldehyde (aq) 1–2% aq
refrigerators insulation, wall insulation, pipes,
Ethylene-urea 1% pet
bottle caps, foam insulation, textiles starches (cot-
Dicyandiamine (fireproof) 1% pet
ton, rayon), surface coatings, wood glues, lava-
tory seats, buttons, clock cases, etc. (Rusu 2009).
Patch tests are performed with: Skin Problems
Melamine-formaldehyde resins are rarely sensi-
Urea-formaldehyde resin 10% pet or 50% in ethanol tizing. However, contact dermatitis may occur,
Uroformin (hardener) 55% pet including purpuric type (Romaguera et al. 1989)
in orthopedic casts (Ross et al. 1992), gypsum
Skin Problems molds (Fregert 1981), or coatings of plastic
Urea-formaldehyde resins are not sensitizers. tubes for cosmetics. Formaldehyde is the primary
Starches are generally only very rarely sensitizing irritant and sensitizer. The potential degradation
of the resins and the consequent migration of the polycarbonate material is produced from bisphenol
monomers was demonstrated as increasing in age- A (4,40 -dihydroxydiphenyl-2,2-propane) and phos-
ing studies (Mannoni et al. 2017). gene (COCl2). Other bisphenols than bisphenol A
The combination of melamine and ammonium can also be used. Polycarbonate is a very durable
chloride produces a resin used in adhesive ban- material (resistant to sunlight, weather, and
dages (ammonium chloride acts as sensitizer). scratches) and highly transparent to visible light
Aalto-Korte et al. described three cases of occu- (with better light transmission characteristics than
pational allergic contact dermatitis from melamine many kinds of glass). Polycarbonates are thermo-
formaldehyde resin without contact allergy to form- plastics but can undergo large plastic deformations
aldehyde: one in the plywood industry, one in the without cracking or breaking (Rusu 2009). Poly-
production of melamine-laminated chipboard, and carbonates are used for electronic applications due
one in laboratory work (Aalto-Korte et al. 2003). to the good electrical insulating characteristics (they
A 28-year-old female plywood worker devel- can serve as dielectric in high-stability capacitors).
oped eczema on the dorsal side of her hands and Polycarbonates are also used in the construction
wrists after 2 years of occupational exposure. She industry (domelights and sound walls) and in the
tested positive to melamine-formaldehyde resin production of compact discs, DVDs, and Blu-ray
and negative to formaldehyde (which is usually discs. Due to their durability, they are used as bullet-
responsible for most skin reactions to formalde- proof windows in automobiles and banks. The use
hyde resins). Contact dermatitis due to melamine of polycarbonate containers for food storage is con-
formaldehyde resin is rare and usually due to troversial. In contact with water, small quantities of
products that are not fully cured or to a close bisphenol are released. Polycarbonate is dissolved
contact with by-products on the assembly line by ammonia and acetone and can be cleaned (of oil
(García Gavin et al. 2008). and grease) with alcohol. Polycarbonates are rela-
tively expensive.
3.1.7 Furfuraldehyde Resins
Furfuryl alcohol (furfurol) and furfuryl aldehyde Skin Problems
(furfural), both from the group of furan, are col- Polycarbonates rarely give orthoergic or allergic
orless liquid substances derived from agricultural contact dermatitis (Bruze et al. 1988). Bisphenol A
waste: corn stalks, reeds, sawdust, sunflower is an endocrine disruptor with weak estrogenic
seeds, etc. (Rusu 2009). activity. Occupational contact dermatitis can be
Furfurol is used as a solvent in refining of associated with Bisphenol A exposure. Most aller-
vegetable and mineral oils and as a reactive in gic contact dermatites occur in workers handling
many organic syntheses: plastic material, nylon, Bisphenol A products, such as plastic product
furan, and certain drugs. workers, and those exposed to epoxy adhesive
Furfuraldehyde resins are produced by poly- tapes, foams, and dental products (Kaddar et al.
merization from the bark of barley treated with 2008).
sulfuric acid. For industrial use, they are com-
bined with phenols, amines, ketones, or casein 3.1.9 Polyamide Resins
and have the same uses as formaldehyde resins. Polyamide resins are produced by polycon-
densation of adipic acid ▬HOOC▬
Skin Problems (CH2)4▬COOH with hexamethylenediamine
Furfuraldehyde resins can induce skin and mucosal ▬H2N▬(CH2)6▬NH▬ or of water with
sensitization (especially respiratory allergy: allergic caprolactam.
asthma). Systemic poisoning may also occur. Polymerization of hexamethylenediamine
adipate generates nylon.
3.1.8 Polycarbonates The main use of polyamides is in the textile
Polycarbonates are polymers containing carbonate industry (synthetic fibers). Polyamides are also
groups (▬O▬(C〓O)▬O▬). The main used for transparent packaging (vacuum
packaging of meat) and hospital wares with good solvents (ethanol, acetone, ethyl acetate, amyl ace-
stability at sterilization temperatures. tate), and plasticizers (dimethyl-phthalate, dibutyl-
The sensitizers are the additives designed phthalate, tricresyl-phthalate, triphenyl-phosphate),
to improve the product, like dihydrochloric and used in paints and waterproof paper.
ethylenediamine – hardener (for patch test 1% Patch tests for cellulose resins can be
pet), which releases formaldehyde. performed with (Jordan and Dahl 1971):
Skin Problems
Polyamide resins rarely induce skin allergies or Cellulose-acetate (film or As such or 10% in
irritation. Allergy of the respiratory mucosa was flakes) methyl-ethyl-ketone
Cellulose acetate propionate As such
also described (Bruze et al. 1988).
film
A group of eight workers who had been Cellulose acetate butyrate film As such
chronically exposed to high atmospheric capro- Resorcinol monobenzoate 1% pet
lactam levels showed no evidence of systemic (rarely used today, it is
toxicity. All workers had a greater or lesser degree UV-absorbent and gives cross-
of skin change in the form of peeling and fissuring reaction with balm of Peru but
not with Resorcinol!)
(Kelman 1986).
2,20 -Dihydroxy-4, 1% in methyl ethyl
Polyamides from medical compression stock- 40 -dimethoxybenzophenone ketone
ings are in direct, tight, and prolonged contact p-tertiary-Butyl-phenol 2% pet
with the skin in patients which work in standing Azo-pigments (“Black dye 1% pet
postures (e.g., teachers, lab workers, surgeons). mixture”)
Even in this conditions, contact eczema to the Carbon black 1% pet
polyamides used in compression stockings are Solvent Yellow 3 (Color Index 1% pet
rare (single reports) (Valesky et al. 2014). No. 11 160)
Solvent Red 26 (Color Index 1% pet
No. 26 102)
3.1.10 Allyl Resins
Mono-ethyl ethylene glycol 5% in methyl-ethyl-
Allyl resins are formed by polymerization of ether acetate ketone
a monomer resulted from the combination of Potassium acid oxalate 0.5% aq
allyl alcohol with diglyco-chloroform. Dimethyl-phthalate As such
Allyl resins are thermostable, widely used in Diethyl phthalate As such
glass factories. Tricresyl phosphate 5% pet
Triphenyl-phosphate 5% pet
Skin Problems Phenyl salicylate 2% pet
Allyl resins are sensitizers (both as monomers
and polymers). Allyl alcohol may be fatal if Skin Problems
swallowed or inhaled, and when in direct contact Cellulose resins rarely act as sensitizers and this is
with the skin, it causes burns. Inhalation may lead mainly due to additives. One of those additives,
to severe irritation or burns. p-tertiary-butyl-phenol, is a thermostabilizer act-
ing as irritant and sensitizer. It can also induce
3.1.11 Cellulose Resins (Cellulose skin hypopigmentation. Plasticizers like tricresyl
Estheric Resins) phosphate and triphenyl phosphate are highly sen-
Cellulose resins are used for manufacturing sitizing, while dimethyl phthalate and diethyl
spectacle frames, hearing aids, wheels, brushes, phthalate only rarely sensitize.
toothbrushes, different handles, pens and pencils, Sodium-carboxymethyl-cellulose allergic con-
toys, cellophane, photographic film, etc. (Rusu tact dermatitis positive patch test to 2% pet was
2009). reported in a baker (Hamada and Horiguchi 1978).
Celluloid is made from cellulose nitrate and It is an anionic cellulosic polymer synthesized from
cellulose acetate, mixed with camphor, various purified cellulose and sodium chloroacetate. It is
used to increase viscosity in foods, cosmetics, and Activators (accelerators):

some drugs (laxatives, antiulcer drugs, antacids).
The occurrence of contact dermatitis from p-ter- Dimethylalanine 2% pet or 10% in
alcohol
tiary-butyl-phenol and tricresyl ethyl phthalate
Diethylaniline 2% pet or 10% in
was reported in a plastic nail adhesive (Burrows alcohol
and Rycroft 1981). Cobalt-naphthenate (powerful 2–5% pet
Triphenylphosphate, the most commonly used sensitizer)
flame retardant for cellulose acetate, exhibits low Cobalt-octate (powerful 5% pet
acute toxicity by dermal or oral contact (Svara sensitizer)
et al. 2006). Peroxide organic catalysts (powerful
sensitizers):
3.1.12 Polyester Resins Benzoyl peroxide 5% pet or 2% aq

Polyester resins are produced from unsaturated Cyclohexanone peroxide 0.5% pet
acids (maleic acid, fumaric acid, etc.) and Antimony-hydroperoxide 0.5% pet
di-alcohols (diethylene glycol and polyethylene UV absorbers:
glycol) (See also ▶ Chap. 55, “Polyester Resins”).
Their properties can be changed by adding colo- Benzophenone 5% pet
Benzotriazole 1% pet
phony, dimethylalanine, diethylalanine, etc. Tri-
glycidyl isocyanurate (TGIC) is used as a curing Inhibitors:
agent in polyester powder paints. Benzoyl perox-
Hydroquinone 5% pet
ide is used as catalyst, methylenamine or cobalt
Quinone 5% pet
salts as accelerators.
p-tertiary-Butyl-catechol 1% in acetone
Polyester resins are used in the manufacture of
bathtubs, car covers, furniture, props, plaster, Consolidating agents:
paint industry, aeronautics, and electric cable
Glass fiber Highly irritating, do not test
insulation. Unsaturated polyester resins are used
as cements in car repair in order to prepare the Others:
surface before painting.
Acetone Irritant
Patch tests that can be performed for polyester Phthalic anhydride (also irritant) 1% in ethanol
resins include:
If contact allergy to polyester resin is
Unsaturated polyester resin 10–20% in suspected, the products used by the patients can
acetone be used (ex. car putties) and sensitization to cobalt
Maleic acid 0.5% in acetone or TGIC must be also taken into consideration
Diethylene glycol 10% aq (Aalto-Korte and Suuronen 2016).
Propylene glycol (sensitizer and 2–5% pet
irritating)
Skin Problems
Polyethylene glycol 10% aq
Contact allergy to raw materials or components
Colophony 20% pet or in
acetone of polyester resin systems is quite rare (Nixon
et al. 2012). Occupational irritation to polyester
Cross-link agents:
resins is produced by contact with solvents and
Methyl methacrylate 5% pet fibers.
Alpha-methylstyrene 1% pet Finished products such as polyester fibers (e.g.,
Styrene (vinyl-benzene – sensitizer and 1% in olive Dacron) and film (e.g., Mylar) have not so far
irritating) oil caused dermatitis. Fibers may be, however,
Vinyl-toluene 1% in olive treated with oils, biocides, and antistatics that act
oil as irritating agents and sensitizers. About 50% of
all exposed and inadequately protected workers 3.1.14 Polystyrene (PS)

can develop occupational allergic contact derma- Polystyrene (PS) is a hard, transparent, thermoplas-
titis of the hands, arms, and neck after 2–4 months tic resin, available in expanded form, film, foam,
of exposure (Piper 1965). Contact allergy to poly- tablets, or pellets, obtained by styrene polymeriza-
ester products is reported to have a poor prognosis tion (vinyl benzene, CH2〓CH▬C6H5) with perox-
as the patients changed tasks or left their jobs ide as initiator. As stabilizers benzotriazoles,
(Aalto-Korte and Suuronen 2016). benzophenones, and nickel organic compounds are
used (Belsito 1997).
3.1.13 Alkyd Resins Hot cutting of large pieces of polystyrene
Alkyd resins are polyesters obtained by poly- and styrene monomers releases methyl chloride
condensation of acid anhydrides or diacids – a colorless and odorless gas which, if inhaled,
(phthalic acid, maleic acid, etc.) with polyalcohols in small doses can give intoxicating and narcotic
(dialcohols, trialcohols, ethylene glycol, propylene effect (or ebrionarcotic syndrome: tiredness,
glycol, sorbitol, mannitol, etc.). The best known are confusion, weakness, drunken-type actions,
the glycero-phtalic resins, the result of combining memory loss, nausea, loss of appetite, and hear-
phthalic anhydride with glycerol. ing and color vision loss) and in large quantities
There are simple alkyd resins and modified can induce dizziness, confusion, stupor, and
alkyd resins by the addition of vegetable oils even coma followed by death (Niculescu et al.
(linseed oil or castor oil) – generating great flex- 2003).
ibility. These oleoglycerophtalic resins are used in In the presence of expanded polystyrene gran-
paints and lacquers for automotive, printing inks, ules, open fire sources should be avoided (the
and dressing for textiles (Martin-Scott 1966). granules contain pentane – a flammable gas).
Combining alkyd resins with other resins (e.g., Polystyrene is used in the production of
melamine-formaldehyde) enhances not only the lacquers, molds, packaging film, disposable
quality of the products but also the sensitizing tableware, and some insulators. Some styrene
properties. If glycocole, vinyl chloride, styrene, cements (styrofoam) contain free molecules of
or glass fibers are added, the risk of skin and styrene.
respiratory irritation is also higher. Polystyrene is used in compound polymers
Patch tests are performed with: such as acrylonitrile-butadiene-styrene (ABS),
Alkyd resin 10% in acetone
styrene-acrylonitrile (SAN), or styrene-butadiene
Phthalic aldehyde 1% in ethanol (SB). Those compounds are used in the manufac-
Diethylene glycol (DEG) 10% aq ture of handles, toys, pipes, electric appliances,
Polyethylene glycol (PEG) 10% aq bags, household ustensils that can produce a
Colophony 20% pet or acetone metallic sound when dropped on a hard surface
(Belsito 1997).
Styrene is also used in the manufacture of syn-
Skin Problems
thetic rubber and acrylic-alkyd resins. In nature, it
The skin and mucosal surfaces can be exposed to
can be extracted from raspberries (as a result of
alkyd resins or to acid anhydrides in form of pow-
enzymatic decarboxylation of cis-cinnamic acid)
der, liquid, or fumes with an irritating effect (on the
or from styrax balm. Styrax is used in the prepara-
respiratory tract or on the skin). Allergic reactions
tion of dyes, perfumes, and soaps and can be
have also been described: allergic contact dermati-
removed from the skin with acetone.
tis, urticaria, allergic rhinoconjunctivitis, or asthma
Methylstyrenes (vinyl-toluenes) occur as
(Helaskaoski et al. 2009; Barker et al. 2000).
by-products in plastics manufacturing (Sjöborg et al.
Allergic lesions are most often generated by:
1984).
Phthalic anhydride Styrene can cross-react with epoxy resins and
Colophony (traces) in the product vinyl-toluene resins.
Propylene or ethylene (as solvents) Patch tests:
Styrax 2% pet esters with diamines. In the technologic process,

Styrene 1% in olive oil, 1–2% pet or 1% in catalysts and amine curing agents are used such as
butyrolactone triethylendiamine, ethylamine, methylamine, tri-
Styrene 1% pet ethylamine, etc. Organostannic catalysts and blowing
oxide agents (dichloromethane, trichlorfluoromethane)
are also used.
Skin Problems Polyurethanes are used for paints, lacquers,
Styrene is a mild primary irritant (Kanerva et al. adhesives, binders for core castings, building
1996; Schmunes 1990) by destroying the protective materials (for sealing cracks and consolidation),
lipid film of the skin surface. Cases of chemical skin synthetic fibers (duraspan, perlon U, gospan),
burns caused by styrene have also been described fiber, and cable insulators (as sprays with flexible
(Bruze and Fregert 1994). Styrene acts only in rare and rigid foams). Polyurethanes are also used to
situations as sensitizer. Styrene presumably func- impregnate textiles, paper, etc. Lacquers are
tions as a pro-haptene that undergoes skin or muco- applied with special guns, the ingredients being
sal metabolization to styrene epoxide which acts as a united automatically at application. In this
true haptene (Belsito 1997; Lanosa et al. 2010). case, the aerosols are not detained by ordinary
There have been reports of immediate type I protection masks but only by milipores or
allergy to styrene (Sjöborg et al. 1984; Bourne and activated carbon filter masks. Polyurethanes
Milner 1963; Condé-Salazar et al. 1989; Moscato are widely used in microcellular foam seals and
et al. 1987). gaskets, durable elastomeric wheels and tires,
In one reported case, the patient which was automotive suspension bushings, high-
allergic to styrene cross-reacted in patch testing performance adhesives, and sealants. Polyure-
with 2-, 3-, and 4-vinyl-toluene (2-, 3-, and thane products are often called “urethanes” and
4-methyl-styrene) and with its metabolites: sty- also confused with the specific substance ure-
rene epoxide and 4-vinyl-phenol (4-hydroxy-sty- thane (ethyl-carbamate). Polyurethanes are not
rene) (Belsito 1997). produced from ethyl-carbamate and do not
contain it.
3.1.15 Polyurethane Resins Hexamethylene 1,6-diisocyanate (HDI) is
Polyurethanes resins are defined by the presence found in lacquers, coatings, and spray paints,
of the urethane sequence ▬O▬CO▬NH▬ mainly composed of HDI trimers, but also
(See also ▶ Chap. 54, “Polyurethane Resins”). containing larger oligomers and under 1%
Isocyanates with the generic formula R▬(N〓 HDI monomers. HDI trimers occur as biuret,
CO)n react with hydroxyl groups (OH) of poly- isocyanurate, and asymmetrical types (Aalto-
alcohols (polyols) to form polyurethanes: Korte et al. 2010). Diisocyanates are used also
as adjuvants in the rubber industry (Rusu 2009).
Polyols (polyesters or polyethers) Isocyanates patch test battery I–1000 – Isocy-
Isocyanates (alkylic or arylic): anate series are listed in Table 4.
4,40 -Diisocyanate dicyclohexyl methane Patch test for polyurethanes can also include:
Methylene bis (4-cyclohexyl-isocyanate)
Diphenyl-methane-4,40 -diisocyanate = MDI
1,6-Diisocyanate hexamethylene = HDI Table 4 I-1000 – isocyanate series
3-Isocyanate-methyl-3,5,5-trimethyl-cyclohexyl- 1. Toluene diisocyanate (TDI) 2% pet
isocyanate = IPDI 2. Diphenylmethane-4,4-diisocyanate 2% pet
Polimethylene-polyphenyl isocyanate = PAPI (MDI)
Toluene-diisocyanates (2,4-TDI and 2,6-TDI), etc. 3. Diamino-diphenyl-methane 0.5% pet
4. Isophorone-diisocyanate (IPDI) 1% pet
Polyurethanes can also be obtained from 5. Isophorone-diamine (IPD) 0.1% pet
the reaction of glycol dichlor carbonic 6. 1,6-Hexamethylene-diisocyanate (HDI) 0.1% pet
Isocyanates: Allergic contact dermatitis from handling

Polymethyl-phenyl isocyanate (PAPI) 0.1% pet the finished resins are extremely rare, but resins
Dicyclohexylmethane p,p0 -diisocyanate 1% pet manufacture can cause skin allergies and irrita-
(Desmodur W or WS) = Hylene W tion, asthma, extrinsic allergic alveolitis, rhino-
Methylene-bis (4-cyclohexyl-isocyanate) 1% pet conjunctival, and respiratory irritation.
Amines: Low molecular weight aliphatic isocyanates
Dimethyl-3,30 -diamino- 0.5 pet are volatile and act as intense respiratory sensi-
4,40 -diphenylmethane (classified as
carcinogen, is proposed for banning) tizers (causing allergic rhinitis, allergic asthma,
Methylene dianiline 0.1% in and extrinsic alveolitis) but are weak skin sensi-
olive oil tizers (face, neck, and V-shape area contact
Tri-isopropanol amine 0.5% pet dermatitis is probably induced by airborne mole-
Ethylamine 2% aq cules). High molecular weight isocyanates (HDI,
Methylamine 2% aq the “aromatics”) are not as volatile and are far less
Triethylamine 2% aq sensitizing. However, catalysts – amino com-
Triethylene diamine (DABCO) 0.05–3% aq pounds (triethylamine, triethylene diamine),
m-Xylene-diamine (MXDA) 0.1% pet cobalt, or copper naphthenate – and other adju-
vants can induce allergies.
Patch test preparations of polymeric Cross-reactivity between isocyanates and their
diphenylmethane diisocyanate (PMDI) are more corresponding amines was studied, and it was
stable than preparations of diphenylmethane- demonstrated that animals sensitized to 4,40 -MDI
4,4;0 -diisocyanate (4,40 -MDI). It is recommended showed cross-reactivity to 4,40 -MDA and 4,40 -
to use PMDIs with a monomer content of at least Dicyclohexylmethane-4,40 -diisocyanate (DMDI).
35% in 2.0% pet, i.e., monomer patch test concen- The aromatic amine 4,40 -MDA showed cross-
tration approximately 0.7%. Reactions to 4,40 -MDI reactivity to the aliphatic amine 4,40 -DMDA
and PMDIs appear late, and it is strongly (Hamada et al. 2017).
recommended to repeat readings at least on days Also positive reactions to 4,40 -MDA seem
3, 4, and 7. 4,40 -diaminodiphenylmethane to be associated with contact allergy to
(4,40 -MDA) was shown to be a good marker for p-phenylenediamine (Engfeldt et al. 2013) – a
4,40 -MDI and patch testing with 4,40 -MDA in common contact allergen. Therefore all this pos-
0.25% pet can be used instead of PMDI. Concom- sible reactions must be discussed if a worker
itant reactions to 4,40 -MDI and 4,40 -MDA are needs relocation for another task due to a positive
probably not caused by conversion of 4,40 -MDI test reaction (Hamada et al. 2017).
into 4,40 -MDA by reaction with water. Another MDI is used as aerosol and therefore involves
explanation is a path of reactions leading to ureas especially respiratory risks and only seldom gen-
and MDI conjugates with skin constituents, which erates skin problems.
are hydrolyzed into 4,40 -MDA (a complex process DMDI is known to be a strong cutaneous sen-
depending upon several factors and probably sitizer. A 27-year-old woman developed a severe
responsable for positive MDI reactions after up to eczematous eruption on the arms, trunk, and abdo-
7 days) (Frick-Engfeldt et al. 2007). men within 2 weeks of employment at a company
using the product Chem-Dec 808 isocyanate
Skin Problems (containing 40–70% weight per weight DMDI).
Of the two components of polyurethanes: Patch testing was performed with the North Amer-
ican screening series, an isocyanate series and 1%
Polyols (polyesters or polyethers) have a reputa- Chem-Dec 808 isocyanate. At day 7, a +++ reac-
tion of not being sensitizers tion to Chem-Dec 808 isocyanate and a ++ reac-
Some of the isocyanates (alkyl 0000000000000000- tion to the aromatic isocyanate diphenylmethane-
0000000000000000000000000000000000000- 4,40 -diisocyanate were observed (Donovan et al.
00 or aryl) may induce sensitization 2009).
TDI (a strong irritant and a weak sensitizer) production represents about 50% of the total out-
induces orthoergic and allergic contact dermatitis, put of plastics worldwide.
extrinsic allergic alveolitis, asthma, and respira- Polyethylenes can be divided into three
tory irritation. groups:
HDI (from polyester resins for textiles and
paints) induces blepharoconjunctivitis, respiratory Low-density polyethylenes – soft, flexible, trans-
irritation, and rarely allergic contact dermatitis or parent, nontoxic (they have no plasticizers),
asthma. Four patients with allergic contact derma- used for food packaging, shopping bags, sacks
titis from HDI-based polyisocyanates in polyure- Linear low-density polyethylenes – with better
thane paints were diagnosed between 2000 and mechanical strength, used for coating of elec-
2009 at the Finnish Institute of Occupational tric cables and wires, hoses, containers, jars,
Health. None of the four patients tested positive deep-freeze boxes and cases
to HDI monomer (Aalto-Korte et al. 2010). High-density polyethylenes – used for bottles,
Naphtalene-diisocyanate (NDI) eliminates containers, pipes, shopping bags
noxious fumes when above 100 C. It is rarely
used. Amine and organostannic catalysts can 3.2.2 Polypropylene
induce orthoergic or allergic contact dermatitis, Polypropylene is a chain of repeating unit
allergies, and irritation of the respiratory tract ▬CH2▬CH▬CH3, derived from propylene
(asthma, rhino-conjunctivitis). (CH2〓CH▬CH3). It is similar to high-density
First aid measures in contamination with polyethylene, but harder and tougher. It is used
isocyanates: in the manufacture of films, pipes, nonwoven
products and carpets, and home furnishings.
Contaminated clothes should be removed quickly,
preferably in an isolated shower in order not to Skin Problems
contaminate the entourage. Polyethylene is not a sensitizer in the form of the
Immediate decontamination of the skin affected polymerized finite product. Skin irritations and
by the liquid monomer (which can cause an allergies may be due to incompletely cured resins,
intense inflammatory reaction, with redness initiators, and catalysts.
and swelling) by washing thoroughly with Processing of polyolefin resins by sawing and
water and treating with isopropanol (isopropyl grinding – under hot conditions – can induce the
alcohol) 30%, followed by further washing reaction of depolimerization and the release of
with soap and water. ketones, aldehydes, acids, which can give itching
airborne contact dermatitis (Thestrup-Pedersen
et al. 1989).
3.2 Polyolefins Occupational contact dermatitis from
irritating airborne molecules of polypropylene
Polyolefins are thermoplastic resins obtained by and polyethylene fibers from the filter of the air
polyaddiction of olefins (unsaturated hydrocarbons). conditioning system in a hospital in Amsterdam
was described in eight workers (Patiwael et al.
3.2.1 Polyethylene 2005). Very low humidity contributed to the
Polyethylene is produced by polymerization of release of fibers from the polymer matrix under
ethylene (CH2〓CH2), at low or high pressure, the influence of the air pressure column and pre-
using initiators and catalysts, into chains of cipitated skin irritations.
repeating unit ▬CH2▬CH2▬. Polyethylene is Sicca syndrome (reduction of exocrine secre-
cheaper, lighter than water, and widely used in the tions, especially tears) can be induced by polypro-
manufacture of protective gloves, film for pack- pylene and polyethylene. Epidermal necrolysis
aging (bags, sacks), filters for air conditioning, was described in workers in contact with
plastic containers (PET), etc. Polyethylene diethylphthalate and polyethylene.
Polyethylene airborne molecules derived containing mainly PEGs. Nitrofurazone allergy

from the mass of polyethylene polymer can induce appears to favor concomitant sensitization to PEG
respiratory disease from extrinsic allergic alveolitis (Özkaya and Kılıç 2017).
to asthma. There have also been described: extrin-
sic allergic alveolitis (Barroso et al. 2002), distur- 3.2.4 Polytetrafluoroethylene (PTFE)
bances in color perception (Kaur et al. 2004), PTFE is a synthetic thermoset fluoropolymer of
smoke fever to polyethylene terephthalate resin tetrafluoroethylene accidentally invented by Roy
(as in exposure to the smoke from polyester, cellu- Plunkett of Kinetic Chemicals in New Jersey in
lose resin, and polybutylene terephthalate resin), 1939 (Rietschel and Fowler 2008). PTFE is most
asthma to polyethylene electrical insulation, blad- well-known by the DuPont brand name Teflon.
der cancer in polyethylene exposure, colorectal Teflon coating consists of microscopic beads of
cancer among workers exposed to polypro pylene. Teflon co-deposited up to 20% with electroless
nickel. Other polymers with similar composition
are also known by the Teflon trade name:
3.2.3 Polyethylenglycol (PEG)
Polyethylenglycol (PEG) is a mixture of glycols. Perfluoroalkoxy (PFA)
The glycols with molecular weights of Fluorinated ethylene propylene (FEP)
200–700 kDal are liquid, while those with molecu-
lar weights of 1,000–6,000 kDal are solid products. PTFE is a fluorocarbon solid with high molecu-
Glycols are good solvents, being used lar weight, consisting entirely of carbon and fluo-
as excipients for drugs, suppositories, shampoos, rine. PTFE is hydrophobic and nonreactive due to
soaps, detergents, conditioners and other cosmetics, the strength of carbon-fluorine bonds. Due to this
insecticides, toothpaste, contraception pills, nitro- property, it is used in containers and pipework for
cellulose, epoxy resin hardeners, glues, etc. reactive and corrosive chemicals. PTFE demon-
Polyethylene glycol ointment is a mixture of solid strates a low friction coefficient against solids, and
polyethylene glycol (molecular weight 4,000 kDal) it is used as a nonstick coating for pans and other
with liquid polyethylene glycol (molecular weight cookware. PTFE is also used as a lubricant because
300 kDal). Carbowax is a polyethylene glycol waxy it reduces friction, wear, and energy consumption
solid (molecular weight 1,500 kDal) used as lubri- of machinery (Funderburg 2000).
cant and softener for textiles).
Skin Problems
Liquid PTFE is a skin irritant. Brief exposures
Skin Problems may cause mild irritation. Frequent or prolonged
PEG can induce both contact urticaria (Fisher contact may cause severe irritation, defatting of
1978), allergic reactions, anaphylaxis (Yamasuji the skin and allergic dermatitis. Irritating and
et al. 2013), and delayed type IV contact dermatitis harmful fumes are released when PTFE is heated
(Braun 1969). There is no cross-reaction with pro- above 300 C (Rudnick 2009).
pylene glycol. The sensitizing potential of PEGs is
inversely proportional to their molecular weight, 3.2.5 Other Rare Plastics
most allergens being in liquid forms with low Coumarone-indene polymers: Synthetic resins
molecular weight (200–400 kDal).PEGs sensitizer produced by polymerization of mixtures of
potential was investigated in a study on 836 patients. unsaturated compounds extracted from the
Thirty-five patients (4.2%) showed positive patch by-products of coal coking and of petroleum
test reactions to PEG. Late patch test readings pyrolysis. The resin is used in the manufacture
diagnosed delayed positive reactions to PEG. PEG of resin slabs for floors, linoleum, glues, adhe-
sensitivity was almost exclusively related to sive insulating tape, artificial leather, printer’s
nitrofurazone allergy. Ten patients (25%) had con- ink, manufacture of abrasive tools, paint, and
comitant contact allergies to various topical drugs varnish materials.
Cyclohexanone resins: used in the manufacture of Allergic rhinitis

nylon with applications in carpeting, automo- Smoke fever when exposed to the fumes of poly-
bile tire cord, and clothing. Also used as ester resins, cellulose resins, polyethylene tere-
a solvent, paint remover, and dry cleaning mate- phthalate, and polybutylene terephthalate
rial. It is also used in pharmaceuticals, dyes, Asthma
herbicides, insecticides, and rubber chemicals. Allergic extrinsic alveolitis induced by exposure
to isocyanates
Skin Problems “Reactive Airways Dysfunctional Syndrome”
There have been cases of dermatitis reported from (RADS) developed after exposure to
these types of resins, but it is unclear whether they cyanoacrylate
were caused by monomers, impurities, or additives
(Bruze et al. 1988; Heine and Laubstein 1990).
5 Primary and Secondary
Prevention Measures
4 Occupational Diseases Induced in Exposure to Plastics
by Plastics
5.1 Primary Prevention
Orthoergic (irritative) contact dermatitis with
different clinical forms: dry, cracked, Judicious selection of masks and gloves, both
desquamative, erosive (chemical burn) in terms of cost-burst resistance report as in what
Allergic contact dermatitis, including contact der- concerns the chemical substances whose contact
matitis to airborne antigens that affects the should be avoided and which must not penetrate
face, neck, and the V-shape area the equipment. Changes in technological processes
Contact urticaria (with immunologic or non- must be introduced whenever possible, in order to
immunologic mechanism) eliminate some low molecular weight volatile
Anaphylaxis by PEG reagents. The replacement of some very harmful
Onixis and perionixis (perionichia) with nail dys- adjuvants with less dangerous ones is a good
trophy and onicholysis (in contact with cyano- option. All workers should undergo proper health
acrylate resin) and safety instruction.
Epidermal necrolysis induced by cellulose ace-
tate, polyesters, PVC, acrylonitrile-butadiene-
styrene, polyethylene, and diethylphthalate 5.2 Secondary Prevention
(plasticizer) (Swan 2008)
Occupational vitiligo induced by p-tertiary-butyl- Patients must receive valuable and useful recom-
phenol mendations from the medical team that treated the
Altered chromatic perceptions from polypropyl- occupational skin disease. Unfortunately most
ene and polystyrene patients will return to the previous jobs and their
Sicca syndrome in polypropylene and polyethyl- occupational exposure will resume. Several socio-
ene workers economic issues prevent improvements of work-
Bladder cancer from polyethylene and acrylic ing conditions and avoidance of the contact with
resins hazards:
Colorectal cancer in polypropylene workers
Poisoning induced by organic solvents and devel- Too expensive technological process changes.
oped as ebrionarcotic syndrome, neurological The impossibility to use protective equipment
syndrome (neuropathy, coma), toxic hepatitis, (gloves that do not allow performing of occu-
hematological syndrome, renal failure, myo- pational gestures or block the leasions’
carditis, cardiac arrest, non-Hodgkin’s lym- healing; masks that hinder breathing; goggles
phoma, etc. (Bucur and Bucur 2006) that obscure the view).
The ineffectiveness of protective equipment (air- profesional. In: Bucur G, Bucur L, S cur iona C, Tiplica
borne molecules that penetrate beneath the GS (eds) Dermatoze profesionale. Niculescu, Bucha-
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Plastic Composites
57
Katri Suuronen and Maria Pesonen
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
3 Structure and Fabrication of Plastic Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
4 Polymer Matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
4.1 Thermoset Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
4.2 Thermoplastic Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
4.3 Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
5 Reinforcements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
6 Occupational Contact Dermatitis from Plastic Composites . . . . . . . . . . . . . . . . . . 845
6.1 Allergic Contact Dermatitis from Plastic Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
6.2 Irritant Contact Dermatitis from Plastic Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
7 Clinical Aspects, Testing, and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
8 Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
Abstract cause both allergic and irritant contact dermati-

A composite is a blend of two or more mate- tis. Allergic contact dermatitis is most often
rials that are mixed in order to gain properties caused by thermoset plastic matrices such as
superior to those of the original components. epoxy resins. Irritant contact dermatitis is typi-
Plastic composites (PCs), also called reinforced cally caused by reinforcement materials such as
plastics, are combinations of a polymer (plastic) glass fiber. Other skin contactants in PC work
matrix and a reinforcing material. Due to their are, for example, plastic additives, solvents,
enhanced properties and versatility, PCs are peroxides, and protective clothing. Clinical
used in nearly all fields of industry. PC may investigation of PC-related dermatitis requires
careful assessment of the workplace exposures
(chemicals and materials) and patch testing the
K. Suuronen (*) · M. Pesonen patient accordingly with plastic chemicals
Occupational Medicine, Finnish Institute of Occupational additives and, when possible, own materials
e-mail: katri.suuronen@ttl.fi; maria.pesonen@ttl.fi from work.

https://doi.org/10.1007/978-3-319-68617-2_56
842 K. Suuronen and M. Pesonen
Keywords PCs are usually produced by mixing liquid or

Plastic composite · Composite · Reinforced semiliquid plastic with a solid reinforcement. The
plastics · Prepreg · Epoxy resin · Hardener · main function of a matrix is to bond the reinforce-
Polyester resin · Vinyl ester · Phenol- ments together, to distribute the loading among
formaldehyde resin · Polyurethane · Acrylate · them, and to protect the reinforcing system. Poly-
Cobalt · Glass fiber · Carbon fiber · mer matrices are either thermosets such as epoxy,
Lamination · Boat building · Wind turbine · acrylate, phenol-formaldehyde, and unsaturated
Contact dermatitis · Contact allergy · Irritant polyester resins or thermoplastics such as polysty-
rene or polyvinyl chloride (PVC). A PC matrix
may also consist of a mixture of several polymers.
1 Core Message Many of the thermosets are able to sensitize the
skin in their unhardened form. Most of the rein-
• Plastic composites are combinations of a poly- forcements are hard and inert fibers or particu-
mer matrix and a reinforcement material. lates, but they often present in a physical form
• PCs cause allergic and irritant contact that is irritating to the skin. The first cases of
dermatitis. contact dermatitis from PC were reported already
• The most common contact allergens in plastic in the 1960s (Bourne 1963; Wehle 1966).
composites are reactive monomers in thermo-
set matrices such as epoxy resins.
• Plastic composites are used in a variety of 3 Structure and Fabrication
applications and industries, and their use is of Plastic Composites
increasing rapidly.
• Risk tasks include lamination work; The polymer composites can be classified
manufacturing of vehicles (boats, aircrafts, heli- according to their physical structure into fiber-
copters, cars), tanks, and other plastic products; reinforced, particulate-reinforced, and laminar
plywood/fiberboard industry; building and ren- (layered) PC. The reinforcements may have either
ovation industry; as well as dental work. random or fixed orientation within the matrix and
may be fabricated to single or multilayer struc-
tures (Elias and Mulhaupt 2015). Different
2 Introduction structures are obtained from matrices and rein-
forcements by techniques such as mixing,
A composite is a blend of two or more materials spraying, filament winding, injection molding,
that are mixed in order to gain properties superior bag and sheet molding, and hand lay-up.
to those of the original components. Plastic com- Semifinished products, consisting of a fiber-
posites (PCs), also called reinforced plastics, are reinforcement pre-impregnated with resins (pre-
combinations of a polymer matrix and a pregs), are a special PC application (Thomas et al.
reinforcing material. The desired properties of 2016). 3-D printing represents a new, rapidly
PC compared with mere plastic include, e.g., emerging technique for making PC (Compton
increased bending strength, lightness, hardness, and Lewis 2014). Prior to or during the fabrica-
and appropriate electric or magnetic properties. tion, the matrices are modified with auxiliary sub-
Both polymer matrices and reinforcements are stances such as antioxidants, lubricants, and fire
numerous, and new, advanced composite mate- retardants. Depending on the resin system, PC
rials emerge continuously. PCs are used all the may require heating, laser, or UV light to be
way from large-scale industrial production (e.g., hardened. The finishing of hardened PC entails,
tanks, vehicles, and other constructions) to sew- e.g., grinding, sanding, cutting, and rinsing as
age pipe relining, sports equipment, health-care well as coating and other surface treatments.
and beauty applications, bio-composites, informa- The production may vary from manual to fully
tion technology, and nano-materials. automated, but even in highly automatized
57 Plastic Composites 843
techniques, manual work is often needed in mov- are a special type of polyesters formed from
ing and adjusting the parts and in preparative and methacrylic or acrylic acids and epoxy resin,
finishing work. The PC manufacturing methods dissolved in styrene. Both UPR and VE are
have been reviewed elsewhere (Compton and cured with peroxides and cobalt accelerators and
Lewis 2014; Ehrenstein and Kabelka 2012; used extensively in varying lamination work.
Thomas et al. 2016). Epoxy resins in PC are most often
two-component systems comprising a resin and
polyamine or anhydride hardener. Also epoxy
4 Polymer Matrices prepregs are available, and new techniques are
emerging in, for example, natural and nano-
4.1 Thermoset Resins composite field (Saba et al. 2016). The resins are
usually based on diglycidyl ether of bisphenol A
Unsaturated polyester resins (UPR) are the (DGEBA) or diglycidyl ether of bisphenol F
commonest matrices representing about 75% of (DGEBF); epoxy resins based on glycidyl amines
the total resin volume used in PC production (aniline epoxy resins) may be used in special
(Thomas et al. 2016), followed by epoxy resins applications such as aerospace systems.
and phenolic resins (see Table 1 for thermoset Depending on the viscosity and the hardener, cur-
matrix types). The polymerized polyester resin is ing of PC with epoxy resin systems may require
dissolved in a reactive cross-linking monomer elevated temperature.
such as styrene to form a low-viscose liquid. Phenol-formaldehyde resins (PFR) include
Vinyl ester resins (VE, also epoxy vinyl esters) resols that are often used for prepregs and
Table 1 Thermoset matrix types in plastic composites: examples of applications, curing agents, and allergens
Type Applications Curing agents Allergens
Epoxy resins (ER) Production of vehicles and Polyamine hardeners, DGEBA and DGEBF epoxy
other structures by lamination acid anhydride resins, aniline epoxy resins;
methods, sports equipment, hardeners (in elevated reactive diluents (CGE,
pipe-relining, prepregs temperatures) HDDGE); polyamine hardeners
(MXDA, IPDA, DETA)
Unsaturated Production of vehicles and Peroxides and cobalt Cobalt
polyester resins other varied plastic structures accelerators
(UPR); epoxy vinyl by lamination methods
esters (VE)
Phenol- Structural (wood) laminates, Resol PFR, pressure and Monomethylol phenol
formaldehyde resins prepregs, casting molds heat; novolac PFR, structures in resin oligomers
(PFR) hexamethylenetetramine
Melamine- Wood laminates, fiberboard, Pressure and heat; acid Formaldehyde; oligomers in
formaldehyde resins e.g., MDF, casting molds, or amine catalysis unhardened resin
(MFR) and urea- decorative laminates
formaldehyde resins
(UFR)
Acrylic resins (AR) Dental composites and UV light or peroxides BIS-GMA, HEMA, MMA
prosthesis materials
Polyurethanes Impregnated fiber laminates; Isocyanates; water/ Isocyanates, e.g., MDI
(PUR) vehicle parts floor laminates, moisture
foam composites (acoustic
walls, etc.)
DGEBA diglycidyl ether of bisphenol A, DGEBF diglycidyl ether of bisphenol F, CGE cresyl glycidyl ether, HDDGE
hexanediol diglycidyl ether, MXDA m-xylylenediamine, IPDA isophoronediamine, DETA diethylenetriamine, BIS-GMA
bisphenol A diglycidyl methacrylate, HEMA hydroxyethyl methacrylate, MMA methyl methacrylate, MDF medium
density fiberboard, MDI diphenylmethane diisocyanate
structural laminates and novolacs used mainly for 4.3 Additives

molding compounds. Pre-polymerized resols are
cured in the final stage of the production with PC matrices are modified with additives
elevated temperature, and novolacs are cured according to the respective polymer and the tech-
with chemicals such hexamethylenetetramine. nical requirements of the product. Plastic addi-
PFR are used in, e.g., glass or carbon fiber lami- tives include, e.g., plasticizers, accelerators,
nates, casting molds, and wood composite mate- polymer inhibitors, flame retardants, stabilizers,
rials such as in particle boards and plywood. Other antioxidants, UV-light absorbers, lubricants, bio-
related resins in, e.g., wood- and paper-based PC cides, and colorants (Wolf and Kaul 2000).
include melamine-formaldehyde and urea-
formaldehyde resins (Diem et al. 2012).
Acrylic resins contain acrylic and methacrylic 5 Reinforcements
monomers in liquid stage. The products are
cured usually by radiation with UV light, while Glass fibers are the most commonly used rein-
peroxides may also be used. Acrylic resin com- forcements in plastic composites (Ehrenstein and
posites are used mainly in dental restorations, Kabelka 2012). They are supplied in several
bone cements, and other prosthesis materials forms including rovings, chopped strands, yarns,
(Syed et al. 2015; Vaishya et al. 2013), but they woven fabrics, tapes, etc. Glass fibers are
may appear also in novel applications (Behera low-priced and have high strength but low modu-
2011). lus and poor abrasion resistance and adhesion to
Polyurethanes are composed of diisocyanates the matrix. The adhesion is increased by adding
and polyols. Polyurethane bonding of a PC is coupling agents such as epoxy, acrylic, and poly-
achieved by one-component moisture-cured sys- urethane resin derivatives onto the fiber; this is a
tems or by two-component systems that cure process called sizing.
when a diisocyanate (hardener) and a polyol Carbon fiber (graphite) reinforcements are also
base are mixed. Two-component polyurethanes common; these are prepared mainly from three
are used in, e.g., instrument panels and other fibrous precursors: polyacrylonitrile, cellulose,
modules in cars and other vehicles and in foam or pitch. Graphite fibers may be circular, dog
composites for acoustic walls, while modern bone, or irregular in their diameter, and they
orthopedic plaster casts are based on moisture- come in, e.g., continuous, chopped, and woven
cure urethanes (BASF 2016). Polymeric MDI is forms, as well as in nanoscale such as nanocarbon
used in wood composites such as medium density tubes. The advantages over glass fibers are, for
fiberboard (MDF) (Adam et al. 2012). example, higher modulus, better endurance, and
lightness, but they have lower impact resistance.
Handling properties and adhesion to matrices is
4.2 Thermoplastic Resins improved by sizing, when needed.
Aramid fibers (aromatic polyamide or
Thermoplastic resins are numerous and include, “Kevlar” fibers) have stiffness and strength
for example, polyethylene (PE), polystyrene between glass and graphite. Their low density
(PS), polyacrylics, acrylonitrile-butadiene-sty- makes them ideal for materials requiring lightness
rene (ABS), fluoropolymers, polycarbonates, such as aircraft, space vehicles, and sports equip-
and polyvinyl chloride (PVC); biopolymers ment. They are available in, for example, contin-
such as polylactic acid (PLA) may also be used. uous yarns, rovings, woven fabrics, and
The matrices are polymerized plastics that are discontinuous staple.
usually supplied in pellet form. These are melted Wood reinforcements include veneer and wood
and mixed with reinforcement to form PC. cuttings of, e.g., spruce, pines, and birch with
The reinforcements are similar to those with varying particle size, orientation, and lay-up struc-
thermosets. tures (Kasal et al. 2015). These are used in the
manufacture of varied wood-based PC such as in PC work. ICD is often caused by the reinforce-
plywood-, particle-, and fiberboard-oriented ments and may therefore be coupled to either ther-
strand board, laminated timber plates, etc. Novel moset or thermoplastic PC. In addition, acid
wood composites are manufactured also from anhydride hardeners in epoxy prepregs have caused
recycled reinforcement materials. IgE-mediated contact urticaria (Helaskoski et al.
Other reinforcements include synthetic (plas- 2009). Solitary cases of accidental skin burns
tic) fibers such as hardened polyesters, polyacry- from chemicals have been reported in PC produc-
lonitrile (PAN), polyamides, and cellulose as well tion (Bruze and Almgren 1988).
as sand, various textiles, and natural materials
such as hemp, bamboo, and straw. Several types
of reinforcements (mineral, synthetic, and natural 6.1 Allergic Contact Dermatitis
fibers) may also be used together to form hybrid from Plastic Composites
reinforcements.
6.1.1 Epoxy Compounds
Epoxy compounds are among the leading skin
6 Occupational Contact sensitizers around the world (see ▶ Chap. 52,
Dermatitis from Plastic “Epoxy Resins”). Based on the available clinical
Composites and epidemiological data, epoxy resin systems
seem to be the most common allergens in
Some epidemiological surveys of occupational PC. All main components of epoxy resin system,
dermatoses in PC production have entailed clini- namely, the resins, polyamine hardeners, and
cal investigations and patch testing. They have reactive diluents, are capable of causing ACD.
identified relatively high frequencies of skin com- Also work with PC has caused contact allergy to
plaints and occupational dermatoses such as aller- resins (Aalto-Korte et al. 2015a), hardeners
gic contact dermatitis (ACD) and irritant contact (Aalto-Korte et al. 2014a), and reactive diluents
dermatitis (ICD). A Swedish study on 341 workers (Aalto-Korte et al. 2015b; Jolanki et al. 1996). A
in an aircraft factory identified clinical dermatitis Danish study on skin diseases in wind turbine
in 69 subjects; ACD was diagnosed in 12 of them production identified several cases of contact
and ICD in 43 of them, respectively, and the total allergy to DGEBA and DGEBF epoxy resin, ali-
prevalence of OCD was 16.2% (Bruze et al. phatic and aromatic reactive diluents, and poly-
1996). In another Swedish PC production plant, amine hardeners (Ponten et al. 2004; Rasmussen
9 out of 88 workers had OCD (Isaksson et al. et al. 2005). In a series of epoxy allergic patients
1999). A Finnish study on glass-fiber composite diagnosed at the Finnish Institute of Occupational
industry identified clinical dermatoses in Health (FIOH) between 1991 and 2014, several
22 workers out of 86; 6 of them were diagnosed industries and products related to PC were identi-
with ACD and 12 with ICD (Tarvainen et al. fied: these were manufacturing of electric
1993). In a ski factory, occupational ACD was machines, aircraft industry, sports equipment pro-
diagnosed in 8 and ICD in 4 out of 22 workers, duction, boat building, sewage pipe relining, and
the total prevalence of OCD being 55% (12/22) dental care (Aalto-Korte et al. 2015a). Based on
(Jolanki et al. 1996). An extensive study on the reports listed above, the most common aller-
603 workers in Danish wind turbine production gen in PC is DGEBA epoxy resin. Although
revealed clinical dermatitis in 36% and OSD in allergy to DGEBF without allergy to DGEBA
17% of the workers; occupational ACD was diag- epoxy resin is rare, the recent Finnish report
nosed in 66 (10.9%) and ICD in 37 (6.1%) (Aalto-Korte et al. 2014b) presented four cases
(Ponten et al. 2004; Rasmussen et al. 2005). of independent DGEBF allergy developed in
OCD has most often been coupled to PC based PC work.
on thermoset resin matrices, while thermoplastics Aircraft manufacturing represents a special
seem to be infrequent causes of contact dermatitis field of PC industry. It entails additional allergens
not covered by the ordinary epoxy allergens. other acrylic monomers (Aalto-Korte et al. 2009;
These include, e.g., aniline epoxy resins, tri-- Goon et al. 2006; Kanerva et al. 1993), while also
glycidyl-p-aminophenol (TGPAP), and, in addi- allergy to a glass ionomer in dental composite has
tion, polysulfide polymers (Pesonen et al. 2015; been reported (Kanerva et al. 1997). Methyl meth-
Kanerva et al. 2000; Bruze et al. 1996). acrylate (MMA) allergy is reported in a dental
In the report by Aalto-Korte et al. (2015a), also technician handling prosthetic composites (see
a series of eight sewage pipe re-liners with contact ▶ Chap. 51, “Acrylic Resins”).
allergy to epoxy resins and polyamine hardeners
were presented. Although sewage renovation 6.1.4 Polyurethane Resins
might often be regarded as a “non-composite Diisocyanate hardeners in polyurethane resin
industry,” this rapidly emerged new pipe-relining systems are well known contact allergens (see
technique entails impregnating a polyester or ▶ Chap. 54, “Polyurethane Resins”). Allergy to
other lining/sock with epoxy resins and leading diisocyanates originating specifically from PC
it into an old sewage pipe, thus forming a com- matrices themselves is rare, but methylene-
posite inside the old pipe. The risk of epoxy diphenyl diisocyanate (MDI) allergy has been
allergy in this work was reported first in 2012 in reported from, e.g., PC boat industry where it was
Sweden (Anveden Berglind et al. 2012; Fillenham used as a raw material for floating foam (Aalto-
et al. 2012). Korte et al. 2012) and from a lacquer in floor
laminate industry (Frick et al. 2003). Allergy to
6.1.2 Phenol-Formaldehyde Resins the respective amine of MDI, namely, 4,4-
and Other Related Resins diamino-diphenylmethane (MDA), has been
There are several allergens in phenol- reported from epoxy composites (Rasmussen
formaldehyde resins (PFR), the commonest ones et al. 2005). Although reports are few, diisocyanate
being monomers and dimers with hydroxymethyl- allergy from PC cannot be ruled out as they may be
phenol structures (see ▶ Chap. 53, “Contact present in various composite applications.
Allergy to Phenol-Formaldehyde Resins”).
Resins of resol type are more allergenic than 6.1.5 Unsaturated Polyester Resins
novolacs. PFR allergy related to PC has been and Epoxy Vinyl Esters
reported from, for example, laminate production Unsaturated polyester resins (UPR) and epoxy
and friction material production, fiberglass manu- vinyl esters (VE) (see ▶ Chap. 55, “Polyester
facture, plywood and foundry work (Aalto-Korte Resins”) are common matrices in PC, but the
and Suuronen 2017; Bruze and Almgren 1988; resins themselves are highly polymerized and
Isaksson et al. 1999), and aircraft processing not allergenic. Instead, they contain organic
(Owen and Beck 2001). cobalt compounds as accelerators and 4-tert-
Melamine-formaldehyde resins (Isaksson et al. butylcatechol as an inhibitor in styrene in which
1999; Finch et al. 1999) and urea-formaldehyde UPR and VE are most often dissolved. Contact
resins (Bell and King 2002) have caused ACD in allergy to cobalt naphthenate and cobalt octoate
PC production. The most potent allergen in them has originated from, e.g., polyester putties (Aalto-
is formaldehyde, but also non-formaldehyde Korte and Suuronen 2016), other polyester resins
allergy from melamine-formaldehyde resin has (Aalto-Korte and Suuronen 2016; Bruze et al.
been reported in wood composite industry 1996; Jolanki et al. 1996; Minamoto et al. 2002;
(Aalto-Korte et al. 2003). Tarvainen et al. 1993), and VE resins (Tarvainen
et al. 1993) (▶ Chap. 45, “Cobalt”). 4-Tert-
6.1.3 Acrylates and Epoxy Acrylates butylcatechol is a rare but possible allergen in
Most of the acrylate and epoxy acrylate allergies PC based on UPR and VE (Bourne and Milner
from PC are due to composite restorations in dental 1963). Diethylene glycol maleate allergy from a
work. The commonest allergens are BIS-GMA, polyester putty has also been described (Pfaffli
2-hydroxyethyl methacrylate (2-HEMA), and et al. 2002). Although VE are synthesized from
epoxy resins and (meth)acrylates, these raw mate- automation, closed systems). Chemical protective
rials are already polymerized in PC matrices. gloves are necessary in all work with chemicals,
Bisphenol A diglycidyl methacrylate and in many PC processes, the skin has to be
(BIS-GMA) and other epoxy acrylates have been protected also from irritant fibers and dusts. The
patch tested at the Finnish Institute of Occupa- glove material must be selected according to the
tional Health (FIOH) in the 2000s in patients chemicals and products used so that it adequately
exposed to VE, however without finding any protects the worker. A concise guide on selecting
VE-associated epoxy acrylate allergy cases so chemical protective gloves based on the resin prod-
far (unpublished results). uct type appears in, e.g., Epoxy Folder, a recent
online publication by the Finnish Institute of Occu-
pational Health (Aalto-Korte et al. 2017). The
6.2 Irritant Contact Dermatitis from employees must be informed about the skin hazards
Plastic Composites in PC work so that they can act accordingly.
As PCs are extremely versatile, develop con-
The reported irritants include chemicals such as tinuously, and are prone to contain materials
styrene and acetone, detergents and peroxides, as harmful to skin dermatologists, occupational
well as glass fiber carbon fiber and other mineral health professionals and workplace safety person-
fibers, composite dusts, and mechanical irritation nel should follow the workers’ skin condition
(see ▶ Chaps. 38, “Fiberglass, Dusts” and ▶ 12, closely and be prepared for detailed investigations
“Contact Dermatitis Due to Irritation”) (Bruze if problems arise. Clinicians should be aware of
et al. 1996; Jolanki et al. 2002; Minamoto et al. novel composite materials and production tech-
2002; Ponten et al. 2004; Tarvainen et al. 1993). nologies in order to identify emerging risks as
early as possible.
7 Clinical Aspects, Testing,

and Prevention
8 Cross-References
Clinical investigations include follow-up of the
▶ Acrylic Resins
symptoms (location of the dermatitis, temporal
▶ Aircraft Industry
variation in relation to exposure), work history,
▶ Automotive Industry
and careful investigation of the exposures. This
▶ Boatbuilders
includes identification of the substances and mate-
▶ Cobalt
rials used at work and the type and area of skin
▶ Contact Allergy to Phenol-Formaldehyde
contact. Inspection of the safety data sheets (SDS)
Resins
of all chemicals is needed in order to detect skin
▶ Epoxy Resins
sensitizers and to target the skin tests accordingly.
▶ Fiberglass, Dusts
Patch testing of patient’s own materials such as
▶ Other Plastics
PC and their thermoset resins may be advisable, as
▶ Polyester Resins
they may contain allergens not available commer-
▶ Polyurethane Resins
cially. However, the testing must be done with
caution, because some unhardened PC materials,
e.g., prepregs, may contain strong allergens in
high concentrations. References
Prevention of dermatoses in PC work includes
safe and clean working habits and physical sur- Aalto-Korte K, Suuronen K (2016) Occupational contact
allergy to components of polyester resin systems. Con-
roundings and favoring processes that help to tact Dermatitis 75(1):14–19
avoid skin contact (avoidance of contamination of Aalto-Korte K, Suuronen K (2017) Screening allergic reac-
tools and workplace premises, separation, tions to resol resin based on phenol and formaldehyde
in a clinic of occupational dermatology. Contact Der- Bruze M, Edenholm M, Engstrom K, Svensson G (1996)
matitis 77(4):208–213 Occupational dermatoses in a Swedish aircraft plant.
Aalto-Korte K, Jolanki R, Estlander T (2003) Contact Dermatitis 34(5):336–340
Formaldehyde-negative allergic contact dermatitis Compton B, Lewis J (2014) 3D-printing of lightweight
from melamine-formaldehyde resin. Contact Dermati- cellular composites. Adv Mater 26:5930–5935
tis 49(4):194–196 Diem H, Matthias G, Wagner R (2012) Amino resins,
Aalto-Korte K, Jungewelter S, Henriks-Eckerman ML, Ullman’s encyclopedia of industrial chemistry
Kuuliala O, Jolanki R (2009) Contact allergy to epoxy [eBook]. Wiley-VCH, Weinheim
(meth)acrylates. Contact Dermatitis 61(1):9–21 Ehrenstein G, Kabelka J (2012) Reinforced plastics,
Aalto-Korte K, Suuronen K, Kuuliala O, Henriks- Ullman’s encyclopedia of industrial chemistry
Eckerman ML, Jolanki R (2012) Occupational contact [eBook]. Wiley-VCH, Weinheim
allergy to monomeric isocyanates. Contact Dermatitis Elias H, Mulhaupt R (2015) Plastic, general survey,
67(2):78–88 Chapter 4. In: Plastic composites, Ullman’s encyclope-
Aalto-Korte K, Suuronen K, Kuuliala O, Henriks- dia of industrial chemistry, 7th edn [eBook]. Wiley-
Eckerman ML, Jolanki R (2014a) Contact allergy to VCH, Weinheim, pp 1–17
epoxy hardeners. Contact Dermatitis 71(3):145–153 Fillenham G, Liden C, Anveden Berglind I (2012) Skin
Aalto-Korte K, Suuronen K, Kuuliala O, Henriks-Eckerman exposure to epoxy in the pipe relining trade – an obser-
ML, Jolanki R (2014b) Screening occupational contact vational study. Contact Dermatitis 67(2):66–72
allergy to bisphenol F epoxy resin. Contact Dermatitis 71 Finch TM, Prais L, Foulds IS (1999) Allergic contact
(3):138–144 dermatitis from medium-density fibreboard containing
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Aalto-Korte K, Kuuliala O, Henriks-Eckerman ML, tis in a company manufacturing boards coated with
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Weinheim Eckerman ML, Mustakallio KK, Kanerva L (1996)
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(2002) Identification of sensitizing diethyleneglycol trial chemistry[eBook]. Wiley-VCH, Weinheim,
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Inks and Dyes
58
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
2 Inks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
2.2 Nonindustrial Inks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
2.3 Inks in Printing Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
3 Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
3.1 Hair Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
3.2 Textile Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.3 Other Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Keywords • CM2. Soaps, detergents, and solvents are mainly

Acid dyes · Disperse dyes · Fiber-reactive responsible for irritant contact dermatitis.
dyes · Nonindustrial inks · Pentaerythritol • CM3. Allergic contact dermatitis due to inks is
triacrylate (PETA) · Textile dyes · Ultraviolet mainly reported from (meth-)acrylic com-
(UV)-cured printing inks pounds in UV-curable inks and varnishes.
• CM4. Permanent hair coloring systems are
frequent sensitizers in hairdressers, with dyes
1 Core Messages ( p-phenylenediamine, toluene 2,5-diamine
and p-aminophenol) and coupling agents
• CM1. Although seldom reported, contact der- (m-aminophenol).
matitis in printing industry seems frequent • CM5. Textile dyes in industry can sensitize
(in almost 50% of workers). workers, mainly in emerging countries, during
the fabrication, the mixing of dyes, and the
tinting textile processes.
• CM6. Among textile dyes, the most frequent
sensitizers are disperse dyes (anthraquinone
C. J. Le Coz (*) and azo dyes), fiber-reactive dyes, and the cou-
Cabinet de Dermatologie, Strasbourg, France pling agent Naphthol AS.
e-mail: christophe.lecoz@wanadoo.fr

https://doi.org/10.1007/978-3-319-68617-2_57
852 C. J. Le Coz
2 Inks 2.2 Nonindustrial Inks
2.1 Introduction Some cases are reported, but rarely concern

occupational activities; inks for stencils, bank
Inks are colored liquids (fluid or viscous) checks, and stamps were reported (Braun 1975).
intended to be applied as thin layers on several Aminoazotoluene and derivatives contained in foun-
media, in order to (re)produce information, mes- tain pens and ballpoint pen inks were used in the
sage, image, or decoration. Inks can be employed 1950s (Foussereau and Benezra 1970; Cronin 1980).
in a domestic, leisure, or medical activity, but Silver nitrate, at a 10% component of the ink
most frequently during an industrial process. contained in a skin marker used to mark patch
Media may be paper, cardboard, wood, glass, testing, is a classical irritant but seems to be a
textile, plastic, ceramics, metals, or even animal rare allergen, with two cases reported in 1948
and human skin (FIPEC 2011; Castaing and and due to marking patch tests (Özkaya 2009). It
Guilleux 2010). was tested 1% pet. and one patient also reacted to
Inks are more or less a complex and subtle silver sulfadiazine cream.
mixture of coloring substance dispersed in a
vehicle or binder. Coloring substances can be
classified into dyes (generally soluble into the 2.3 Inks in Printing Industry
binder) and pigments (nonsoluble, but dispersed
after crushing and mixing). The binders differ in Different ways of application can be used for
the type of ink used: they can be fat binders printing inks: direct application on the support
(mixture of resins and oils), solvent-based, (by writing or painting) or a mechanical printing
water-based, and can contain resins, oils and process like letterpress (the older process), flex-
lubricants, UV-curing or electronic-curing sys- ography, photogravure, offset, silk-screen print-
tems, charges, and many additives like plasti- ing, digital printing, or roller coating. The main
cizers, surfactants, stabilizers, (photo-) classes of inks depend on the type of application.
initiators, and preservatives. Offset inks contain pigments (carbon, mineral, or
Numerous allergens can be contained in clas- organic type), resins, oils, and additives. Flexog-
sical inks, some of them being tested by the raphy and photogravure processes use solvent or
standard series like colophony or chromates water-based inks.
(Meyer et al. 2000) but mostly at very low con-
centration. Printing industry is automated; some 2.3.1 Composition of Inks
products like lead-based or chrome-based pig- Solvent inks contain pigments, resins, solvents,
ments are or will progressively be banned, and and additives. Water-based inks include water
at least in occidental countries, occupational (10–75%), pigments, resins, solvents, and addi-
medicine highly contributes to prevention of tives: the binder is generally a blend of polymers
allergies in workers, but direct skin contact with like polyester-acrylics, polyurethane-acrylics, with
inks are frequent (constant) among workers. surfactants, antifoam, and alcohols as additives.
With the exception of UV-curable inks, occupa- Some compositions are indicated in Table 1.
tional allergy to classical inks is now seldom For silk-screen printing, the quality of the inks
reported, most cases being published before strongly depends on the medium: some are listed
1990 (Foussereau and Benezra 1970; Castelain in Table 2.
et al. 1980; Foussereau 1991). Nevertheless, a Since industrial processes are – at least in occi-
recent study based on questionnaires reported a dental countries – highly automated, occupational
prevalence of skin complaints among 49% of skin contact with inks, and consecutive occupa-
274 workers from contact with inks in the print- tional dermatitis induced by such agents, seems
ing industry in the United Kingdom (Livesley more rarely reported than in earlier times. Most
et al. 2002). cases of dermatitis are described in people who
58 Inks and Dyes 853
Table 1 Ingredients and compositions of some inks, with indication of some irritant (a) allergenic (b) compounds.
(Adapted from Castaing and Guilleux (2010))
Solvents (for
Dyes and pigmentsa,b Resinsa,b solvent inks)a Oilsa Additivesa,b
Offset Carbon black Hard resins: Mineral Siccatives: metal
Metals and metallic Colophony and oils carboxylates like
salts: titanium derivatives like gum cobaltb or
dioxide, calcium estera,b magnesium
carbonate, zinc oxidea octoate
and sulfur, silicatesa, Maleic (or fumaric- Vegetal Waxes:
iron oxidesa, chromate reacted) resinsa,b oils: polyethylene, etc.
oxides (III) and Phenol-formaldehyde linen, Antoxidantsa,b:
(VI)a,b, etc. resinsa,b tung, oximes
colza, (2-butanone
soybean oxime), BHT,
hydroquinone,
etc.
Azo-dyes (mono- and Alkyd resins: Rheology
di-azo)a,b obtained by modifiersa: silica,
Phthalocyanine esterification of alcohols,
dyesa,b glycerol or triethanolamine,
Dioxazin dyesa pentaerythritol by etc.
phthalic anhydride
and vegetal fatty
acidsa,b
Flexography Carbon black Cellulosic resins Alcohols: Plasticizers:
and (nitrocellulosic) n-propanol, citrates, adipates,
photogravure isopropanol, phthalates
solvent inks ethanol, etc.
Metals and metallic Vinyl resins: polyvinyl Glycols and Surfactants and
salts: titanium acetate, polyvinyl glycol ethers antifoam
dioxide, calcium chloride, etc.
carbonate, zinc oxide Polyurethane resins Esters, ketons, Biocides:
and sulfur, silicates, (isocyanates baseda,b) hydrocarbons, isothiazolinonesa,b
iron oxidesa, chromate with polyfunctional etc.
oxides (III) and (VI)b, aziridinesb
etc. Acrylic resinsa,b
Azo-dyes (mono- and Other: polyamides,
di-azo)a,b ketonic, maleic,
Phthalocyanine polyester, urea-
dyesa,b formaldehydeb,
Dioxazin dyes epoxyb, etc.
make the inks, but are rare in the users. Moreover, Air contamination may induce respiratory symp-
pigments or dyes themselves are rarely the cause toms. Washing hands, frictions, and use of irri-
of dermatitis from inks. tants seem to be the main causes for skin
symptoms due to contact with inks (Livesley
2.3.2 Irritants Associated with Use et al. 2002).
of Inks
Workers using inks (mainly printers, typesetters, 2.3.3 Ultraviolet (UV)-Cured
and press operators) are exposed to many irritants Printing Inks
that include soaps and detergents, alcohols, sol- UV-cured ink binders are composed by mono-
vents, greases and waxes, alkalis, and developers. mers, prepolymers, photoprimers, and additives.
854 C. J. Le Coz
Table 2 Examples of inks used for silk-screen printing. Table 3 Some components of UV-curable inks and over-
(Adapted from Castaing and Guilleux (2010)) print varnishes
Some special Photo Acetophenone and alpha-
solvents and initiators hydroxyacetone derivatives
Medium Ink additives Phosphine oxides
Paper and Nitrocellulosic, Methoxypropanol, Alpha-aminoketones
cardboard vinyl, acrylic, esters Benzophenones
styrene-acrylic
Thioxanthone and derivatives
Metals Epoxy, polyester, Butylglycol,
Monomers Acrylates (A), diacrylates (DA),
nitrocellulosic hardening agents like
triacrylates (TA), etc.
diethylenetriamine
Monofunctional: isodecyl A,
Plastics Cellulosic, vinyl Mineral oils, ketones
phenoxyethyl A, isobornyl A, etc.
or acrylic
Bifunctional: 1,4-butanediol DA,
Leather Polyurethane Isocyanates
1,6-hexanediol DA, neopentylglycol
and Plastisol Phthalates, PVC DA, polyethyleneglycol DA,
textiles (polymer within copolymers tripropyleneglycol DA, etc.
solvent)
Trifunctional: pentaerythritol TA,
Glass and Epoxy Epoxy-silane, trimethylolpropane TA, glycerol TA,
china glycols etc.
UV (UV-curable) Polyfunctional Multifunctional: dipentaerythritol
curable acrylic acrylates, primers pentaacrylate, ditrimethylolpropane
inks tetraacrylate, etc.
Prepolymers Unsaturated polyesters
Acrylated polyols: epoxy-acrylates,
UV exposition will induce polymerization of the polyurethane-acrylates, polyester-or
ink. Main compounds of dermatological interest polyether-acrylates, etc.
are indicated in Table 3. Additives Antioxidants: hydroquinone,
Sensitization to such inks has been reported at hydroquinone monomethylether, etc.
the end of the 1970s (Emmett and Kominsky
1977) and most reports of allergic contact derma-
titis are due to inks used by silk-screen printers. propane (epoxy diacrylate, also named Bis-GA)
Allergens include (meth)acrylic compounds, were reported in silk-screen printers (Kanerva
sometimes of epoxy type (epoxy (di) (meth)acry- et al. 2000). One patient also reacted to DGEBA,
lates), isocyanates, and photoactivators (Emmett and the other one to other acrylate compounds like
and Kominsky 1977; Björkner et al. 1980; 2-phenoxyethylacrylate and tripropylene glycol
Nethercott 1981; Malten and Seutter 1984; diacrylate (TPGDA). Patients sensitized to
Nethercott et al. 1983; Aalto-Korte et al. 2009). TPGDA, contained in UV-cured inks or in
It is important to test patients with their own UV-curing overprint varnishes, generally react to
products but a short screening series with several (di) (meth) acrylates (Aalto-Korte et al.
EGDMA, DEGDA, 2-HPMA, and PETA could 2009). TPGDA and a bifunctional aromatic meth-
screen around 90% of patients occupationally sen- acrylate related to Bis-GMA, were responsible for
sitized to (meth-)acrylates (Aalto-Korte et al. dermatitis in a silk-screen maker also reacting to
2010). other resins Bis-GMA and ethyleneglycol
2-Hydroxyethyl methacrylate (2-HEMA) was dimethacrylate EGDMA (Goossens et al. 1998).
pointed out in a silk-screen printer that had worked TPGDA was reported as the only acrylate and
in the manufacture of circuit boards (Jolanki et al. sensitizer indicated on safety data sheet in a patient
1994). Another bifunctional methacrylate, who reacted to several (meth) acrylates too
2-hydroxypropyl methacrylate (2-HPMA) was (Skotnicki and Pratt 1998). In an advertisement
reported (Björkner 1984) Several cases due to and silk printing worker, sensitization was
2,2-bis[4-(2-hydroxy-3-acryloxypropoxy)phenyl]- observed to bis-GA and diethyleneglycoldiacrylate
(DEGDA) contained in a UV-curable silk print 3.1.1 Vegetal and Metallic Dyes
primer, and to urethane acrylate resins, and other Henna, also known as lawsonia inermis (extract
acrylates as well (Aalto-Korte et al. 2009). Ure- from Lawsonia inermis L.), contains lawsone, a
thane acrylates and trimethylolpropane triacrylate naphthoquinone that may be responsible for aller-
(TMPTA) were reported in a series of six patients; gic contact dermatitis (Oztas et al. 2001) or imme-
three were also sensitized to pentaerythritol tri- diate symptoms like urticaria, rhinitis, and asthma.
acrylate (PETA), two to polyester acrylate, and On the other hand, “black henna” contains henna
two to Bis-GA (Björkner et al. 1980). and synthetic dyes like aminobenzenes, amino-
Polyfunctional aziridine hardeners are sensitizers toluenes, and/or aminophenols. Contact allergy to
(Garabrant 1985). Ink hardeners may contain 4,4- lead acetate, still authorized in hair dyes, seems to
0
-diaminodiphenylmethane (Jolanki et al. 1994). be rare and not reported in hairdressers (Cronin
Triglycidyl isocyanurate (TGIC) was reported 1980; Le Coz 2007).
in a silk-screen printer on circuit boards (Jolanki
et al. 1994). 3.1.2 Synthetic Dyes and Coupling
Benzophenone-4 contained at 32–55% in Agents
printing lacquer was described as a sensitizer as The oldest synthetic permanent dye, p-phenyl-
well (Caruana et al. 2011). ene diamine (PPD), remains the most frequent
delayed-type occupational sensitizing dye in
2.3.4 Various Inks hairdressers, despite being less used than tolu-
Hybrid offset inks are formulated like offset inks, ene-2,5-diamine. In a retrospective study
but also contain UV-curable components. of 729 hairdressers, 19% were sensitized to
EB (electron beam) inks harden after use of an PPD (O’Connell et al. 2010). Toluene-2,5-
electron beam, and are sparingly used. diamine (sometimes named p-toluene diamine
Overprint varnishes is a coating applied after a or PTD) is the most used permanent hair dye
piece is printed. More than one type of overprint (100 tons in 2002), but stands second in terms
varnish may be used to create special effects. The of sensitization rate (Søsted et al. 2004).
overprint varnish may be applied as an all-over 2-Nitro-p-phenylene diamine, although less
varnish or only to parts of the piece. Their com- frequently used in permanent hair dyes, is
position can be close to offset inks (fat varnishes), often positive in hairdressers sensitized to
acrylic type (water-based or solvent-based) or PPD (Søsted 2007). Immediate-type reactions,
UV-curable (close to UV-curable inks). including anaphylactic shock, have been
reported in consumers.
Among aminophenols, m-aminophénol is a
3 Dyes coupling agent, as o- and p-aminophenols are
used as dyes. Resorcinol is a coupling agent
The most implicated dyes in (occupational) con- widely used in permanent dyes, almost rarely
tact dermatitis are textile and hair dyes. Hair dyes positive in patch testing.
frequently cause both irritation and sensitization Other dyes (2-chloro-p-phenylene diamine)
in workers of hairdressing industry and con- or coupling agents (2,7-Naphthalenediol or
sumers as well, but most cases of textile dyes 2,7-dihydroxynaphthalene, pyrocatechol or
dermatitis are claimed occurring in consumers. 1,2-benzenediol) have not been reported in occu-
pational sensitizations. Semipermanent or transient
dyes like 3-nitro-p-hydroxyethylaminophenol,
3.1 Hair Dyes 4-amino-3-nitrophenol, 2-hydroxyethylamino-5-
nitroanisole, Basic Blue 99, Basic Red 22, and
They can be separated into “natural” (vegetal and HC yellow 7 were reported only in consumers
metallic) and synthetic dyes (Le Coz 2007). (Le Coz 2007).
856 C. J. Le Coz
3.2 Textile Dyes 3.2.1 Disperse Dyes

Disperse dyes, partially soluble in water, are used
There are thousands of textile dyes, marketed to color synthetic fibers like polyester, acrylic, and
under different names (up to 30 for some of acetate, and sometimes nylon, particularly in stock-
them) and the Color Index (C.I.) does not contain ings. They are not employed for natural fibers.
all information about them. A final textile color
often results from a subtle mixture of several dyes. Anthraquinone Dyes
Because of this, a priori unexpected dyes can be These dyes consist of substituted anthraquinones.
employed as yellow, red, or orange dyes, for black They are plastosoluble and used to stain synthetic
or blue garments, respectively. Moreover, a com- fibers such as polyester, acetate, or nylon. Dis-
mercial dye often comprises one or two major perse Blue 7, structurally related to Disperse
components, and even impurities. For example, Blue 3, showed positive reactions in patients sen-
Disperse Blue 124 contains several dyes and sitized to Disperse Blue 106 contained in their
traces of Disperse Blue 106, and “non-azo” impu- occupational uniform (Mota et al. 2000).
rities as ascertained by comparative thin layer
chromatography. These impurities can also be Azo Dyes
responsible for sensitization. The manufacturing Azo dyes are characterized by an R1-N = N-R2
processes are complex and additional procedures chemical structure. They represent the majority
such as bleaching can also lead to allergenic prod- of commercial colorants, enabling a broad spec-
ucts. Skin metabolism may be responsible for trum of shades and fastness properties. They are
transformation of dyes. For example, Disperse suitable for coloring various substrates, includ-
Orange 3 is degraded to p-phenylenediamine ing both synthetic and natural fibers. These
(PPD) and nitroaniline in the skin (Fig. 1) molecules are trapped within the fibers in which
(Le Coz 2011). they are formed during the dyeing process. Azo
According to their chemical structures and the dyes, disperse type, are used in synthetic fibers.
Color Index system, dyes can be classified into They are the molecules most often implicated in
17 groups: nitro dyes, triphenylmethane deriva- textile dye dermatitis, mainly in nylon stocking,
tives, xanthenes, acridine derivatives, quinoline socks, trousers, dresses, and underwear. Disperse
derivatives, azines, anthraquinones, indigoid Yellow 3, Disperse Orange 3, and Disperse Red
dyes, phthalocyanines dyes, oxidation bases, 1 were the principal sensitizers until the 1980s.
insoluble azo dye precursors, and azo dyes (clas- Today, Disperse Blue 124 and/or 106, Disperse
ses XII–XVII). In practice, textile dyes are classi- Orange 3, Red 1, or Yellow 3 are frequently
fied into different application classes: disperse, encountered.
acid, basic, direct, vat, fiber-reactive, sulfur, pre- The monoazoic compound Disperse Blue
metallic, solvent dyes, and naphthols. Sensitiza- 124 has been responsible for occupational derma-
tion can occur from the dye itself, from titis in the textile industry (Soni and Sherertz
intermediate products during the dyeing process 1996). It is closely related to another azo dye
or after-treatments, or from metabolites arising in Disperse Blue 106, marketed since 1985 and for-
the skin. This chapter focuses on textile dyes merly known as Disperse Blue 357. Five cases of
reported as occupational allergens only, but it is occupational allergic dermatitis were reported
very likely that the majority of sensitizations, among 200 employees wearing a working dark
occurring in dyeing and textile industry of emerg- blue smock (Mota et al. 2000). Thin layer chro-
ing countries, are not pointed out. matography revealed that the uniform contained
NO2 N N NH2 O2N NH2 + H2N NH2
Fig. 1 Degradation of Disperse Orange 3 into nitroaniline and PPD

Disperse Blue 106 and Disperse Red 1. Two Vat Dyes

patients also reacted to anthraquinonic Disperse Such water-insoluble dyes are applied in a
Blue 7, a third one with multiple reactions more reduced soluble form and then reoxidized to the
likely due to an angry back. original insoluble form once absorbed into the
Occupational airborne dermatitis has been fiber. They have high wet-fastness and are used
reported in occupational plants (Manzini et al. to dye cotton, flax, wool, and rayon fibers. Vat
1996) and in workers who sewed and ironed Blue 1 (synthetic indigo) is used to dye Levi
clothes (Carretero Anibarro et al. 2000), for Strauss 501 “shrink to fit” blue jeans. Vat Green
which reactive dyes and Disperse Blue 106 and 1, an anthraquinone derivative, has been reported
124 dyes were responsible, respectively. as an occupational cause of contact dermatitis due
Disperse Orange 3 remains a frequent allergen, to clothing, from navy-blue uniforms of nurses
but sensitization seems in frequent cases acquired (Wilson and Cronin 1971).
from hair dyes. With Disperse Yellow 3, they were
reported as contact allergens in textile industry Fiber-Reactive Dyes
(Soni and Sherertz 1996). Reactive dyes consist of a two-part, direct coloring
agent. The first moiety is a chromophore with an
3.2.2 Other Textile Dyes azo, anthraquinone, or phthalocyanine derivative
structure. This moiety is connected to a second
Acid Dyes reactive group, which is able to form covalent
These are used to color silk, wool, and other bonds with the amine or sulfhydryl groups of pro-
animal protein fibers, or nylon (polyamide) teins in the textile fibers. Such dyes are used for
when high wet-fastness is needed. Such dyes coloring cellulosic fibers (cotton, silk), wool, or
include monoazoic, diazoic, triphenylmethane, polyamides and are widely used for the production
and anthraquinone compounds. Acid Blue of clothes, most sources of sensitization being
158, an azo dye contained in suture material occupational. Sensitization can occur during occu-
(Raap et al. 2008), was reported in two non- pational exposure, but reactive dyes should not be
occupational cases, although one of them was tested in nonoccupational patients, although the
suspected to have been induced by toluene risk of active sensitization is theoretically of little
2,5-diamine sensitization in a hairdresser consequence. Occupational airborne dermatitis has
(Hausen 2003). been reported in occupational plants (Manzini et al.
1996), and in workers who sewed and ironed
Basic Dyes clothes (Carretero Anibarro et al. 2000). Reactive
These are mainly used to dye wool and silk, dyes, and Disperse Blue 106 and 124 dyes were
acrylic, modacrylic, nylon, polyester, and blends responsible, respectively.
of these fibers with cotton. They can be applied to
cotton with a mordant. Basic dyes comprise Dye-Fixing and Dye-Coupling Agents
monoazoic, diazoic, and azine compounds. Basic Naphthols are coupling agents, used for staining
Red 46, a monoazoic dye was implicated in occu- and dyeing. β-Naphthol (2-naphthol, Azoic cou-
pational dermatitis (Chave et al. 2003). It seems to pling component 1, CAS [135-19-3]) is no
be an important cause of foot dermatitis, being a longer used in textile industry. Naphthol AS
frequent allergen in acrylic socks (Opie et al. (3-hydroxy-2-naphthoic acid anilide, Azoic Cou-
2003). pling Component 2), a coupling agent used for
cotton dyeing, has replaced beta-naphthol because
Direct Dyes of a stronger affinity for cellulose. Naphthol AS
These dyes are directly applied on fibers, most first caused pigmented contact dermatitis in
often cotton, wool, flax, or leather, in a neutral or workers at a textile factory in Mexico in the
alkaline bath. They have low wet-fastness and 1970s, where it was widely used. It was reported
frequently need after-treatments. as an agent of, sometimes, pigmented contact
858 C. J. Le Coz
dermatitis in several patients (Roed-Petersen et al. contact dermatitis from disperse dyes. Contact Derma-
1990). Several other naphthols are used for textile titis 43:44
Caruana DM, McPherson T, Cooper S (2011) Allergic
dyeing, like Naphthol ASD (3-hydroxy- contact dermatitis caused by benzophenone-4 in a
2naphthoic acid o-toluidine), Naphthol AS-E printer. Contact Dermatitis 64:183–184
[2-naphtalenecarboxamide, 3-(acetyloxy)-N- Castaing G, Guilleux A (2010) Encres et vernis
(4-chloro-phenyl)-, azoic Coupling Component d’impression. Composition, risques toxicologiques et
mesures de prévention. INRS ED 6069
10], but they have not been reported as contact Castelain PY, Pirious A, Raulot-Lapointe H, Robaglia JL
allergens. (1980) Sensitization to abieto-formo-phenolic resin in
printing ink. Contact Dermatitis 6:145–146
Chave TA, Nicolaou N, Johnston GA (2003) Hand derma-
titis in a student caused by Basic Red 46. Contact
3.3 Other Dyes Dermatitis 49:161–162
Cronin E (1980) Contact dermatitis. Churchill Livingstone,
Except for textile and hair dyes, occupational Edinburgh
contact allergy to dyes seems to be rare. Emmett EA, Kominsky JR (1977) Allergic contact derma-
titis from ultraviolet-cured inks. Allergic contact sensi-
Food dyes are infrequently reported. Some tization to acrylates. J Occup Med 19:113–115
cases concern asthma due to carmine (E120), a FIPEC (2011). http://www.fipec.org/afei
natural dye extracted from cochineal (Acero et al. Foussereau J (1991) Guide de dermato-allergologie pro-
1998). fessionnelle. Masson, Paris
Foussereau J, Benezra C (1970) Les eczémas allergiques
Solvent Yellow 33 (CI 47000), also known as professionnels. Masson, Paris
D and C Yellow 11, caused occupational allergic Garabrant DH (1985) Dermatitis from aziridine hardener in
dermatitis in an explosive factory (Noster and printing ink. Contact Dermatitis 12:209–212
Hausen 1978), although the main cases reported Goossens A, Coninx D, Rommens K, Verhamme B (1998)
Occupational dermatitis in a silk-screen maker. Contact
with regard to this dye are due to the use of Dermatitis 39:40–42
cosmetics, mainly lip cosmetics (Sasseville and Hausen BM (2003) Allergic contact dermatitis from col-
Joncas 2009). ored surgical suture material: contact allergy to epsilon-
caprolactam and Acid Blue 158. Am J Contact Dermat
14:174–175
Jolanki R, Kanerva L, Estlander T, Tarvainen K (1994)
Concomitant sensitization to triglycidyl isocyanurate,
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Occupational Skin Infections
59
Burkhard Kreft and Cord Sunderkötter
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
3 Skin Infection as Occupational Diesease in Germany . . . . . . . . . . . . . . . . . . . . . . . . 865
3.1 Recognition as Occupational Skin Infection in Germany . . . . . . . . . . . . . . . . . . . . . . . . 865
4 Primary Skin Infections Due to Occupational Activity . . . . . . . . . . . . . . . . . . . . . . . 866
4.1 Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
4.2 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869
4.3 Mycoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 870
4.4 Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872
5 Skin Infections on Pre-Existing Occupational Dermatoses or
Pre-Damaged Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872
5.1 Pre-Existing Disease Not Occupational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
5.2 Pre-Existing Occupational Dermatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
6 Colonization of (Normal or Occupationally Damaged) Skin or Mucous
Membranes (Esp. in the Nose) with Infectious Agents . . . . . . . . . . . . . . . . . . . . . . . . 874
6.1 Colonization of Skin or Mucous Membranes with Multiresistant or
Potentially Hazardous Infectious Agents in Context of Occupational
Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
Abstract costs. Occupational skin infections are caused

“Occupational skin infections” are rarely life- by bacteria, viruses, fungi, or parasites. One
threatening, but they can be capacitating, lead needs to distinguish primary skin infections
to sick certificates, and cause considerable from skin infections secondary to pre-existing
occupational dermatoses or pre-damaged skin
and colonization of skin or mucous membranes
B. Kreft · C. Sunderkötter (*) with multiresistant or potentially hazardous
Universitätsklinik und Poliklinik für Dermatologie und infectious agents in context of occupational
Venerologie, Universitätsklinikum Halle (Saale), Halle activity. When an occupational skin infection
(Saale), Germany is suspected, a detailed history needs to be
e-mail: burkhard.kreft@uk-halle.de;
cord.sunderkoetter@uk-halle.de taken, including information of the workplace

https://doi.org/10.1007/978-3-319-68617-2_213
862 B. Kreft and C. Sunderkötter
and its conditions. This is important to under- Occupational skin infections are caused by bac-
stand the causal relation between the occupa- teria, viruses, fungi, or parasites. Primary and sec-
tional situation and the infection. ondary occupational infections (i and ii) are
sometimes interwoven or closely associated,
Keywords because certain working conditions encompass
Skin infection · Profession · Health care both (a) a skin-harming environment (due to activ-
worker · Bacteria · Virus · Mycoses · Parasitic ities prone to lead to abrasions and/or to exposure
infection to moisture) and (b) contact with materials which
harbor or are contaminated with occupation-spe-
cific pathogens or high quantities of common infec-
1 Core Message tious microbes. An example would be workplaces
of meat- or fishworkers, because they encompass
• Occupational skin infections are caused by work procedures that are physically stressful to
bacteria, viruses, fungi, or parasites. the skin and because they expose undamaged or
• Primary skin infections have to be distinguished pre-damaged skin to, e.g., S. aureus, Strep.
from infections secondary to pre-existing occu- pyogenes, Erysipelothrix rhusiopathiae, or HPV 7.
pational dermatoses or pre-damaged skin. In addition, workplace conditions can make
• Colonization of skin or mucous membranes workers susceptible to infections with partially
with multiresistant or potentially hazardous opportunistic pathogens. As such humidity or
infectious agents in context of occupational occlusive dressing or footwear causes maceration
activity has also to be taken into account. of the skin and provides favorable conditions for
• Protective measures are often helpful to mini- infections with dermatophytes, Candida spp., and
mize the risk of occupational skin infection. Corynebacterium spp.
Since certain professions have a higher risk of
occupational skin diseases and occupational skin
2 Introduction infections than others (see Table 1), persons who
work in such professional fields have to be
In several workplaces or occupations, especially advised how to protect and which measures are
when involving contact with animals, there is useful to prevent the risk of infection. For exam-
a risk of acquiring skin infections. These “occupa- ple, outdoor workers are exposed to stings by
tional skin infections” are rarely life-threatening, potential vectors which transmit, e.g., borrelia,
but they can be capacitating, lead to sick certificates rickettsiae, or Francisella tularensis and also to
and cause considerable costs. It must be taken into pathogens in the environment which can be
account that these infections can in some cases be implanted from soil or plants (e.g., Nannizzia
transmitted to other persons, for example, to family gypseum, pathogens causing mycetoma). There-
members (Harries and Lear 2004). fore they need to be informed how to minimize,
One needs to distinguish three conditions of e.g., risk of stings or other respective exposures.
occupational skin infections or occupational harm This chapter does not deal in detail with
by infectious agents: (a) systemic infections with cutaneous signs or
symptoms which are contracted, e.g., by health
(i) Primary skin infections. workers (such as measles, scarlet fever), (b) bite
(ii) Skin infections secondary to pre-existing injuries, (c) contact with poisonous (instead of
occupational dermatoses or pre-damaged infectious) animals, or tropical diseases which
skin. could be contracted by business travelers or field
(iii) Colonization of skin or mucous membranes workers.
with multiresistant or potentially hazardous When an occupational skin infection is sus-
infectious agents in context of occupational pected, a detailed history needs to be taken,
activity. including information of the workplace and its
59 Occupational Skin Infections 863
Table 1 Risk of occupational skin infections in different professions

Pathogen
Profession group Pathogen Disease
Butchers Bacterial Streptococcus pyogenes Impetigo
Slaughterhouse workers infections Staphylococcus aureus Impetiginization
Poultry dressers Erysipelothrix rhusiopathiae (from Erysipeloid
birds, pigs, and other mammals)
Brucella (Brucella suis, B. abortus, Brucellosis
B. melitensis)
Bacillus anthracis Anthrax
Viral Human papilloma virus type 7 Warts
infections (HPV 7)
Fishworkers Bacterial Streptococcus pyogenes Impetigo
Fishermen infections Staphylococcus aureus Impetiginization
Fish- or water-based Erysipelothrix rhusiopathiae (from Erysipeloid
occupations fish, shellfish)
Professional handling of Vibrio vulnificus from seawater or raw Severe soft tissue infection,
marine shells fish cellulitis
Mycobacterium marinum Fish tank granuloma
Farmer Bacterial Erysipelothrix rhusiopathiae (from Erysipeloid
Farm workers infections birds, pigs, and other mammals)
Agricultural workers Bacillus anthracis Anthrax
Brucella (Brucella suis, B. abortus, Brucellosis
B. melitensis)
Francisella tularensis Tularemia
Rickettsia Rickettsiosis
Viral Parapox virus Ecthyma contagiosum
infections (Orf)
Paravaccinia virus Milker’s nodules
Mycoses T. verrucosum (cattle) Tinea corporis, tinea
T. equinum (horses) capitis, tinea barbae
M. canis (cats/dogs)
M. gallinae (poultry)
T. mentagrophytes
Sporothrix schenckii Sporotrichosis
Veterinarians Bacterial Brucella (Brucella suis, B. abortus, Brucellosis
infections B. melitensis)
Viral Orthopoxvirus from cats, rodents Cowpox
infections (infrequently from cows)
Parapoxvirus (from sheep goats) Ecthyma contagiosum
(M. Orf)
Paravaccinia virus Milker’s nodules
Mycoses T. benhamiae (old name Tinea
T. mentagrophytes granulosum, Microsporia
Arthroderma benhamiae),
T. mentagrophytes, T. quinckeaneum
(old name T. mentagrophytes var.
quinckeaneum) (from small animals
such as guinea pigs)
T. verrucosum
M. canis (from cats and dogs)
(Professional) outdoor Bacterial Borrelia spp. Borreliosis
sportsmen infections
(continued)
Table 1 (continued)
Pathogen
Gardeners Bacterial Borrelia spp. Borreliosis
infections
Mycoses Nannizzia gypseum (so far Microsporia
Microsporum gypseum), Sporotrichosis
Microsporum fulvum (from soil)
Sporothrix schenckii
Workers in sewerage systems Bacterial Streptobacillus moniliformis (from rat Rat bite fever
infections bites)
Forestry workers Bacterial Borrelia spp. Borreliosis
Lumberjacks infections Rickettsia Rickettsiosis
Mycoses Sporothrix schenckii Sporotrichosis
Hunters Bacterial Rickettsia Rickettsiosis (in endemic
infections areas)
Francisella tularensis Tularemia
Tanners Bacterial Bacillus anthracis Anthrax
infections
Bath attendants Bacterial Pseudomonas aeruginosa Folliculitis/“whirlpool
infections dermatitis”
Wet workers, possibly in Mycoses Candida albicans Candidiasis
combination with sweet food
products: dishwashers,
barkeepers
Beach workers in tropical and Helminths Ancylostoma braziliense Larva migrans (creeping
subtropical regions eruption)
Lifeguards Helminths Schistosomatidae from fowl or birds Cercarial dermatitis
Water sport workers (e.g., Trichobilharzia regenti) (swimmer’s itch)
Paddy field, pond, and
aquarium workers
Athletes (contact sport), people Bacterial PVL positive S. aureus Furuncle, abscess
wearing occlusive footwear, infections Corynebacterium species, Pitted keratolysis
hyperhidrosis Micrococcus sedentarius
Mycoses Dermatophytes Tinea
Soldiers (especially navy), Bacterial Treponema pallidum (other) causative Syphilis and other STI
sailors infections agents of STI
Soldiers, especially in times of Bacterial Bartonella quintana Trench fever
combat and warfare infections Rickettsia Rickettsiosis
Treponema pallidum (other) causative Syphilis and other STI
agents of STI
Bacillus anthracis Anthrax (theoretical
exposition as terrorist weapon)
Parasitic P. vestimentorum and capitis Pediculosis (and respective
infections transmittable infections
such as trench fever)
Sarcoptes scabiei var. hominis Scabies
Sex workers Various STI
Bacterial e. g., Treponema pallidum Syphilis
infections
Viral e. g., HIV HIV/AIDS
infections
Parasitic Sarcoptes scabiei var. hominis Scabies
infections
(continued)
Table 1 (continued)
Pathogen
Pathologists Bacterial Mycobacterium tuberculosis Cutaneous tuberculosis
infections
Industrial workers Mycoses Anthropophilic dermatomycoses Tinea pedum
Laboratory workers Protozoa Different strains of Leishmania Leishmaniosis
Tropical forest workers infections
Mine workers Mycoses Tropical fungi Mycetoma
Helminths Ancylostoma duodenale, Necator Ancylostomiasis (primarily
americanus intestinal nematode, but
dermatitis at sites of entry)
People working with potentially infectious material in medical, diagnostic, or even research laboratories (e.g., technicians)
are generally at risk to contract infectious diseases from infectious agents they have to handle
Healthcare workers (physicians, nurses, etc.) are at risk to be exposed to all kinds of skin infections which are
transmittable from humans to humans
conditions. This is important to understand the – Helminthic diseases of mine workers (BK
causal relation between the occupational situation 3103) caused by Ancylostoma duodenale or
and the infection. The diagnosis should be proven Strongyloides stercoralis. This occupational
by microbiological investigations (Harries and disease has nowadays only historical signifi-
Lear 2004). cance (Dulon et al. 2015).
– Tropical diseases and spotted fever (BK 3104).
3 Skin Infection as Occupational People working with potentially infectious

Diesease in Germany material in medical, diagnostic, or even research
laboratories (e.g., technicians) are generally at risk
Skin infections and occupational groups or pro- to contract infectious diseases to all infectious
fessions (see Table 1). agents they have to handle.
Healthcare workers (physicians, nurses, etc.)
are at risk to be occupationally exposed to all
3.1 Recognition as Occupational skin infections which are transmittable from
Skin Infection in Germany humans to humans.
There may be controversy about acknowledg-
In Germany the list of occupational diseases in the ment of infections as an occupationally acquired
“Berufskrankheitenverordnung” (BKV) appendix disease in people who are working in foreign
includes diseases caused by infectious agents or countries upon delegation by companies or insti-
parasites as well as tropical diseases. The following tutions of their home country and who contract an
occupational diseases are listed and distinguished: infectious disease during that time whose preva-
lence is markedly higher than in their home coun-
– Infections with pathogens transmitted from try. It is acknowledged by some institutions as an
human to human in persons who work as occupationally acquired disease even when it is
healthcare workers or in a laboratory or if likely that the infection has been contracted by
persons are exposed to similar risk of infection private activities, because the exposure to higher
by another professional activity (BK 3101). prevalence is “a conditio sine qua non” (e.g.,
– Infections with pathogens transmitted from dengue fever, malaria, or HIV in office workers
animals to humans (BK 3102) which in endemic countries). According to German law
could include, e.g., trichophytia profunda in a – HIV/AIDS is acknowledged as an occupational
farmer, butcher’s warts, milker’s nodules, or disease (BK 3101 in the BKV appendix) only if
borreliosis in lumberjacks (Diepgen 2012). the insured person works as healthcare worker or
in a laboratory or if the person is exposed to malaise are rarely associated (Harries and
similar risk of infection by another professional Lear 2004). In about 80–90%, the infection is
activity and has been infected by this professional self-limiting; nevertheless, antibiotic treatment is
activity. For recognition as an occupational dis- recommended to reduce the risk of progression to
ease, it should be recognized as probable that the systemic disease and sepsis (Dixon et al. 1999).
infection has been caused by the insured profes- Postexposure prophylaxis can be discussed in
sional activity and no other source of infection selected cases (Swartz 2001). Reasonable preven-
might be considered (causal relation) (Jarke tive measures comprise livestock vaccination,
1993). Thus it has to be carefully investigated, if reduction in soil pollution, decontamination of
the risk of infection has been occupation-related, hides, and early isolation and treatment of
and this risk predominated suchlike that the sta- suspected cases (Harries and Lear 2004).
tistically much more important risk of extra-
professional, privately acquired infection (e.g., in 4.1.2 Brucella
case of HIV transmission through sexual inter- Brucella is a Gram-negative bacterium with
course) seems to be insignificant. The same worldwide distribution (Harries and Lear 2004).
has to be applied for infection with Treponema Whereas Brucella suis is usually found in pigs; B.
pallidum. abortus can be detected in cattle. Sheep and goats
are preferentially colonized with B. melitensis
(Harries and Lear 2004). The main risk of infec-
4 Primary Skin Infections Due to tion results from ingesting milk or cheese
Occupational Activity from contaminated animals. Occupations at risk of
infection are farmers, vets, abattoir workers, meat
4.1 Bacterial Infections packers, and laboratory technicians. Cutaneous
manifestations are infrequent and non-specific and
4.1.1 Bacillus anthracis rather a sign of systemic disease. Involvement of the
Bacillus anthracis, a Gram-positive, spore- skin can manifest as urticaria-like or violaceous
forming rod, is endemic in parts of Africa and papules, plaques or papulonodular exanthemas, ery-
Asia but can be observed worldwide (Harries thema nodosum-like lesions, or extensive purpura
and Lear 2004). In the UK and USA, infection is (Ariza et al. 1989; Metin et al. 2001).
rare (Bales et al. 2002). Animals can be infected Treatment is with antibiotics. Prevention is
by spores when feeding on contaminated soil. The achieved by reducing exposure to infected ani-
spores are quite resistant and survive for decades mals through vaccination (Schurig et al. 2002).
in soil and contaminated animal material (Harries Control and eradication programs in different
and Lear 2004). People handling with meat, wool, livestock groups seem to be useful (Hunter et al.
or hides, such as tanners, butchers, and agricul- 1994).
tural workers, are at risk for infection. As Bacillus
anthracis has also been used as a terrorist weapon, 4.1.3 Erysipelothrix Rhusiopathiae
now postal workers and military personnel could Erysipelothrix rhusiopathiae is a Gram-positive
become theoretically exposed (Harries and Lear bacterium which causes erysipeloid. The bacte-
2004). In most cases of infection, the skin is rium infests fish and shellfish but also mammals
affected usually when there is cutaneous trauma and poultry. There is risk of infection when han-
with contaminated materials (wool, occasionally dling with decaying animal products (Harries and
called woolsorter’s disease). An initial painless Lear 2004). Risk occupations concern people who
pruritic papule with vesiculation (no pustule are working as fishermen, butchers, cooks,
despite the name “malignant pustule”) transforms farmers, and poultry dressers (Wang et al. 2002;
in painless (!) necrosis and ulceration, called Fidalgo et al. 2000). Clinically a localized cutane-
“black eschar” and is surrounded by edema. ous infection manifests as intensely red, slightly
Local lymphadenopathy, low-grade fever, and raised often painful slowly spreading well-
demarcated patches or plaques. Due to exposition, of erythema chronicum migrans, arising from the
the hands are involved (Harries and Lear 2004), tick bite site as a gradually enlarging annular rash
and lymphangitis is often associated. Rarely dif- (Harries and Lear 2004). The occurrence of sev-
fuse cutaneous and systemic infection with septi- eral erythemata chronica migrantia indicates dis-
cemia and then typically endocarditis occur. semination of Borrelia. In the later course
Cutaneous infections are usually self-limiting. lymphocytomas (lymphadenosis cutis benigna)
Antibiotic treatment with penicillin and ceftriax- can be observed. Various neurological, ophthal-
one as first-line drugs is recommended however to mic, and cardiac disorders can manifest as well as
reduce the risk of septicemia and endocarditis arthritis and psychiatric symptoms in the further
(Harries and Lear 2004). Strict hygiene of work course. Acrodermatitis chronica atrophicans is a
environments is useful as preventive measure. dermatological sign of late chronic borreliosis.
Fidalgo et al. support commercially available Treatment options include doxycycline or paren-
home disinfectants as effective measure to kill teral ceftriaxone, depending on the stage of dis-
these bacteria (Fidalgo et al. 2000, 2002). ease (Goodwin et al. 1990). Prevention is through
avoidance of tick bites and antibiotic treatment in
4.1.4 Treponema Pallidum case of infection.
Syphilis is a sexual transmitted disease and caused
by the spirochaete Treponema pallidum. 4.1.6 Rickettsial Infections
Venereal disease can facilitate transmission of Rickettsia are Gram-negative obligate intracellu-
other sexual transmitted diseases like gonorrhea lar microorganisms which multiply within
or HIV so that control of syphilis, along with other endothelial cells and in some cases also within
sexually transmitted infections, should be an leukocytes. There are roughly two groups: spotted
important public health issue (Fleming and fever group and typhus fever group rickettsiae. It
Wasserheit 1999). Sex workers are at risk for is transmitted by an arthropod vector, and there-
infection. Treatment with penicillin is effective fore besides travelers (Schlinsog et al. 2016), peo-
and is recommended as first line except in case ple working outdoors can be infected, such as
of hypersensitivity to penicillin. Preventive mea- farmers, trappers, rangers, hunters, surveyors, sol-
sures to reduce risk of syphilis spreading are the diers, and guides. A study conducted between
consistent use of condoms, regular and frequent 1984 and 1987 in Egypt found antibodies to
medical examination of particularly sensitive risk R. typhi in 19% (33/178) of garbage collectors
groups like sex workers to detect an eventual (Botros et al. 1989). Rickettsial infections can
infection in a very early stage and a consistent be imported by people working in countries
treatment management. Finally, in Germany pseu- where certain rickettsia groups are endemic. This
donymous registration and the tasks of the public can be expected predominantly for infections
health services are regulated by legislation (§19 with R. conorii in Mediterranean countries,
Infektionsschutzgesetz). R. africae in Africa (Smoak et al. 1996), and
Non-venereal syphilis was traditionally a haz- R. tsutsugamushi in southeastern parts of Asia
ard for glassblowers who shared mouthpieces (Marschang et al. 1995).
(Harries and Lear 2004). In most spotted fever rickettsiosis and in scrub
typhus, an eschar can be detected at the inocula-
4.1.5 Borrelia tion site. A maculopapular rash, sometimes
Borreliosis is caused by the spirochaete Borrelia admixed with petechiae or other signs of hemor-
and is transmitted by the Ixodes tick. Various rhage and high fever of several (often 5–7) days,
species are known. Ixodes is a parasite on small and headaches are clinically relevant signs for
mammals and deer in wooded areas. Occupational diagnosis and prompt treatment usually with
infections mainly affect forestry workers, outdoor doxycyclines. Some rickettsioses only manifest
sportsmen, and gardeners. The first clinical signs with an eschar and accompanying lymphadenop-
of borreliosis are characterized by the appearance athy (tick-borne lymphadenopathy by R. slovaca).
Murine (endemic) typhus is caused by Rickett- susceptibility testing reveal the best combination
sia typhi and transmitted by rat and cat fleas of antimicrobial agents. Combination with sur-
(Harries and Lear 2004). Scrub typhus is caused gery is possible. Preventive measures include
by Orientia tsutsugamushi that is transmitted by hand protection recommendations for profes-
mites that live on field rodents. Fever, primary sionals and all persons manipulating fishes or
cutaneous lesion, lymphadenopathy, hepatosple- fish tank water. Furthermore the use of alcohol
nomegaly, and exanthema can be observed. It is disinfection after contact is important (Aubry
potentially life-threatening without treatment et al. 2017).
(Sirisanthana et al. 2003). Rocky Mountain spot-
ted fever is caused by Rickettsia rickettsii that 4.1.8 Mycobacterium Tuberculosis
infects humans through tick bites causing fever, Occupational cutaneous inoculation tuberculosis
malaise, headache, gastrointestinal bleeding, and such as lupus vulgaris, scrofuloderma, and tuber-
petechial rash. Without treatment Rocky Moun- culosis verrucosa cutis is nowadays rare in the
tain spotted fever can be fatal. developed countries but can affect pathologists.
4.1.7 Mycobacterium marinum 4.1.9 Francisella Tularensis

Mycobacterium marinum is an acid-resistant, Francisella tularensis is a Gram-negative,
non-tuberculous mycobacterium. Among non- pleomorphic, non-motile bacterium responsible
tuberculous mycobacteria, it is the leading cause for the zoonosis tularemia (Jenzora et al. 2008).
of extra-respiratory human infections worldwide Even if the bacterium does not form any spores,
(Aubry et al. 2017). There is risk of infection in it is relatively environmentally resistant especially
case of skin lesions following exposure to fresh, in lower temperatures. Francisella tularensis is
salt, and brackish water contaminated with Myco- divided into four subspecies: F. tularensis ssp.
bacterium marinum. People with fish- or water- tularensis (Biovar Type A), ssp. holarctica
based occupations are at risk (Harries and Lear (Biovar Type B), ssp. mediasiatica, and ssp.
2004), such as people processing fish or cleaning novicida, which differ in their virulence and geo-
fish tanks in restaurants or fish markets. Non- graphic occurrence (Jenzora et al. 2008). Small
professional risk is in aquarium owners or swim- mammals such as rabbits, hares, but also domestic
ming in non-chlorinated pools, esp. when skin and wildlife animals can be infected by
lesions serve as a port of entry (Aubry et al. F. tularensis. In addition blood-sucking arthro-
2017). Clinically skin lesions usually appear at pods such as ticks and horseflies are another,
the site of inoculation as a painless, sometimes perhaps underestimated, source (source: www.
painful papule that may transform in verrucous rki.de). Hunters in endemic areas and meat
lesion or become ulcerated. Skin lesions can be workers have an elevated risk to be exposed to
single or multiple and can disseminate to joint F. tularensis by handling animal skins or carcasses.
and bones (Aubry et al. 2017). The lesions Infection of skin manifests as ulcer at site of
typically occur on the extremities in swimming tick or inoculation, regional lymphadenopathy
pool-related cases and especially on the hands and fever. Tularemia is treated with antibiotics
and fingers. In general, the cooler parts of the like aminoglycosides, fluoroquinolones, tetra-
body like the extremities are preferentially cyclines, chloramphenicol, and rifampicin. Pen-
involved by infection through Mycobacterium icillin and other beta-lactam antibiotics are
marinum as growth of M. marinum is slow at without effect (source: www.rki.de). Preventive
temperature 37 C. Papules and nodules develop measures: Hunters should wear protective
along the regional lymphatics resembling sporo- gloves when they have contact to animals, espe-
trichosis (sporotrichoid distribution). Treatment is cially during skinning dead animals. If there is
performed with clarithromycin until results of risk of development of aerosol, a protection
breathing mask is recommended. Subjects zoo animals, and circus animals for cowpox
working in laboratories have to be informed when they present with skin lesions. As preven-
when there is suspicion of infection with tive measures protection gloves should be used
F. tularensis (source: www.rki.de). (Hemmer et al. 2010).
4.1.10 Bartonella Quintana 4.2.2 Parapoxvirus

B. henselae causes cat scratch disease and bacil- Orf (ecthyma contagiosum) is caused by para-
lary angiomatosis; B. quintana causes trench fever poxvirus, a paravaccinia subgroup of poxviruses
and bacillary angiomatosis. B. bacilliformis that can infect sheep and goats. The virus is dis-
causes Carrion’s disease. Acute or chronic courses tributed worldwide. The infected animals present
depend on immune status and other factors. a pustular dermatitis around the mouth and feet.
The human body louse, Pediculus humanus Zoonotic infections in humans mostly occur after
corporis, which lives in clothes and is associated occupational exposure (Kitchen et al. 2014). Pro-
with poverty, lack of hygiene, cold weather, and fessions at risk are veterinarians, farmers, and
circumstances of warfare is the usual vector sheep herders. The clinical course is characterized
of Bartonella quintana (Raoult and Roux 1999), by development of red papule or nodule with
the agent of trench fever. It is characterized surrounding erythema. Multiple lesions can
by attacks of fever that last 1–3 days and recur occur (Larcher et al. 2009). In most cases the
every 4–6 days. Headache, skin pain, and dizziness hands are concerned. Ulceration can sometimes
may be associated (Karem et al. 2000; Ohl and be observed. Lymphangitis may be associated.
Spach 2000). The lesion often heals without sequelae within
8 weeks. Usually lifelong immunity develops
after the primary infection.
4.2 Viral Infections
4.2.3 Paravaccinia Virus
4.2.1 Orthopoxvirus Paravaccinia virus is transmitted by direct contact
Orthopoxviruses can cause cowpox disease. Cow- from udders of infected cows to humans causing
pox virus infection of humans is an uncommon, the “milker’s nodules.” Farmers and vets, espe-
potentially fatal skin disease. Nowadays cats and cially who have not yet developed immunity, are
rats are more responsible often for transmission. frequently affected. Clinically painful nodules
Animal care personnel who have direct contact usually on exposed sites are seen which can be
with orthopoxvirus-inoculated or orthopoxvirus- similar to the lesion in Orf’s disease. These nod-
infected animals or their secretions are at risk. ules become crusted in the further course and
Furthermore, healthcare personnel can be exposed resolve spontaneously (Harries and Lear 2004;
when involved in caring for orthopoxvirus- Schuler et al. 1982). Preventative measures
infected persons. include wearing protective gloves, isolation of
Patients infected with orthopoxvirus bovis infected cattle, and automated milking procedures
develop within 1–2 weeks flu-like symptoms. Red (Harries and Lear 2004).
patches which can transform in papules, pustules, or
ulceration develop preferentially on the hands and 4.2.4 HIV
fingers but can also be observed on face and neck. The human immunodeficiency virus (HIV) is a
Within 6–8 weeks healing with cicatrices can usu- retrovirus and is responsible for HIV infection and
ally be observed. Lymphangitis can be associated. acquired immunodeficiency syndrome (AIDS).
As preventive measure, contact between cap- Occupational-related transmission is a result of
tive animals and small rodents should be avoided. parenteral inoculation of HIV-containing body
Furthermore, it is advisable to investigate pets, fluids, blood, or blood components. The transmission
risk in case of occupational exposition is, depending of patients with active infection and wearing of
on the nature of the exposition, statistically at an gloves during exposure prone procedures (Harries
average of 0.3%. Persons at risk for occupa- and Lear 2004).
tional infection are medical staff, e.g., through
needlestick injury and also in sex workers (pros- 4.2.6 Human Papilloma Virus (HPV)
titutes). It should be noted that these risk situa- Butchers and meat and fish handlers are at risk
tions also go along with risk of infection with of acquiring viral warts in the course of their
hepatitis B/C virus. The infectivity is up to 100 work, probably due to a combination of trauma,
times lower than infection with hepatitis B. low working temperatures, and humidity. Without
The actual European AIDS Clinical Society meat contact or contact with meat juice, there is
Guidelines (EACS Guidelines 2017) provide usually no occurrence of butcher’s warts
beside the immediate measures of skin disinfec- (Schindera and Schindera 2005). Various types
tion for the following course of action in case of of HPV are responsible for development of warts
occupational HIV exposure with possible risk of (Gabal and el Geweily 1990; Jablonska et al.
infection (e.g., needlestick injury): 1988); however, HPV 7 (“butcher’s wart virus”),
as an ubiquitously occurring virus which does not
– Rapid testing of the source person for HCVand cause warts among the general population and
HIV (if HIV-status unknown). which is not transmissible from animals to man
– If source person HIV-positive on antiretroviral (no zoonosis), seems nevertheless to be almost
treatment, order resistance testing if HIV-virus exclusive to this group of workers (Orth et al.
load detectable. 1981), for example, workers in slaughterhouses.
– Individualize postexposure prophylaxis Working with meat or meat juice seems therefore
according to the source’s treatment history to be an essential causal factor. Protective gloves
and previous resistance tests. and an automated working environment can
reduce the prevalence of warts (Gabal and el
Preventive measures consist of wearing protec- Geweily 1990; Jablonska et al. 1988).
tive gloves and information on the safe handling
and disposal of injecting equipment. Sex workers 4.2.7 Dengue Virus
should be consequently advised to use condoms. Symptoms, such as fever, rash, as well as head-
ache, myalgia, and arthralgia (dengue triad),
4.2.5 Herpes Simplex occurring in the interval between entering an
Herpes simplex virus can be transmitted from endemic region and up to 2 weeks after leaving
human to human, also to those previously that region may indicate dengue fever (Tjandra et
infected. The infection occurs at the site of inoc- al. 2017). People working professionally in
ulation (which differs from the site of usual recur- endemic areas are at risk for the infection. Preven-
rence). Subjects at increased occupational risk tive measures such as repellants and avoiding
include professional sportspeople performing areas of stagnant water are useful.
contact sports with direct skin contact (wrestlers)
and health personal, especially dentists exposed to
oral or respiratory tract secretions. A localized, 4.3 Mycoses
painful erythema with vesicle formation occurs
often with local lymphadenopathy (Harries and 4.3.1 Dermatophytes
Lear 2004) (e.g., herpetic whitlow at fingers). Occupationally related anthropophilic mycoses
Diagnosis can be confirmed indirectly by Tzanck usually occur secondary to workplace conditions
smears and directly by PCR (Jain et al. 2001). which provide favorable conditions such as occlu-
Preventative measures include avoiding treatment sive footwear.
Certain groups such as miners, sailors, farmers, of deep subcutaneous mycoses. Sporothrix
laborers, and sportsmen are at greater risk of tinea schenckii, for example, is a typical cause of
pedum due to humid, occlusive footwear. It has rose grower’s disease. The mycetoma is an
been shown that humidity is the most important example of a tropical mycosis caused by
factor aiding skin penetration of the fungus. Madurella mycetomatis which can be acquired
Minor skin trauma and higher temperatures also as a result of barefoot walking.
help. Prevention measures should include daily
foot washing (Ninomiya 2000). Treatment can
4.3.2 Candida Infections
be realized by topical antifungal agents; in more
Candida is normally a saprophyte for immuno-
severe cases, oral antifungal agents in combina-
competent individuals with an intact skin and
tion with topical treatment are sometimes required
mucous barrier. For this balance an intact innate
(Crawford et al. 2004; Bell-Syer et al. 2004).
immune response is required. Candida com-
Clearly occupationally related mycotic infec-
monly cause infection of skin and mucosal sur-
tions are those from zoophilic fungi transmitted
face. Infection with Candida is often facilitated
from domestic animals or pets.
by local or systemic predisposition (Harries and
Trichophyton verrucosum is detected in
Lear 2004). Also the nail organ can be affected
cows but also in other animals such as horses,
under clinical picture of chronic paronychia.
sheep, and dogs. The mycotic infection is trans-
Working in humid conditions is a risk factor for
mittable from animal to human. Persons at risk
candida infection. At risk are subjects who have a
are those who have regular contact with animals
working place with frequent water contact, e.g.,
like farmers, veterinarians, or butchers. Clini-
dishwashers, barkeeper, and laundering. Combi-
cally superficial tinea corporis can develop, but
nation of wet work and handling of sweet prod-
deep trichophytia is common. Predilection areas
ucts (e.g., fruit cannery) gives adequate condition
are the face, scalp, extremities, and nails. In
for growth of candida. Also exposure to cutting
most cases the infection is associated with
oils seems to be a risk factor (Harries and Lear
inflammation and sometimes with bacterial infec-
2004). Prevention should include proper drying
tion, which can result in sequelae like cicatrices
of the skin and by wearing protective gloves
and post-inflammatory hyperpigmentation (Gina
eventually combined with under gloves of cot-
et al. 2012).
ton material.
Geophilic dermatomycoses (e.g., Micro-
Also diabetes mellitus use of broad spectrum
sporum gypseum, Microsporum fulvum) can be
antibiotics, steroids and immunosuppressive agents,
seen in gardeners. Development workers are at
iron and vitamin deficiencies is associated with a
risk for infection with tropical fungi like myce-
higher risk of cutaneous and mucocutaneous candi-
toma (Seyfarth et al. 2010).
diasis, independent of working conditions.
As opposed to infection with common
dermatomycoses, tropical mycoses often have a
serious course. Differentiation of occupational- 4.3.3 Sporotrichosis
induced dermatomycoses with anthropophilic Sporotrichosis is caused by Sporothrix, a
dermatophytes (e.g., tinea pedis with T. rubrum geophilic fungus which is found in the soil
or T. interdigitale) from extraprofessional causa- (de Carvalho Aguinaga et al. 2014). Subacute or
tion can be much more difficult than zoophilic chronic mycosis usually develops after trauma
dermatophytoses, where occupational contact with twigs, branches, thorns, and other vegetals
with infected animals is often clear and easier to by which the fungus is inoculated into the skin.
prove (Seyfarth et al. 2010). Sporotrichosis has been described as “gardener’s
In case of injury, gardeners, farmers, veterinar- disease,” primarily to be seen in rose planters. But
ians, forester, fishermen, or miners can be at risk also people working in rural areas such as farmers,
miners, lumberjacks, and others are at risk for 4.4.3 Helminths

infection (Ramos-e-Silva et al. 2007; Barros et Larva migrans (“creeping eruption”) is usually
al. 2011). Osteoarticular involvement is possible caused by the hookworm Ancylostoma braziliense
but very rare. Professionals should be informed to (Sunderkötter et al. 2014). Risk for transmission
wear gloves as an effective prevention measure to to humans is, when barefoot walking on con-
reduce risk of infection. taminated soil, particularly on beaches where
the animal feces are not always seen. Beach
workers in tropical and subtropical regions are
4.4 Parasitic Infections at risk for creeping eruption. The larvae pene-
trate intact skin and lead to a serpiginous, cuta-
4.4.1 Scabies neous itchy lesion which can move at up to 1 cm
Scabies is caused by the mite Sarcoptes scabiei per day (Chabasse et al. 1995). Keeping animals
var. hominis as an obligate parasite exclusively off the beach seems to be a reasonable preven-
affecting humans. In general, scabies is transmit- tive measure.
ted through direct skin-to-skin contact lasting at Responsible for cercarial dermatitis (“swim-
least 10–15 minutes. The risk of infestation mer’s itch”) are over 20 different schistosomas
increases with the number of mites on the patient’s that usually infect birds and do not cause systemic
skin surface and is exceedingly high in crusted infections. Feces of water birds as primary hosts
scabies (disseminated scabies, Norwegian sca- can be contaminated with ova of the pathogen.
bies), with thousands to millions of mites on The ova develop into larvae and infect water
affected skin areas. snails as intermediate hosts. The cercariae can
Contact persons are at risk for occupational penetrate the human skin but are not able to sur-
infection. Any occupation involving close contact vive in humans. There is occupational risk of
with large numbers of people is at risk. Examples infection especially in lifeguards, water sport
include medical personnel, workers in care homes workers, fishermen, paddy field, and pond and
or children’s day care, soldiers, and prostitutes aquarium workers (Folster-Holst et al. 2001;
(Harries and Lear 2004). Bastert et al. 1998).
As preventive measures patients suspected of Clinically itchy skin eruption mainly on
having scabies should only be examined with exposed skin can be seen, which is thought to be
gloves. Handwashing is not a reliable preven- an immune reaction against the cercariae. Treat-
tive measure and hand disinfection even less so ment is symptomatic as the skin eruptions resolve
(Sunderkötter et al. 2016). Large outbreaks of spontaneously within 2 weeks.
scabies require effort in terms of money, time,
and organization. Furthermore a coordinated
cooperation by dermatologists, primary care 5 Skin Infections on Pre-Existing
physicians, and health department are indis- Occupational Dermatoses or
pensable (Hewitt et al. 2015; Sunderkötter Pre-Damaged Skin
et al. 2018).
Concerning secondary infections which begin on
4.4.2 Protozoa pre-existing skin disease, one has to differentiate
Cutaneous and mucocutaneous leishmaniasis is between underlying diseases which are caused by
transmitted by sand flies and is endemic in cer- working conditions or infections on pre-existing
tain tropical and subtropical regions (Boecken non-occupational skin disease.
et al. 2011). Treatment response depends on the The cause of secondary infection is often a
Leishmania species (Harries and Lear 2004). damage to the epidermal barrier. This impair-
Persons at occupational risk for infection are ment of the epidermal barrier could be induced
laboratory, development, and tropical forest by genetically associated defects in key compo-
workers (Herwaldt 2001). nents of the epidermal barrier (primary barrier
disorder) as in ichthyoses or atopic dermatitis or on the plantar skin; sometimes large erosions can
through secondary barrier disorders in case of occur (Takama et al. 1997).
inflammatory skin diseases (e.g., allergic or irri- Topical antiseptic/antimicrobial treatment is
tant contact eczema) in which the epidermal helpful in many cases. Moreover the underlying
barrier homeostasis is disturbed (Schmuth et hyperhidrosis should be treated. This implies also
al. 2015; Mahler 2017). The people at risk are to avoid occlusive footwear wherever the working
those who are regularly exposed to physical and circumstances permit this.
mechanical damage of the skin in their profes-
sions (wet and/or dirty conditions, activities 5.2 Pre-Existing Occupational
which lead to abrasions). Dermatosis
Occupational contact dermatitis either as allergic

5.1 Pre-Existing Disease Not or irritative contact dermatitis can be complicated
Occupational by secondary infection. This can cause difficulties
to detect the underlying disease.
Patients with pre-existing atopic dermatitis Another example could be a possibly occupa-
have the risk of secondary infection usually due tional acquired tinea barbae with secondary bac-
to S. aureus, as skin barrier in atopic dermatitis is terial infection under the clinical picture of
reduced. There is also a certain risk of second- absceding tissue infection. Microbiological tests
ary infection with herpes simplex virus, and the are indispensable to prove the correct diagnosis.
complicated course can manifest as eczema Injuries, for example, as a result of work-related
herpeticum. Patients working in dirty condi- accident can manifest as infected wound in the
tions are at risk of bacterial infection. The further course. Usually bacterial infections with
pre-existing disease itself, even if not occupa- the Gram-positive bacteria staphylococci aureus or
tionally induced, can be aggravated by working hemolytic streptococci are secondary infections due
conditions with risk of secondary infection. to skin lesions (cuts, burns, puncture wounds, or
This should to be taken in account in the context abrasions) and ensuing invasion by these bacteria.
of occupational disease. Patient’s history and Many occupations are at risk, and these superficial
indicative atopic signs are to be examined to infections are apparently widely underreported
support the diagnosis of atopic dermatitis. Like (Harries and Lear 2004). Predisposed are, for exam-
atopic dermatitis, ichthyosis can also give rise ple, meatpackers as meat is thought to act as a
to secondary infection. vehicle of transmission for the infection (Harries
Wet working conditions (aggravation of and Lear 2004). Also fishworkers can be affected
atopic dermatitis) and working in dirty working as wounds on the hands are quite frequent in such
conditions have to be regarded as risk factor. professions. Hand eczema for whatever reason is at
Otherwise healthcare workers with atopic der- risk for infection.
matitis can be exposed to herpes simplex virus Bullous impetigo is caused when S. aureus
infection. expresses the gene for exfoliative toxin A or B
Corynebacterium species from the normal (ETA or ETB). Clinical hallmark in initial non-
microbiome can cause “pitted keratolysis” espe- bullous impetigo is a thin-walled vesicle on ery-
cially in people suffering from hyperhidrosis thematous ground which, however, ruptures rap-
or wearing occlusive footwear while having a ten- idly and extends peripherally, while the roof of the
dency for constitutive plantar hyperhidrosis. When blisters and the exuding serum leave honey-col-
they proliferate and infect the stratum corneum espe- ored brownish-yellow crusts. Therapeutic princi-
cially of the plantar skin, they cause malodor ples are as follows: (1) elimination or avoidance
(Harries and Lear 2004); pain and itching as well of eliciting factors and (2) antimicrobial treatment
as clinically whitish macerations and superficial ero- depending on the extent of impetigo; in limited
sions, particularly affecting pressure areas, are seen impetigo local antiseptics are sufficient (local
antibiotics must not be used); if infection spreads, References

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Leather and Shoes
60
Contents
1 Core Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
3 Manufacture of Leather . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
3.1 Pretanning Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
3.2 Tanning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
3.3 Post-Tanning Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
4 Occupational Dermatoses in the Leather Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
5 Production and Repairing of Shoes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
6 Occupational Dermatoses in the Shoe Industry and in Shoe Repairers . . . . . 884
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
Keywords Chloroacetamide · Octylisothiazolinone ·

Leather · Tanning · Chromium salts · Cobalt · Dimethylfumarate
Formaldehyde · Glutaraldehyde · Azo dyes ·
Mercaptobenzothiazole · Bismarck brown ·
Metanil yellow · Disperse orange 3 · 1 Core Message
• In the production and processing of leather and

J. Geier (*) in the manufacture of shoes, various allergenic
Information Network of Departments of Dermatology and irritating substances are used.
(IVDK), University Medical Center Goettingen, • Occupational skin disease is infrequently
Goettingen, Germany
e-mail: jgeier@gwdg.de; jgeier@ivdk.org reported in these branches.
• The most important allergens are chromium
H. Lessmann
Information Network of Departments of Dermatology salts, p-tert-butylphenol formaldehyde resin,
(IVDK), Department of Dermatology, University of rubber chemicals, and various biocides.
Goettingen, Goettingen, Germany • Many possible allergens are not available for
Information Network of Departments of Dermatology routine diagnostics, so sensitization may be
(IVDK), University Medical Center Goettingen, overlooked.
Goettingen, Germany
e-mail: hlessma1@gwdg.de

https://doi.org/10.1007/978-3-319-68617-2_58
878 J. Geier and H. Lessmann
• Residuals of allergens in leather or shoes also be cured using saturated brine, usually with addition
pose a risk for the consumer. of bactericides. Further methods of curing have been
established, e.g., application of disinfectants like
quaternary amines, radiation sterilization, or refrig-
2 Introduction eration, but these are less frequently used. The cured
hides are shipped from the slaughterhouse to the
Manufacturing leather is a process consisting of tannery (Heidemann 1990; Thorstensen 1995;
several subsequent steps which should be known Reich and Taeger 2009).
in detail to the occupational dermatologist, because On arrival at the tannery, the hides are soaked
every step is characterized by a particular chemistry, in water, thus removing the salt, dirt, and manure.
adding up to a variety of exposures and possible skin Bactericides and proteolytic enzymes are added to
hazards. Manufacturing shoes does not only involve the soaking water. This procedure takes about 6 h.
leather and glues but also various chemicals, of Afterward, the hides are trimmed and freed of
which several may cause a skin disease. flesh and subcutaneous tissue (fleshing), which is
usually done by machines with rotating knives. For
unhairing, the hides are then treated for 4–12 h with
3 Manufacture of Leather sodium sulfide (Na2S or NaSH) and lime (calcium
hydroxide). Under these alkaline conditions (pH 12),
Leather is made from the dermis of animal hides. the disulfide bridges in the keratin proteins of the hair
The subcutaneous tissue and the epidermis and and epidermis are broken, the hair fiber structure is
hair are removed during the production process. destroyed, and the hair can easily be removed
Generally speaking, the production of leather mechanically together with the epidermis. Other
includes three broad steps: (1) removal of all methods of unhairing like the use of proteolytic
parts of the hide which are not needed, (2) improv- enzymes, acids, or oxidizing agents are not frequently
ing physical resistance of the hide and stabilization applied (Heidemann 1990; Thorstensen 1995).
of the collagen and protection against biodegrada- After unhairing, the hides are again floated with
tion by tanning, and (3) processing of the tanned lime, but without sulfide. This makes them swell,
material in accordance with the desired qualities of so an opening of the structure for the following
the final product (Reich and Taeger 2009). tanning step takes place. In this state, the hide can
be splitted into sheets of desired thickness.
As tanning requires acid conditions, the hides
3.1 Pretanning Process have to be “delimed” before further processing.
By addition of ammonium salts and acids, a neu-
Bacterial degradation starts immediately after the tral pH is achieved. Proteolytic enzymes are added
removal of the hide from the animal corpse, so a to eliminate undesirable by-products from the
temporary conservation is necessary. One simple connective tissue and break down elastin in the
possibility is air drying, but this is not applicable hide (so-called bating), because elastin may make
for thick hides (>2 mm) because the surface may the leather too firm and stiff.
be sealed by drying, thus preventing water in deeper After removal of the degradation products, the
layers from evaporation which results in bacterial bated hides are pickled, i.e., brought to acid con-
growth in the center of the hide. Only thin hides ditions for tanning, which are reached by treating
like sheep or goat skins can be air-dried. Usually, the hides again with acids and salts.
the hides are protected with insecticides during this Pickled hides can be stored for a long time.
process. Salt curing by spreading sodium chloride However, mostly a continuous process of subse-
between the piled hides is the most frequently quent bating, pickling, and tanning is preferred,
applied curing method in modern commercial cattle during which the hides remain in the same pro-
hide production. This curing procedure takes about cessing drum (Heidemann 1990; Thorstensen
20 days, and the required amount of salt is about 1995; Reich and Taeger 2009; Febriana et al.
50% of the hide weight. Alternatively, the hides may 2012a).
60 Leather and Shoes 879
3.2 Tanning Table 1 Vegetable tanning materials (selection, modified

from Haslam 1989; Hausen 1981; Reich and Traeger 2009)
The most widely used tanning system is chrome Barks
tanning. Chrome tanning is usually done using Golden and black wattle (Acacia sp.), Oak (Quercus sp.),
basic chromium sulfate (2Cr(OH)SO4Na2SO4), spruce (Picea sp.), hemlock (Tsuga sp.), chestnut
(Castanea sp.), larch (Larix sp.), birch (Betula sp.),
in which chromium is trivalent and forms a com- yellow pine (Pinus ponderosa), beech (Fagus sylvatica)
plex which penetrates the hide at pH < 3. In the Woods
beginning of the process, the pH of the tanning Quebracho (Schinopsis lorentzii), redwood (Sequoia
solution usually is adjusted to 2.5. After the pen- sempervirens), oak (Quercus sp.), chestnut (Castanea sp.),
etration of Cr(III) into the hide, the pH is raised to red cedar (Thuja plicata)
3.5–4. Now the chromium complex is bound Leaves
firmly to the collagen protein forming cross- American sumach (Rhus sp.), Gambier (Uncaria gambir)
Fruits, fruitpods
links. The pH is raised further by adding sodium
Myrobalans (Terminalia chebula), valonea (Quercus
bicarbonate, thus transforming the chromium pro- aegilopsis)
tein complexes into stable structures (Heidemann Plant galls
1990; Thorstensen 1995; Reich and Taeger 2009; Oak (Quercus sp.), tamarisk (Tamarix articulata), aleppo
Febriana et al. 2012a). (Quercus infectoria)
Vegetable tanning has a far longer history
than chrome tanning. Although it is more time-
consuming than chrome tanning, it is still done leather is sold and shipped semifinished as so-
for special purposes, especially heavy leathers called wet blue. This is unsplit chrome-tanned
like in shoe soles, saddles, belts, etc. Vegetable leather which is protected against mold by bio-
tannins are polyphenolic compounds and can be cides, stacked in piles, and covered with plastic
classified into two groups: hydrolyzable tannins foil to prevent drying. The biocides in former
can be regarded as derivatives of pyrogallol, or current use are mercury salts, mercaptobenzo-
condensed ones as derivatives of (pyro)catechol. thiazole, DDT (dichlorodiphenyltrichloroethane),
The water molecules within the hide protein HCH (hexachlorocyclohexane) (Foussereau
structures are replaced by the phenolic groups et al. 1982), chloroacetamide (Jelen et al. 1989),
of the tannins. Subsequently, hydrogen bonds octylisothiazolinone, quaternary ammonium salts,
with the proteins are established (Heidemann chlorinated cresols, and derivatives of
1990; Thorstensen 1995; Reich and Taeger benzothiazole (Koch et al. 1996; Aerts et al.
2009). Vegetable tanning agents coming from 2016, 2017), in particular 2-thiocyanomethylthio
various sources (see Table 1) are brown, and benzothiazole (Febriana et al. 2012b, 2014, 2015;
they cause the typical odor of leather. Solutions Nardelli et al. 2005). The use of the latter sub-
of vegetable tanning agents contain residues stances is said to be increasing due to the prohibi-
from the plants like sugar, salt, and proteins. tion of pentachlorophenol, e.g., in Germany
Thus, growth of mold is promoted. (Koch et al. 1996). However, “wet blue” is often
Synthetic tanning agents are sulfonated con- produced in developing countries and sold to
densation products of formaldehyde and phe- European or other tanneries for further pro-
nols. They have fungistatic properties and are cessing, and the preservatives used in the produc-
therefore used in combination with vegetable tion countries are mostly not known to the
tannins. importing companies (Koch et al. 1996).
Other, less frequently used tanning agents are Usually, the leather is retanned using vegetable
salts of aluminum, iron, titanium, and zirconium. and/or synthetic tannins. This increases softness
These tanning methods are often combined with and makes the leather look more like vegetable-
chrome or vegetable tanning (Heidemann 1990; tanned leather (“natural look”). Furthermore,
Thorstensen 1995; Reich and Taeger 2009). retanning improves the structure of those sites in
Chrome-tanned leather has a light blue color the hide where chrome tanning has by accident
and tends to become stiff when dried. A lot of not fastened the fiber structure sufficiently.
Retanning with amino resins, i.e., oligomers and applied to the leather in a warm bath. Coming
constructed from urea, dicyanoamide, or mela- into contact with the chrome-tanned fibers of the
mine, results in a smooth leather. These resins, leather, the emulsion breaks, and the fat remains
cationic under acidic conditions, improve the fix- on the leather. The oils used are sulfated or
ation of other anionic compounds like dyes. Poly- sulfonated plant, animal, or fish oils or synthetic
acrylates and polymethacrylates are used for products usually biocide preserved (Heidemann
similar purposes (Heidemann 1990; Podmore 1990; Podmore 1995; Thorstensen 1995; Reich
1995; Thorstensen 1995; Reich and Taeger and Taeger 2009).
2009; Febriana et al. 2012a). As the leather has only little water resistance
Formaldehyde and glutaraldehyde (syn. glutaral, after all these processes, a hydrophobic treatment
glutaric dialdehyde) as well as some formalde- is necessary. For this purpose, silicones, organic
hyde-releasing substances are also used as cross- chlorofluoropolymers, or water-in-oil emulsions
linking agents in tannery. While glutaraldehyde are used (Heidemann 1990).
performs tanning properties under acidic condi- The colored and fatliquored leather is dried,
tions, formaldehyde requires a pH above 7. Glu- staked, and buffered. Staking and buffering are
taraldehyde is widely used in the production of mechanical treatments to increase flexibility and
upper shoe leather and formaldehyde in the pro- softness and to achieve special surface aspects.
duction of white leathers (Rietschel and Fowler The last step is finishing, i.e., application of a
1995). Both aldehydes are used for pretanning to protective and decorative coat. According to the
accelerate vegetable tanning. Glutaraldehyde is purpose for which the leather will be used, the
also used for retanning after chrome tanning finishes should protect, e.g., against abrasion or
(Heidemann 1990; Rietschel and Fowler 1995; water. Surface defects and irregularities in color
Thorstensen 1995; Febriana et al. 2012a). Glutar- should be leveled out. Usually, several layers of
aldehyde or mixtures of glutaraldehyde and form- finishing are applied. Water-based latex finishes
aldehyde are used to improve colorfastness and containing dyes or pigments may be applied first
washability of the final product (Koch et al. 1996). (Thorstensen 1995). Other base coats are poly-
acrylate dispersions which are often padded or
brushed onto the leather surface. After application
3.3 Post-Tanning Process the leather is ironed, so thermoplastification and
adhesion of the polymer to the leather fibers can
Almost every leather is dyed, mostly with syn- take place. The second coating, often poly-
thetic organic colors. The majority of the dyes acrylate, polybutadiene, or polyurethane disper-
used are anionic azo dyes which bind to the cat- sions, usually containing pigments as well, is most
ionic surface of the leather. For completion of the important for the appearance of the leather. It is
dyeing process, formic, acetic, or lactic acid is applied by spraying several times. After this, the
added. Afterward, basic dyes can be applied which leather is ironed again. The third layer is important
give the leather a brilliant shade. Metal complex for the feel and the rub resistance of the leather.
dyes are also widely used in the leather industry Usually, a solvent-based nitrocellulose solution or
(Heidemann 1990; Thorstensen 1995). The manu- water-based polyurethane or nitrocellulose emul-
facturers regard dyeing of leather as an art rather sions are used (Heidemann 1990; Podmore 1995;
than as a technique. Therefore, combinations of dyes Thorstensen 1995; Reich and Taeger 2009). Bio-
used are kept secret (Koch et al. 1996). cides are added to the finishing chemicals, if nec-
According to the final product, leather requires essary (Podmore 1995).
a certain softness which is achieved by application Dimethylfumarate (DMF) is used as fungicide
of fat. A fat content of 5% is essential; gloves, for mold prevention in finished leather products
garments, and upholstery may contain up to 15%. such as furniture (arm chairs, sofas), shoes, or
So, after dyeing, the leather is oiled. For this handbags. DMF is added to siccative sachets
process, called fat liquoring, oily fat is emulsified placed inside the furniture or in the shoe box
(Rantanen 2008; Williams et al. 2008; Giménez- among 37 patients working in the leather and fur
Arnau et al. 2009; Lammintausta et al. 2010; industry with an initial report of occupational skin
Susitaival et al. 2010). At room temperature, disease recorded in the register of occupational
DMF sublimates, thus impregnating the leather skin diseases in Northern Bavaria, Germany,
products with varying DMF concentrations. between 1990 and 1999, 10 cases of chromate
Alarmed by the epidemic of contact dermatitis, sensitization were diagnosed, of which 8 were
the use of DMF in consumer products is banned regarded occupationally relevant (Dickel et al.
EU wide since May 2009 (Anonymus 2009; 2001). Sensitization to chromate due to exposure
Anonymous 2012). to leather also was a significant cause of occupa-
tional hand dermatitis in a Danish survey from
2001 to 2002 (Skoet et al. 2004).
4 Occupational Dermatoses in As written above, tanning is done with trivalent
the Leather Industry chromium salts. Although it is known that triva-
lent chromium compounds penetrate the skin by
Considering the variety of potentially sensitizing far not as easily as hexavalent chromium com-
or irritating substances used, occupational derma- pounds (Spruit and van Neer 1966), it has been
toses in the leather industry are infrequently shown by analysis of chromium in the urine that
reported (Dickel et al. 2001). This may be due to tanners, apart from absorption via the respiratory
two facts: the increasing automation and the shift tract, may have a relevant chromium uptake via
of hazardous works to developing countries where absorption through the skin (Bulikowski and
attention to occupational dermatoses is less than Tyras 1976). Under alkaline conditions which
in industrialized ones (Cavelier and Foussereau may occur during the finishing process, trivalent
1995; Foussereau et al. 1982; Koch et al. 1996; chromium (Cr(III)) in leather can be oxidized to
Wardenbach et al. 1989). the hexavalent state (Cr(VI)) (Fregert 1981; Koch
Some decades ago, dichromate allergy was et al. 1996). In tanning, it happens that trivalent
more frequently observed in the leather industry chromium salts are not completely bound to the
in Europe, too. Wagner and Wezel (1966) ana- collagen fibers or that excessive chromium is not
lyzed expert opinions on occupational dermatoses washed out sufficiently. This can lead to a certain
in the department of dermatology of the Univer- amount of free Cr(III) in the leather which under
sity of Kiel, Germany, from 1952 to 1962. Of the the a.m. circumstances is oxidized to the hexa-
598 patients, 36 worked in the leather industry. valent state easily (Geier et al. 1995). In the epi-
Among these, the most frequent contact allergens dermis, Cr(VI) is reduced to Cr(III) by
were dichromate (19 patients), formaldehyde methionine, cysteine, or glutathione, and subse-
(8 pat.), leather dyes (8 pat.), and tanning quently Cr(III) binds to proteins forming the aller-
agents (2 pat.). Approximately until 1970, “occa- gen (Cavelier and Foussereau 1995; Samitz and
sionally” chromate sensitizations among tanners Katz 1964; Stein 1992). About one third of leather
were observed in France (Cavelier and products bought in Denmark had a Cr(VI) content
Foussereau 1995). Among 280 Swedish male of 3.6–14.7 ppm, while leachable Cr(III) was
patients with occupational contact allergy to chro- detected at levels of 430–980 ppm (Hansen et al.
mate observed by Fregert (1975) in 1960–1969, 2002). Release of total Cr and Cr(VI) depends on
12% were tannery workers. environmental factors, particularly on relative
In contrast, an analysis of approved occupa- humidity (Hedberg et al. 2015; Hedberg and
tional diseases from 1978 to 1984 in Germany Lidén 2016). In an earlier study, positive reactions
revealed that none of the 941 cases of allergic to samples of these leather products were not in
contact dermatitis due to chromium salts occurred line with their Cr(III)/Cr(VI) content (Hansen et
in the leather industry (Wardenbach et al. 1989). A al. 2006b). However, more recent investigations
similar development in France was stated by proved that a relevant amount of chromium is
Cavelier and Foussereau (1995). However, deposited on the skin when handling leather
(Bregnbak et al. 2016). Since 2015, the EU Com- feet caused by contact allergy to vegetable-tanned
mission Regulation No. 301/2014 limits the shoe leather exist (Cronin 1966; Minkin et al.
Cr(VI) content of leather goods which are made 1971). The allergens in the vegetable tannins,
for skin contact to 3 ppm. So, hopefully, this however, have not been identified.
exposure will lose its significance as cause of Also, occupational contact allergies to syn-
allergic contact dermatitis in the future. thetic tannins in the leather industry have not
Although trivalent chromium rarely sensitizes, been reported yet. However, Müller and Hausen
contact sensitization has been reported in tannery (1994) described a patient with contact allergy to a
workers who had exclusively been exposed to synthetic tannin present in a tincture for topical
Cr(III); on patch testing, they reacted to both, dermatological therapy.
Cr(III) and Cr(VI) salts (Estlander et al. 2000). Azo dyes like used in the leather industry have
Nygren and Wahlberg (1998) found small amounts a certain sensitizing capacity. Probably, p-
(average 0.08%) of sweat leachable hexavalent phenylenediamine (PPD) is an intermediate or
chromium in both, chromium- and vegetable- final product of the decomposition of some azo
tanned leathers. Patch testing with samples of dyes in the skin. This might explain the high rate
these leathers elicited allergic reactions in chro- of concomitant patch test reactions to these azo
mate-sensitized individuals. In a repeated open dyes and PPD in up to 50–80% of patients allergic
application test (ROAT) with a potassium dichro- to PPD (Hausen 1997). Although PPD cannot be
mate solution containing 50 ppm Cr(VI) and 1% regarded as a perfectly reliable indicator of a con-
sodium lauryl sulfate (SLS), about half of the tact allergy to azo dyes, it is often needed in this
patients reacted positively. Twenty percent even function because the incriminated dyes are
reacted at 5 ppm Cr(VI) in the presence of 1% SLS unknown (Estlander et al. 1990).
(Basketter et al. 2001). The authors drew the con- Occasionally, metanil yellow (acid yellow 36)
clusion that household products should not contain has been reported as a cause of contact allergy due
more than 5 ppm of Cr(VI). Recently, an increas- to leather products. A young man suffered from a
ing prevalence of chromate allergy due to leather foot eczema after wearing industrial leather pro-
goods has been reported from Denmark, which is tective shoes. On patch testing he reacted to meta-
plausible considering the mentioned amounts of nil yellow, which was present in the leather of the
Cr(VI) found in leather products (Thyssen et al. inners and stiffeners. He also reacted to the leather
2009). In chromate-sensitized patients, patch test itself and p-aminoazobenzene, PPD, and some of
elicitation threshold for Cr(III) was significantly its derivatives (Ancona et al. 1982). A woman
higher than for Cr(VI) (Hansen et al. 2006a). The working in a leather shop developed a contact
minimum concentration, to which at least 10% of allergy to metanil yellow, probably by contact to
the patients showed a positive reaction, was 6 ppm a brown leather portfolio. She also reacted to p-
for Cr(III) and 1 ppm for Cr(VI) (Hansen et al. aminoazobenzene and p-aminodiphenylamine in
2003). For routine diagnostic purposes, i.e., for the patch test (Hausen 1994).
patch testing, potassium dichromate in which Recently, cobalt, most probably from so-called
chromium is hexavalent is generally premetallized acid dyes, has gained interest as
recommended (Cavelier and Foussereau 1995; a relevant contact allergen in leather, causing
Fuchs et al. 1996; Rietschel and Fowler 1995). allergic contact dermatitis. Chemical analyses
Vegetable tannins have not been reported as a revealed high cobalt contents in leather goods;
cause of occupational contact dermatitis yet. but the cobalt spot test proved not to be reliable
Calnan and Cronin (1978) have seen a man suf- method to screen for cobalt in leather (Bregnbak
fering from allergic contact dermatitis due to a et al. 2015, 2017; Hamann et al. 2016; Thyssen
leather watch strap. In the patch test, he reacted et al. 2013). A certain pattern of contact allergens
to dichromate, myrobalan extract powder, and in the leather industry may be expected from
quebracho extract powder. Furthermore, some analyses of occupational dermatoses in this
case reports on patients with dermatitis of the branch. Foussereau et al. (1982) mention
potassium dichromate, dyes, and formaldehyde as mentioned callosities as occupational marks

the most frequent contact allergens in tanners. The caused by mechanical trauma in leather buffers
authors cite a manual from 1947 in which on the thumb, in cutters on the right index finger,
nigrosine, chrysoidine, and dimethyl amino and in glazers on the knuckles.
azobenzene are listed as sensitizing dyes, but
they state that these substances are no longer or
only rarely in use. 5 Production and Repairing of
Koch et al. (1996) analyzed data of the Infor- Shoes
mation Network of Departments of Dermatology
in Germany (IVDK) on contact allergies in Shoes are not only made of leather but of a broad
patients working in the leather and shoe industry. variety of materials. As shoes are subject to fash-
Of the 30,678 patients registered in the IVDK ion, their design and the materials used change
in the years 1990–1994, only 85 (0.3%) had more or less rapidly. Shoes are produced in many
an actual or former profession in this field. Com- countries of the world in different ways which
pared to all other patients, increased rates of makes it impossible to give a complete description
sensitizations to the following possibly occupa- of the occupational exposure of those working in
tional allergens of the standard series were the shoe industry. “It must be remembered that a
noted: potassium dichromate, p-phenylenediamine, modern shoe is so complex that the final assem-
formaldehyde, p-tert-butylphenol formaldehyde bler may not be aware of all of the chemicals that
resin (PTBP-F-R), mercaptobenzothiazole, and have been used to prepare each of the shoe’s parts,
nickel sulfate. On patch testing with the leather because they may have come from all over the
industry series, allergic reactions were noted world to finally come together in a finished piece
to glutaraldehyde, p-aminoazobenzol, Bismarck of footwear” (Rietschel and Fowler 1995).
brown, octylisothiazolinone, disperse orange 3, Shoe uppers can be made of textiles, leather,
1,3-diphenylguanidine, and chloroacetamide. An rubber, or polyurethane. Outer and inner soles are
additional analysis of contact allergies and their made of rubber, polyurethane, polyvinylchloride,
occupational relevance in the expert opinions or Evaflex, a combination of ethyl vinyl acetate
from the department of dermatology at Homburg/ and rubber polymers (Podmore 1995). For
Saar included in this study revealed a similar aller- insoles, also fiberboard is used. Fiberboard is
gen spectrum. Although nickel is mentioned as made of wood or leather fibers, suspended in a
allergen in shoes (buckles, trims) (Cronin 1980; mixture of rubber resins or acrylic resins, which
Podmore 1995), the origin of the increased rate of are preserved with biocides, often copper-8-
allergies to nickel in the patients of this study quinolinolate or sodium o-phenylphenate
remained unproved. The general occupational (Podmore 1995). In wooden shoes, an insole
allergen pattern in tannery and leather production may be present which has a cardboard-like
workers has been confirmed in a more recent study appearance. This material is made from wood
from Indonesia (Febriana et al. 2012b). pulp, and tetramethylthiuram disulfide is added
Polyfunctional aziridine (PFA) hardeners, as an antimicrobial agent (Fogh and Pock-Steen
which are used to harden surface coatings or fin- 1992). Other parts like the reinforcements above
ishes, have gained interest in occupational derma- the toes and around the heels are made of plastics
tology because they are potent sensitizers. or textile materials hardened with plastics, e.g.,
Estlander reported cases of combined skin and a nylon cloth to which rubber or polyurethane
respiratory sensitization to PFA in leather dyers foam is flame-bonded or cotton material impreg-
(Estlander et al. 2001). nated with various resins, e.g., formaldehyde
As far as clinical findings are concerned, there resins (Cronin 1980; Grimalt and Romaguera
is no characteristic aspect, localization, or clinical 1975; Podmore 1995). The protective toe caps of
course of occupational contact dermatitis in tan- industrial protective shoes are made of stainless
ners (Foussereau et al. 1982). Adams (1990) steel, which may be coated with epoxy resin to
increase the resistance of the metal to corrosion. colophony is used as a tackifier or in finishes in
The metal toe cap is protected by a synthetic foam shoe production (Fisher 1991; Podmore 1995;
padding (Foussereau et al. 1986). Linings can be Strauss and Wilkinson 2002).
made of polyvinylchloride or polyurethane. In shoe manufactures, the different parts of the
Rubber boots may contain N-isopropyl-N0 - shoes are prepared and assembled. Uppers, toe
phenyl-p-phenylenediamine (IPPD), chemically caps, quarters, linings, and insoles are cut and
related compounds, and mercury compounds edged which includes folding, glueing, and sewing.
which are used for preservation of plasticizers The insoles and heels are also cut and glued. After
(Cronin 1980; Koch and Nickolaus 1996; assembly, the shoe is finished and trimmed. Possible
Nishioka et al. 1996). Occupational sensitizations occupational exposure covers a broad spectrum of
to phthalates and coal tar were observed in a allergens: preservatives, dyes, tanning agents, neo-
factory producing shoes from polyvinyl chloride prene materials and neoprene glues, polyurethane
granulate in former Yugoslavia. Both substances materials and polyurethane glues, epoxy resins, dil-
were present in the granulate (Vidovic and uents and epoxy resin glues, rubber materials
Kansky 1985). and rubber glues, and acrylic resins (Mancuso et
In shoe production, urethane, neoprene, natural al. 1996). Podmore (1995) mentioned occupational
rubber, and hot melt adhesives are used. The latter exposure to the preservatives benzisothiazolinone,
ones are inert high molecular weight polymers octylisothiazolinone, di-iodomethyl-p-tolylsulfone,
which are melted and applied to heated material 2-thiocyanomethylthio benzothiazole, sodium o-
surfaces. They are used, e.g., for glueing of sole or phenylphenate, copper-8-quinolinolate, N-tri-
heels, and are not known as a cause of contact chloromethyl thiophthalimide, and in some East
allergy (Podmore 1995). Urethane adhesives are Asian countries trichlorophenol and pentachloro-
modified polyurethane solutions. Additives, e.g., phenol. Although occupational contact allergy
isocyanates, epoxy resins, and acrylic or phenol due to dimethyl fumarate has not yet been
formaldehyde resins, depend on the material to be reported, exposure to this highly allergenic fungi-
glued (Podmore 1995). Further chemicals (cata- cide should be considered in cases of occupational
lysts, hardeners, plasticizers, etc.) such as tri- dermatitis due to leather contact.
ethylenediamine, 4,40 -diaminodiphenylmethane,
or dibutyl tin which are used in the production of
polyurethanes have not been reported as a prob- 6 Occupational Dermatoses in
lem in the shoe industry. However, Rietschel and the Shoe Industry and in Shoe
Fowler (1995) emphasize that contact allergies to Repairers
these substances may be underreported and there-
fore recommend to keep these substances in mind “Shoes are manufactured from a vast range of
for unclear cases of contact allergy. Neoprene potentially sensitizing chemicals” (Podmore
glues may, in addition to neoprene itself, contain 1995). The most frequent allergen in shoemakers
isocyanates, phenolic resins like PTBP-F-R, eth- is PTBP-F-R in neoprene-based glues (Foussereau
ylene thiourea, dioctyl-p-phenylenediamine, et al. 1976, 1982; Mancuso et al. 1996). A sensiti-
tetramethylthiuram disulfide, di-o-tolyl guani- zation to PTBP-F-R is probably due to intermediate
dine, sodium dibutyldithiocarbamate, and zinc products, but not to the resin itself or to the two basic
oxide, magnesium oxide, and silicates (Podmore chemicals, formaldehyde and PTBP (Bruze 1986;
1995). Dodecyl mercaptan has been used to Geldof et al. 1989; Malten and Seutter 1985;
arrest polymerization in neoprenes and neoprene Mancuso et al. 1996; Schubert and Agatha 1979;
glues (Grimalt and Romaguera 1975). Natural Zimerson und Bruze 2000, 2002a, b; Zimerson et al.
rubber glues are water-based solutions of natural 2002). Allergic contact dermatitis caused by PTBP-
rubber, preserved with biocides, e.g., phenol, form- F-R often appears as hyperkeratotic eczema of the
aldehyde, or p-chloro-m-cresol. They may contain fingers and palms with fissures (Foussereau et al.
triethanolamine (Podmore 1995). Occasionally, 1982). Malten (1958) and Malten and van Aerssen
(1962) describe allergic contact eczema due to beeswax that was used by a shoemaker for seams
PTBP-F-R containing neoprene glue in right- of handmade heavy boots.
handed shoe repairers preferably being local- Although under quite different local condi-
ized at the finger tips and finger sides of the tions (occlusion, sweat), patients with allergic
left hand because the parts to be glued are held contact dermatitis of the feet due to shoes have
with the left hand while the glue is brushed on an exposure similar to those working in shoe
with the right hand. Additionally, the face may production or repairing. These patients show a
be affected. Sometimes eczematic lesions are similar pattern of contact allergens including
also seen on the thighs when the shoe repairer mercaptobenzothiazole and derivatives like
holds the shoe between his knees (Foussereau 2-thiocyanomethylthio benzothiazole, thiurams,
et al. 1982). 1,3-diphenylguanidine, p-phenylenediamine,
Mancuso et al. (1996) have studied occupa- N-isopropyl-N 0 -phenyl-p-phenylenediamine
tional dermatoses in 246 shoe factory workers (IPPD), and other p-phenylenediamine deriva-
in Italy from 1992 to 1994. Twenty suffered tives, azo dyes, N,N-dibutyl thiourea, PTBP-F-
from irritant contact dermatitis, 16 from allergic R, dodecyl mercaptan, colophony, potassium
contact dermatitis. Most frequently, occupational dichromate, DMF (meanwhile historically), and
contact dermatitis occurred in the assembly formaldehyde (Angelini et al. 1980; Bajaj et al.
department (20 out of 70 employees). Irritant 1991; Correia and Menezes Brandao 1986; Cro-
occupational dermatitis was mostly caused by nin 1980; Foussereau et al. 1986; Freeman 1997;
organic solvents (toluene, xylene, n-hexane) in Jung et al. 1988; Lynde et al. 1982; Oumeish and
adhesives and varnishes. Among those patients Rushaidat 1980; Romaguera 1987; Scutt 1966;
with occupational allergic contact dermatitis, five Suurmond and Verspijck Mijnssen 1967; Strauss
were sensitized to PTBP-F-R; three to mercapto- and Wilkinson 2002; Rani et al. 2003; Onder et al.
benzothiazole; two each to diphenylmethane- 2004; Holden and Gawkrodger 2005; Nardelli et
4,40 -diisocyanate, epoxy resin, potassium dichro- al. 2005; Teixeira et al. 2005; Corazza et al. 2006;
mate, tetramethylthiuram disulfide, and thiuram Chowdhuri and Ghosh 2007; Oztas et al. 2007;
mix; and single patients to Bismarck brown, Verma et al. 2007; Warshaw et al. 2007;
carba mix, chloroacetamide, colophony, 4,40 - Castanedo-Tardan et al. 2008; Giménez-Arnau et
diaminodiphenylmethane, 1,3-diphenylguanidine, al. 2009; Febriana et al. 2015). Ethyl butyl thio-
dodecyl mercaptan, ethylenediamine dihydro- urea is mentioned as an allergen in a rubber adhe-
chloride, mercapto mix, nickel sulfate, p-phenylene- sive (for neoprene/polychloroprene) used in
diamine, phenyl glycidyl ether, phenylmercuric athletic shoes (Roberts and Hanifin 1979). Cronin
nitrate, and triethylenediamine. The authors give (1966) gives a very good synopsis of the historical
an extensive, detailed list of possible occupational development of the diagnostic in this field.
allergens in this branch which is partly incorporated Non-allergic occupational dermatoses in the
in the tables shown in ▶ Chap. 192, “Shoe Man- shoe industry were observed by Mancuso et al.
ufacturers and Repairers.” The abovementioned (1996), too. Fifteen workers in the upper and sole
allergen pattern has been confirmed in a cutting departments presented with hyperkerato-
more recent study on occupational contact der- sis and scaling of the fingertips, mechanically
matitis in Indonesian shoe factory workers provoked by continuous trauma of the leather. A
(Oosterhaven et al. 2017). work-dependent localized itching of uncovered
The case history of an apprentice cobbler was areas was reported by eight workers employed in
reported. He was occupationally exposed to the sole cutting and scraping departments. This
leather, rubber, plastic items, and several glues pruritus sine materia was probably caused by dust
and acquired a contact allergy to the major mono- in the work place. Two workers who had been
mer of an ethyl cyanoacrylate glue (Bruze et al. exposed to p-tert-butylphenol-based glues for a
1995). Henschel et al. (2002) reported a case of long time showed leucodermic lesions on the
occupational contact sensitization to propolis in back of the hands. The depigmenting activity of
p-tert-butylphenol has been described previously samples of leather and metal. Contact Dermatitis
(Gellin 1990). 75:89–95
Bregnbak D, Opstrup MS, Jellesen MS, Johansen JD,
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Adhesives and Glues
61
Judit Lukács, Jana Präßler, Matthias Gebhardt, and Peter Elsner
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
3 Formaldehyde Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
4 Epoxy Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893
5 Acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 894
6 Colophony . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895
7 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
8 Patch Testing with Adhesives and Glues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
9 Other Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
Keywords occupational glues in which the adhesive is a

Adhesives · Glues · Epoxy resins · Acrylates · polymerization product formed by a complex
Colophony · PTBP chemical reaction between the macromolecules.
• Phenol-formaldehyde resins have occupational
1 Core Messages relevance for shoemakers, in car manufactur-
ing, in the wood industries, and in construction
• Exposure to adhesives and glues is common in industries.
occupation, leisure time, and household activi- • Epoxy resins, used in a wide range of indus-
ties. There is a constantly growing group of tries, penetrate regular gloves and may cause
aerogenic contact dermatitis.
• While acrylic adhesives are less sensitizing
J. Lukács · J. Präßler · P. Elsner (*) than epoxy and colophony rosin, acrylates pre-
sent with cross-reactions among each other, but
Jena, Germany
e-mail: Judit.Lukacs@med.uni-jena.de; not between methacrylates and cyanoacrylates.
elsner@derma-jena.de • Colophony rosin is a natural material and also
M. Gebhardt used in many occupational fields.
Dermatology Practice, Zwickau, Germany

https://doi.org/10.1007/978-3-319-68617-2_59
892 J. Lukács et al.
• Glues should be tested epicutaneously either turn, need heat to cure (Malten 1984). Para-
using commercial patch-test substances or as is substituted phenol resins do not cross-link but
but only after having completely dried in order adhere readily under pressure. Among them,
to minimize the risk of active sensitization via para-tertiary butylphenol-formaldehyde resin
patch testing. (PTBP-FR) is a well-known allergen with partic-
ular use as neoprene-based leather glue. Therefore
it has occupational relevance for shoemakers. An
2 Introduction Italian survey revealed PTBP-FR-containing neo-
prene adhesives to be the major allergens in a
Exposure to adhesives and glues is common in shoe factory (Manusco et al. 1996). Apart
occupational, leisure, and household activities. from PTBP-FR, mercaptobenzothiazole (MBT),
Multiple types of glues and adhesives are in use, two-component-polyurethane-, and epoxy resin-
depending on the materials to be joined. Whereas based glues were also found in the same study as
a century ago only paper, wood, leather, and tex- relevant glue allergens with special applications
tiles could be glued, today almost any type of each in shoe manufacture. PTBP-FR-based glues
materials can be fixed to each other. have also been reported for their use in car man-
In the majority of glues, the action is simply ufacture (Schubert and Agatha 1979).
due to removal of solvents, cooling, or crystalli- Phenol-formaldehyde resin is used, for exam-
zation. In these cases, it is not the action of the ple, in glass microfiber production as a blend for
macromolecular molecules but rather the preser- the fiber to strengthen it (Sripaiboonkij et al.
vatives, detergents, and other additives added to 2009). Exposure of the workers to the coated
the adhesive preparation that may cause dermato- microfibers occurs via inhaling and direct contact.
logical problems, although this is rare. There is, This leads besides respiratory, nasal, and eye
however, a constantly growing second group of symptoms also to skin symptoms with an
glues in which the adhesive is a polymerization exposure-response relation.
product formed by a complex chemical reaction Foot dermatitis elicited by shoes and wrist
between macromolecules. This second group may dermatitis by watch straps and by other leather
cause many more irritant and allergic reactions on articles is mostly not occupationally relevant
the skin (Malten 1984). (Freeman 1997). Of 839 Finnish patients,
In this instance, two-component systems are 9 patch tested with a glue series reacted to
common that react only after being mixed. Other PTBP-FR, which turned out to be the most com-
ways to start the reaction include heating, UV mon relevant glue allergen (Tarvainen 1995).
irradiation, oxygen and air exposure, pressure- Despite the similar chemical nature, there is no
induced rupture of catalyst reservoirs, etc. The evidence for cross-reactivity between phenol-
focus is mainly on this second group of adhesive formaldehyde resin and PTBP-FR (Geldof et al.
chemicals and their occupational use. 1989). Some authors have attributed test reactions
to PTBP-FR to free formaldehyde; however, most
patients are actually not allergic to formaldehyde.
3 Formaldehyde Resins Schubert and Agatha (1979) performed patch-test
studies with the chromatographically extracted
Phenol-formaldehyde resins resemble a group of ingredients of commercially available PTBP-FR.
chemicals that contain the formaldehyde structure They found two linear condensates named 2-hydroxy-
but are not necessarily associated with formalde- 5-tert-butylbenzylalcohol and 2,20 -dihydroxy-3,3-
hyde allergy. Resols and novolacs are distin- di-(2-hydroxy-5-tertiary butyl)-benzyl-5,5-ditertiary
guished within that group. While the chemical butyl-diphenylmethan to be the real allergens.
curing of novolacs requires the presence of form- PTBP is used in the production of PTBP-FR.
aldehyde to react with the phenol terminate group, Formerly, PTBP has been added in excess, which
resols do not. Resols are intermediates, which, in might have caused concomitant reactions,
61 Adhesives and Glues 893
whereas nowadays this is no longer relevant. been included in most cosmetic patch-test trays. In
PTBP and para-tertiary butylcatechol, both anti- addition to TS-FR, acrylates are gaining more and
oxidants in plastics, might cross-react. As a more importance in nail varnishes and lacquers.
PTBP-FR, they are also known for their toxic Chemotechnique provides a separate acrylic nail
effects on skin. Toxic exposure to PTBP-FR may test series for this purpose.
cause chemical burn and even toxic leukoderma.
Vitiligo-like leukoderma on the hands of PTBP-
FR-exposed shoe-manufacturing workers has 4 Epoxy Resins
been found in the above-cited Italian study. For
patch-test purposes, PTBP-FR is available 1% in When used for industrial adhesive purposes,
petrolatum by all well-known suppliers, either in a epoxy resins occur mostly in the construction
special plastic and glue or in the shoe series. industry; the assembly of cars, ships, and air-
Urea-formaldehyde resin and melamine- planes; the manufacturing of sports equipment;
formaldehyde resin are used as glues in the wood as well as in the optical and electronic industries.
industries to make furniture press plates. Despite a Much is similar between the chemistry of epoxy
low constant release of formaldehyde from these resins and acrylates. Both are (often) two-
plates into the indoor air, the health effect for indi- component systems. They are not sensitizing
viduals living or working in the room is way over- when fully cured but frequently contain an
estimated in our opinion. Construction workers are amount of remaining monomer, which is enough
also exposed to formaldehyde resins in modern to booster a preexisting sensitization. Both pene-
building materials. Textile finishes are another use trate regular gloves which makes skin protection a
for these formaldehyde resins (Fowler et al. 1992). real problem, especially for sensitized people.
Even cosmetics may contain PTBP-FR as Epoxy resin monomers are polymer precursor
Angelini and others have shown (Angelini et al. units that are reacted with hardeners to give the
1993). Both resins are currently available from polymeric material (Hagvall et al. 2016). Approx-
Chemotechnique, Sweden, urea-FR as a 10% pet- imately 75–90% of all epoxy resins are polymers
rolatum and melamine-FR as a 7% preparation in of diglycidyl ether of bisphenol A (DGEBA), and
the textile color and finishes series. 1% of epoxy resins are polymers of diglycidyl
If nail varnishes are considered to be adhe- ether of bisphenol F (DGEBF). DGEBA and
sives, then toluene-sulfonamide-formaldehyde DGEBF are considered to be the major sensitizers.
resin (TS-FR) should be included in this chapter. The contact allergenic effect of the epoxy resin
As a very common ingredient of nail lacquers and monomers depends on the reactive epoxide
hardeners, it may be an occupational allergen for groups (Hagvall et al. 2016; O’Boyle et al. 2012).
cosmetologists, beauticians, and, in a wider sense, Many different chemicals may be added to
those who use these products and who are in improve or adapt the material to the required
public service, such as bank clerks, office condition. Hardeners of the amine or acid anhy-
employees, and salespersons. Among patients dride type are cross-linking agents for the resin
with cosmetic-related contact dermatitis, TS-FR (White 1990). They are usually dissolved in
was found to be relevant in 12.6% of the cases, organic solvents. Some of those additional
second only to skin care products (De Groot et al. chemicals, such as glycidyl ether, benzol, and
1988). Typically, TS-FR allergy involves the eye- toluol, are skin irritants, which may enhance the
lids, lateral aspects of the neck, and, more seldom, skin damage and thereby booster the induction or
the truly exposed periungual area. Because traces elicitation of an allergic reaction.
of the allergen are easily transferred to the eyelids, Workers in the electronics, optical, paint, and
it has been included in the topical eye preparation glue industries are most likely to acquire occupa-
series of several allergen providers. Almost all tional allergy to epoxy resins (Richter 1974; Tosti
brands of nail polishes contain TS-FR (Hausen et al. 1993). A Dutch survey among employees of
et al. 1995; Sainio et al. 1997). TS-FR has recently several companies that specialize in epoxy resin-
related work in the construction industry revealed most likely etiological agent in the epoxy resin is
hand eczema in 23 of 135 persons. Of these, 61% cyclohexylamine. Nevertheless, correlations
of the eczema population and 12% of the healthy between epoxy resin as a possible causer and
skin group had positive patch-test reactions. sclerotic skin diseases are weak, not at last
Almost all positive patch-test reactions were due because of the low frequency of these diseases in
to epoxy resin. This shows the tremendous rele- comparison to the exposure rate to epoxy resins
vance of epoxy resin as occupational allergen (van (Steen 1999).
Putten et al. 1984). Epoxy resin-coated fiberglass
fibers have been reported as a cause of dermatitis
in this particular field of industry (Holness and 5 Acrylates
Nethercott 1989).
Pesonen et al. (2015) analyzed the pattern of Apart from their use in plastics, colors, lacquers,
patch-test reactivity to allergens in the European coatings, dental materials, orthopedic appliances,
baseline series of patients with occupational con- etc., acrylates are now increasingly used in adhe-
tact dermatitis in different occupations. Contact sives (Kanerva and Alanko 1998; Table 1)
allergy to epoxy resin was most commonly found because of their excellent properties, such as
among floor layers and tile setters, 23.8% of strong adhesion – even to metals, ceramics,
whom were patch-test positive for epoxy resin glass, and other building materials – fast curing,
(Pesonen et al. 2015). and easy handling. Stickers, tapes, and office
Occupational exposition to epoxy resin should material may also be based on acrylic adhesives.
be considered in patients with face dermatitis and An extensive list of ingredients in pressure-
proved sensitization to epoxy resin. The German sensitive tapes was published in Fisher’s Contact
information network of dermatology clinics Dermatitis. The most common allergenic ingredi-
reported higher rates of sensitization to epoxy ent of those tapes is 2-ethylhexyl acrylate. Occu-
resin especially in men with face dermatitis pational problems can arise from workplaces
which correlates with the more frequent occupa- where stickers and labels are put on the final
tional (aerogenic) contact to epoxy resin, for products or, theoretically, in the medicine. How-
example, in the production of cars, ships, ever, compared with epoxy and colophony rosin,
machines or in metal, chemistry, and construction which have been preferred in the past, acrylate-
industries (Schnuch et al. 2009). based tape adhesives are less sensitizing, and
There are frequent reports about non- reports are based on single cases. There are one-
occupational cases of epoxy resin sensitivity too. and two-component acrylic adhesive systems.
Contact dermatitis due to the epoxy resin in textile Epoxy (meth)acrylates are a combination of
label patches has been attributed to the epoxy- epoxy resins or its raw materials bisphenol A
containing adhesive (Fregert and Orsmark 1984). and epichlorohydrin with acrylates and methacry-
Limiting patch tests with epoxy chemicals to the lates. Positive patch-test results to epoxy (meth)
standardized test series is recommended because acrylates are often not caused by a specific
of the danger of active sensitization. Once proven,
epoxy resins should not be retested, in our opin-
ion. When testing epoxy-exposed individuals, Table 1 Adhesives based on acrylates, methacrylates, and
epoxy diacrylates according to Kanerva and Alanko (1998)
never forget to include chemical additives such
as the broad range of hardeners. Anaerobic sealants
Epoxy resins are in discussion to cause or Cyanoacrylates
trigger the onset of systemic sclerosis. There was Ultraviolet-cured sealants
also a description of a disease of skin sclerosis and Methyl methacrylate
Metal and glass glues
muscle weakness after occupational exposition to
Epoxy diacrylates (vinyl resins)
vapor of epoxy resin (Yamakage et al. 1980).
Acrylic dental bonding agents
Animal and patient studies revealed that the
occupational exposure to these substances but due methacrylate, 2-hydroxpropyl methacrylate, and
to a sensitization to diglycidyl ether of bisphenol ethylene glycol dimethacrylate (Lazarov 2007).
A. This has relevance for various occupational Aluminum test chambers should be avoided when
fields (Aalto-Korte et al. 2009) testing cyanoacrylates, because they may contain
Hazardous health effects on the skin are aller- catalysts for the polymerization process. The vehi-
gic sensitizations and irritation to several acry- cle acetone further enhances the tendency to poly-
lates. Glue-induced adherence of contaminated merize spontaneously (Bruze et al. 1995). Due to its
skin (finger, eyelids) may be very difficult to sep- excellent adhesive properties with various mate-
arate. If possible, wait for spontaneous resolution; rials, cyanoacrylate glues may occur in many dif-
gentle teasing with repeated moistening of the ferent occupations. When sticking something to
skin may be applied in this otherwise harmless glass, ceramics, or metal surfaces, 2-hydroxy
condition. Respiratory diseases like asthma, ethyl methacrylate (2-HEMA), 2-hydroxy propyl
eosinophilic bronchitis, and rhinitis have often methacrylate (2-HPMA), and (tri)ethylene glycol
been reported when handling acrylics (Savonius dimethacrylate (TEGDMA or EGDMA) are com-
et al. 1993; Kopferschmidt-Kubler et al. 1996; mon ingredients of industrial adhesives (Kanerva
Quirce 2004). et al. 1995). Methacrylates and cyanoacrylates do
As known from other fields of (meth)acrylate not cross-react.
use (dental prostheses, daily plastic wear), allergy Some acrylates have higher potential of sensi-
can only be initiated and elicited by uncured tization than others. In workers with contact to a
monomers. In contrast to plastic wear, monomers glue containing different acrylates, some sub-
are always available when using glues. So the rate stances like tri- and diethylene glycol diacrylate
of sensitization could be rather high and similar to showed a high number of positive tests, while
that of monomeric acrylate use in other occupa- other ingredients like isobornyl acrylate did not
tional fields, such as dentistry. There is, however, obtain any reaction in patch testing (Kiec-
only scanty data about real incidence of acrylate Swierczynska et al. 2005).
sensitivity caused by acrylic adhesives or glues in For patch-test purposes, a test screening
occupationally exposed individuals or even those with several acrylates should therefore be
within the normal population. Obviously there is carried out when suspecting acrylate allergy.
(still) no major problem evolving from non- Chemotechnique has the most diverse patch-test
occupational temporary use of these substances, tray on methacrylates; however, other companies
although several reports on sensitization from an also provide a suitable screening composition. It
adhesive in an electrosurgical grounding plate was as early as 1975 when Jordan recommended
were reported (Kanerva and Alanko 1998). In that MMA alone is not a good screening for acry-
occupational medicine, acrylates are important late allergy (Jordan 1975). Aalto-Korte et al.
sensitizers to keep in mind. Sometimes it may be (2008) recommended 2-hydroxyethyl methacry-
hard to find suitable personal protective equip- late and ethylene glycol dimethacrylate as
ment for sensitized people because most acrylates screeners for occupational contact allergy to
do penetrate gloves easily. anaerobic sealants and acrylic glues. Accelerators,
Cyanoacrylates are among the most common inhibitors, and catalysts, which may be added to
ingredients of acrylate glues (loctite is a well- the acrylates, can also sensitize.
known brand example). Eyelid eczema, nummular
eczema on the hands, and periungual dermatitis and
even allergic onycholysis (Kanerva and Estlander 6 Colophony
2000) are features of allergic contact dermatitis
caused by cyanoacrylate glue used to fix artificial Colophony rosin, a naturally occurring rosin from
nails. Ethyl cyanoacrylate and methyl methacrylate trees, is another natural base of glues and adhesives.
were seen as allergens in these patients (Belsito Abietic acid, also available as patch-test allergen,
1987; Guin et al. 1998) as well as 2-hydroxy and its oxidative derivatives are the causative
allergens (Guin 1995). It ranks high on hit lists of reactions may appear after repeated instillations of
contact allergens because of widespread exposure fibrin sealants containing bovine aprotinin. Dif-
reaching from occupational use in wood, paper, ferent surgical procedures in the dental, cardial,
paint, electronics, metal, and cosmetics industries vascular, pulmonary, and other fields are
to household contacts to natural exposure (Sadhra described for this problem (Ockenfels et al.
et al. 1997). Some tackifiers for heel and toe stiff- 1995; Wuethrich et al. 1996; Shirai et al. 2005;
eners in shoes are based on colophony and may Kober et al. 2008). Aprotinin-specific IgG and IgE
therefore be relevant allergens in shoe manufac- can be found in the affected recipients.
turers (Freeman 1997). Contact dermatitis due to
colophony has also been reported for musicians
(Lombardi et al. 2003; Gambichler et al. 2004). 8 Patch Testing with Adhesives
This is of a special difficulty because the contact and Glues
of the allergen to the skin cannot be avoided, for
example, by using gloves, and the affected persons The most important part of allergological diagno-
cannot change their work place/conditions easily. sis is to think about possible exposure to glues and
Medical use of rosin derivatives on tapes, ban- adhesives. Optimally, one should only consider
dages, surgical and dental dressings, wart paints patch tests with possible allergenic glue ingredi-
(Lachapelle and Leroy 1990), and hydrocolloid ents when the chemical composition of the glue or
dressings has been reported (Sasseville et al. adhesive is known. This can be determined by
1997). For several hydrocolloid dressings, the asking the manufacturer or, to a lesser extent, by
allergen is a modified ester of colophony, the looking at the material data safety sheets. In daily
pentaerythrite ester (Hausen and Kulenkamp practice, however, this very often fails. Therefore,
1998). Most patients with a sensitization to colo- a glue-screening series makes good practical
phony report intolerance of brown-colored tapes. sense. Table 2 includes information from two
However, no report has been found of occupa- major European patch-test provider companies,
tional contact dermatitis to medical colophony namely, Chemotechnique and SmartPractice
resin adhesives. Europe ALG. Their adhesive and glue series
were combined in order to get an overview about
available glue contact allergens. That not all sub-
7 Others stances in these trays are glue allergens is worth
mentioning; many are plastic allergens such as
A very special kind of biological adhesives are the phthalates, accelerators and inhibitors, or UV
so-called fibrin tissue glues. They are adsorbers. To make it easier, the real glue aller-
two-component systems consisting of fibrinogen gens listed in the table are marked in boldface.
and factor XIII in one syringe and thrombin in the Screening with the chemical subgroups after get-
second syringe. By adding thrombin to the ting information about the basic glue composi-
fibrinogen/factor-XIII mixture, there is a coagulation, for example, epoxy, acrylic, and
tion reaction. Tissue adhesives are used to recom- formaldehyde resin, is proposed.
bine skin and organ cuts (liver, spleen, etc.), to The plastic and glue series as provided by
seal wounds in surgically opened body cavities or several suppliers is a mixture of glue and plastic
vascular prostheses and to stop bleeding. There ingredients as well as substances involved in the
has been no report of either occupational contact synthesis of these products. Substances relevant
dermatitis or immediate-type contact reactions to for glues and adhesives are marked in bold. Many
this product because skin contact to the medical of the abovementioned substances are provided
person is always prevented by gloves worn for by all of the companies, but the ordering number
reasons of hygiene. Allergic reactions of the recip- is not mentioned. That is because the substance is
ients are not the focus of this chapter, but it may be not included in the glue and plastic series of this
mentioned that moderate to severe anaphylactic company. As an exception to this rule,
Table 2 Plastics and glue series as recommended by several distributors

Miscellaneous Chemotechnique SmartPractice Europe ALG (allergEAZE)
1 Abitol A-002 D 0915
2 Abietic acid A-001 D 2382
3 Benzoyl peroxide B-007 D 0201
4 Turpentine oil D 2322
5 o-Cresyl glycidyl ether D 0917
6 2,6-Ditert-butyl-4-cresol (BHT) D-006 D 0110
7 2-tert-Butyl-4-methoxyphenol (BHA) B-022 D 0111
8 Diphenyl thiourea D-025 D 1021
9 Cyclohexanone resin C-027
10 2-n-Octyl-4-isothiazolin-3-one O 004 D 2427
11 N, N-Dimethyl-p-toluidine D-016 D 0963
Formaldehyde resins
1 Toluene-sulfonamide-formaldehyde resin T-010 D 0908
2 p-tert-Butylphenol-formaldehyde resin B-024 D 0030
3 Resorcinol-formaldehyde resin P-005
4 Para-tertiary butylphenol B-023 D 0920
5 2-Monomethylol phenol M-015
Epoxies
1 Triethylenetetramine T-019 D 0905
3 4-40 -Diaminodiphenyl methane D-001 D 0906
4 Diethylenetriamine D-010
6 Isophoronediamine I-006
7 Hexamethylenetetramine H-003 D 2318
8 Cresylglycidylether D 0917
9 Epichlorhydrin, epoxidharz E-002 D 0021
10 Triglycidyl isocyanurate T-028
11 Bisphenol A B-013 D 0965
Plasticizer
1 Diethylphthalate
2 Di-n-butylphthalate D007 D 0903
3 Tricresyl phosphate T-015 D 2511
4 Triphenyl phosphate T-022
5 Dimethylphthalate D 0954
Plastic stabilizers
1 2-Phenylindole P-007
Plastic inhibitors
1 Azodiisobutyrodinitrile A-018
2 Hydroquinone H-007 D 0800
3 4-tert-Butylcatechol (PTBC) B-030B D 2810
UV adsorbers in plastics
1 2(2-Hydroxy-5-methylphenyl)benzotriazole H-016
2 Resorcinol monobenzoate
3 Phenyl salicylate
Isocyanates
1 Diphenylmethane-4,4-diisocyanate D-023B
2 Phenylisocyanate
3 Toluenediisocyanate
(continued)
Table 2 (continued)
Miscellaneous Chemotechnique SmartPractice Europe ALG (allergEAZE)
Acrylates
1 (2-Hydroxyethyl) methacrylate (2-HEMA) H-010 D 2477
2 (2-Hydroxypropyl) methacrylate H-018
(2-HPMA)
3 2-Hydroxyethylacrylate H-009
4 1,6-Hexanediol diacrylate H-004
5 Tetrahydrofurfuryl methacrylate T-027
6 Tetraethyleneglycol dimethacrylate T-029
7 N, N-Dimethylaminoethyl methacrylate D-045
8 Methyl methacrylate M-013 D 1800
9 Ethyleneglycol dimethacrylate E-007 D 1850
10 Triethyleneglycol dimethacrylate T-018 D 1851
11 Triethyleneglycol diacrylate T-017
12 BIS-GMA H-013 D 1852
13 BIS-MA M-007
14 Butylacrylate B-018
15 n-Butyl methacrylate B-021
16 2-Ethylhexyl acrylate E-009
17 Ethyl acrylate E-004
18 Ethyl methacrylate E-012
19 Diurethane dimethacrylate
20 Urethandimethacrylat U-004 D 2475
Chemotechnique methacrylates have been with acrylates and epoxy resins are referred to
included in this table because, in addition to the (see ▶ Chaps. 64, “Coatings,” ▶ 56, “Other Plas-
glue and adhesive series, they provide an exten- tics,” ▶ 207, “Polyvinyl Resins,” and ▶ 52,
sive list of acrylic adhesives and acrylics for arti- “Epoxy Resins”).
ficial nails which are therefore considered to be
adhesives/glues. 9 Other Tests
Under special circumstances it is also
recommended testing the glue itself. When the Since some of the mentioned allergens do not only
complete composition is known and the single cause type VI sensitizations with subsequent con-
allergenic ingredients are available, testing the tact dermatitis but also allergic asthma, it seemed
native glue is avoidable. It is warned against test- useful to find other methods than patch testing.
ing unknown epoxy resin-based glues because of Elms et al. (2005) tested serum samples for spe-
possible active sensitization. Active sensitization cific IgE antibodies against colophony which
is also well known for acrylics and has been could be detected in colophony-exposed workers
reported even after a single exposure. However, with symptoms of occupational asthma. The test
by leaving the glue exposed to air and letting it dry is based on the production of a protein extract by
on the patch-test chamber, the risk of strong patch- mono-mac-6 cells after in vitro challenge with
test reactions is minimized. colophony extract.
The easiest way to patch test a patient’s own Another method to determine exposure toward
products is using tapes and medical self-adhesive allergens is measuring components of allergens in
dressings. Simply cut a small piece and stick it body fluids. Jones et al. (2001) described the
to the skin for 24–48 h. For further information, analysis of dehydroabietic acid in urine as a bio-
the other chapters in this book that deal marker of colophony exposure. There was a
detectable correlation of the levels of Hausen BM, Kulenkamp D (1998) Allergische

dehydroabietic acid in workers of a soldering kontaktdermatitis auf einem hydrokolloidverband
bei kolophoniumallergikern. Aktuel Dermatol 24:
factory to their colophony exposure. 174–177
In terms of contact dermatitis, these tests are Hausen BM, Milbrodt M, Koenig WA (1995) The aller-
of course of lower interest but can give further gens of nail polish. Contact Dermatitis 33:157–164
information about the correlation of the present Holness DL, Nethercott JR (1989) Occupational contact
dermatitis due to epoxy resin in a fiberglass binder. J
skin disease and the underlying workplace Occup Med 31:87–89
situation. Jones K, Garfit SJ, Calverley A, Channa K, Cocker J
(2001) Identification of a possible biomarker for colo-
phony exposure. Occup Med (Lond) 51(8):507–509
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Dermatol Monatsschr 160:785–789 Tosti A, Guerra L, Vincenzi C, Peluso AM (1993) Occu-
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Electronic Industry
62
E. J. Roberts, V. Smith, and John S. C. English
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
3 Part 1: Manufacturing Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
3.1 Semiconductor Device Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
3.2 Printed Circuit Board (PCB) Fabrication and Assembly . . . . . . . . . . . . . . . . . . . . . . . . . 908
4 Part 2: Cutaneous Hazards and Skin Disorders in the Electronic
Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
4.1 Specific Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911
5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915

Irritant contact dermatitis · Allergic contact
dermatitis · Solvents · Metals · Soldering flux · • The electronic industry employs millions of
Epoxy and acrylate resins · Oils and coolants · people worldwide. The size of workforce and
Fiberglass · Rubber chemicals the use of hazardous chemicals may lead one to
suppose that the number of occupational der-
matological cases should be large.
• The industry is constantly changing as a
result of evolving scientific knowledge and
increasing demand. The manufacture of
goods is evermore automated. There is height-
ened productivity. Cheap labor costs elsewhere
E. J. Roberts
Nottingham Circle NHS Treatment Centre, Nottingham, UK mean that the UK workforce is now more
involved with product design and innovation.
V. Smith
Salisbury District Hospital, Salisbury, UK • A semiconductor is a material that has an elec-
trical conductivity between that of a conductor
J. S. C. English (*)
Department of Dermatology, Nottingham Circle Treatment and an insulator. Devices made from these
Centre, Nottingham University Hospital, Nottingham, UK materials form the vital components of almost
e-mail: John.English@nhs.net

https://doi.org/10.1007/978-3-319-68617-2_60
902 E. J. Roberts et al.
all electronic products. Historically silicon has been subject to changes in working practices occur-
been the most widely used, though gallium ring as a consequence of evolving scientific knowl-
arsenide and various other materials are assum- edge. What has always been a complicated industry
ing increasing importance. is now even more so as technological advances
• The basic steps involved in chip manufacture substitute older materials with newer, potentially
are chip design, crystal purification and growth, advantageous ones at various stages in the
wafer preparation, epitaxy and oxidation, pho- manufacturing process. This fact, along with the
tolithography, doping and type conversion, met- inherent intricate and convoluted nature of many of
allization, and interconnection formation. the methods involved, means that the numbers of
Device assembly involves chip separation, die materials used in the industry are large and so,
attach bonding, wire bonding, encapsulation, consequently, is the potential for employee expo-
housing, marking, and testing. sure to the various chemicals involved. Owing to
• New materials are developed and used before the vast size of the workforce, one might expect
reliable toxicological data is produced. Secrecy employees of this industry to contribute significant
within the industry makes it impossible to produce numbers of cutaneous problems to the
exhaustive lists of the chemicals used. To investi- dermatologist.
gate a case of occupational-related dermatosis, The industry is diverse, and differing defini-
patients must be managed individually, taking tions of what occupations may be classified as
into account at which stage in chip manufacturing being within the “electronic industry” mean that
they work and what chemicals they use. it can be difficult to determine the precise number
• There is little information available on pre- of workers involved in the industry. As of 2016,
cisely how common occupationally related 1.05 million people were employed in the
skin disorders in this industry are. Both ICD manufacturing of “computer and electronic prod-
and ACD appear to be important, and the major ucts” in the United States. Despite a projected
hazards are solvents, metals, soldering flux, increase in the output of this industry, and with
epoxy and acrylate resins, oils and coolants, sales of over US $ 41 billion, the number of jobs is
fiberglass, and rubber chemicals. expected to decline by 1.3% per annum over the
• Despite the size and hazards of the electronic next decade as a result of heightened productivity
industry, it is considered to be relatively safe and cheaper labor costs elsewhere (U.S.A. Data:
with regard to cutaneous risk. The incidence of Bureau of Labour Statistics 2016; U.S.A. Sales
occupational skin disease among its workers is Data: U.S. Census Bureau 2007). Developing
much lower than in other manufacturing indus- countries in particular are a favorite site for larger
tries. This may be due to processes taking place multinational companies to locate to, since the
in closed systems with a high degree of auto- comparatively low labor costs found in these
mation. Worker exposure to the chemicals countries are well suited to this labor-intensive
involved is minimal; but cleaning, repair, and industry (Koh 1997).
maintenance staff are at special risk. However, Microelectronic devices are found in appli-
the lower incidence may be accounted for by the ances of almost every description, and projections
industry being “top heavy,” the underreporting unsurprisingly show an industry that is likely to
of skin disease, and debate over which pro- continue to grow in the future (US Department of
cesses fall into the “electronic industry.” Health and Human Services 1985). For the pur-
poses of this chapter, the electronic industry will
be taken to encompass (1) the manufacture of
2 Introduction computer chips and other electronic components,
(2) the manufacture of printed circuit boards
The electronic industry today is a major worldwide (PCBs), and (3) the assembly and packaging pro-
industry with a workforce numbering millions. cesses that bring the two together. Clearly, there-
Since 1950, this complex scientific industry has fore, this arbitrary definition embraces the
62 Electronic Industry 903
manufacture of many electronic products, includ- electricity. Assembled according to a pre-

ing computers, communication equipment, audio determined pattern, these layers will go on to
and video consumer products, compact discs, form the multiple transistors that function as
electronic office machinery, military electronic switches controlling the flow of electricity
equipment, some larger electrical goods – such through the circuit. “On” and “off” switches
as washing up machines, whose technology is manipulate the binary code that is the language
semiconductor based – and a large number of of modern technology.
other, miscellaneous electrical products, and The first transistor was developed in 1947 by
components. Walter Brattain, John Bardeen, and William
The first part of this chapter will concentrate in Shockley, and this replaced the cumbersome vac-
some detail on the manufacturing processes uum tube. Bridging the gap between the transistor
involved in the production of semiconductor and the integrated circuit was the “planar” pro-
devices and printed circuit boards (PCBs). It is cess, devised in 1957 by Jean Hoerni and devel-
hoped that this will be of scientific interest to the oped in 1958 by Robert N. Noyce, which
reader but, more importantly, that it will give an provided a means of creating a layered structure
outline of the diverse chemicals and materials on the silicon base of a chip. Chip technology has
used (Barrett 1997; Morgan and Board 1985; moved on at an astonishing rate over the last few
Beasley 1988). The second part of this chapter decades. In the early 1970s, the smallest transis-
will concern the range of dermatosis and cutane- tors available measured 10 μm across the gate, and
ous hazards encountered in the industry. early chips contained less than a dozen transistors;
today, transistors of 45 nm are being produced,
allowing chips to contain several billion transis-
3 Part 1: Manufacturing tors; in a millimeter squared area, there may be
Processes over 1 million. A chip combines the functions of
discrete devices and performs complicated elec-
3.1 Semiconductor Device tronic functions in a fraction of a second. Micro-
Fabrication processors or “cores” are complex chips, central
to the workings of the computer, which serve to
A semiconductor is a material that has an electri- integrate various tasks and have access to memory
cal conductivity between that of a conductor and chips.
an insulator. Devices made from these materials The hundreds of different steps involved in
form the vital components of almost all modern chip manufacture can be grouped into a few
electronic products. Their manufacture is there- basic operations. These are chip design, crystal
fore a central process in the electronic industry purification and growth, wafer preparation, epi-
and, as such, a significant portion of this chapter taxy and oxidation, photolithography, doping and
will focus on their production. type conversion, metallization, and interconnec-
Semiconductor devices are manufactured both tion formation. The devices are then assembled,
as single discrete devices (diodes and transistors) involving the process of chip separation, die
and as integrated circuits that may consist of mil- attach bonding, wire bonding, encapsulation,
lions of discrete devices as well as other electrical housing and marking, and testing. These pro-
components such as resistors and capacitors. cesses and their hazards have been described in
These integrated circuits, more commonly detail before (Rohm et al. 1986; Lewis 1986;
known as microchips or chips, are the fundamen- Harrison 1986; Teitelbaum 1986; Wald and
tal device of the digital world. They are small Jones 1987), and although these are still the
(millimeter-sized) squares of semiconducting sub- same today, though with some notable changes
stance, usually with a silicone base, that are made in the materials being used, it is nevertheless
by building up several microscopically thin layers worthwhile repeating a summary of the different
of material that either insulate or conduct steps here. The text will attempt to concentrate on
those areas of the manufacturing process where mixture to remove impurities such as calcium,
there may be greater personnel exposure to cuta- manganese, and aluminum. In the presence of a
neous hazards and will not attempt to deliver all copper catalyst, it is then reacted with hydrochlo-
the minutiae of every material or chemical reac- ric acid to form trichlorosilane, which is then
tion involved. reacted with hydrogen to produce polycrystalline
silicon (polysilicon) at 110–1160 C by chemical
3.1.1 Chip Design vapor deposition onto starter silicon seed rods.
Chip design is the first operation. When hundreds These polysilicon rods are used to manufacture
of thousands of transistors are to be built on an single-crystal silicon ingots using one of two tech-
area of silicon the size of a pinhead, the placing nologies: Czochralski (the more popular) or float
and interconnections of the transistors must be zone. In the former, polysilicon is placed in a
meticulously worked out. Each transistor must quartz crucible in a pressurized chamber and
be designed for its intended function, and groups heated to 1200 C in an inert argon atmosphere.
of transistors are combined to create circuit ele- The ingot of single-crystal silicon is produced by
ments, such as inverters, adders, and decoders. being pulled from the melt using a seed crystal
The designer must also take into account the attached to the end of a puller. Precisely controlled
intended purpose of the chip; for example, a pro- amounts of impurities may be added to the silicon
cessor chip carries out instructions in a computer, during this stage to give the desired electrical
and a memory chip stores data. The two types of properties.
chips differ somewhat in structure. This design Newly made ingots are ground to a uniform
work is today usually computer aided, although diameter, have their crystal structures verified by
engineers often print out an enlarged diagram of a X-ray diffraction, and are epoxy bonded to a
chip’s structure to examine it in detail. graphite carrier in preparation for wafer slicing.
3.1.2 Crystal Purification and Growth 3.1.3 Wafer Preparation

By far the most common base material for build- Ingots are sliced into wafers with diamond-bladed
ing an integrated circuit is still silicon. Silicon is a saws and then washed. They are then rounded by
natural semiconductor; it can be altered to be automatic machines, which rotate the wafers at
either an electrical insulator or a conductor. high speeds and at the same time grind them.
These differing electrical properties are conferred Surface irregularities from sawing are etched
upon the silicon by the introduction of precisely away in an acid bath containing usually either
controlled amounts of dopant chemicals. It is this nitric, hydrofluoric, or acetic acid. Finally, the
ability to conduct electricity that forms the basis of wafer surfaces are automatically polished using a
the function of the chip. mixture of colloid silica and sodium hydroxide,
Silicon is produced in ingots, which are large cleaned with hydrofluoric acid and surfactant
(up to several feet long) cylindrical structures and inspected and packaged in shrink-wrapped
which are sliced into circular wafers about cellophane for contamination control. Most
0.775 mm thick and 300 mm (1200 ) in diameter. A semiconductor manufacturers purchase wafers
single wafer is able to yield hundreds of chips. These from firms specializing in wafer production.
wafers are the substrate for all subsequent steps in
the semiconductor manufacturing process. 3.1.4 Gallium Arsenide
The silicon required for these wafers must be Gallium arsenide (GaAs) is assuming increasing
extremely pure. A detailed analysis of the process importance as a semiconductor substrate use in
of the production of the semiconductor-grade sil- the microelectronic industry. In the mid-1980s, it
icon is available elsewhere (Wald and Jones 1987; accounted for 5% of semiconductor manufactur-
Oldham 1977). Quartzite (silica sand) is reduced ing (Robinson 1983) and is likely today to count
with coke in an electric arc furnace and then for more. GaAs have certain advantages over sil-
blown with oxygen or an oxygen-chloride icon. It can produce light and therefore is
extremely useful in the manufacture of light- on the parent compounds themselves or on their
emitting diodes (LEDs), lasers, solar cells, and constituent elements and on other compounds
photodetectors. This property also makes GaAs released during their manufacture. It is likely to
suitable for use in compact disc players as the be some time therefore before the true hazards
laser “stylus” that bounces off the CD’s micro- involved will be fully documented.
code of pits and spaces before shining onto semi-
conductor photodetectors for eventual conversion 3.1.5 Epitaxy and Photolithography
into sound. The heart of this laser is an exquisitely It is perhaps during these stages of semiconductor
thin strip of GaAs sandwiched between slices of fabrication that there exists the greatest potential
gallium aluminum arsenide, which is more elec- for exposure to cutaneous hazards because the
trically insulating. The infrared light emitted from numbers of chemicals involved are vast. With
this sandwich is produced when electrons and the wafer prepared, the process of building the
positively charged electron deficiencies (holes) chip’s circuitry begins. Making the transistors
recombine, annihilating one another and releasing and their interconnections requires several differ-
photons (Amato 1997). ent basic steps to be repeated many times to create
GaAs integrated circuits (ICs) are also of levels of variable circuitry and conductivity.
higher speed than their silicon counterparts and Many modern chips have over eight levels, and
are radiation resistant, making them more useful the more complex ones have over 50. In order for
for military applications. Set against these advan- this to be achieved, several hundred different pro-
tages is the increased cost of production of GaAs cessing steps are involved.
wafers, currently several times higher than silicon, Epitaxy is the process of depositing a
which is due to the rather higher melting and monocrystalline film on a monocrystalline sub-
boiling points of arsenic and gallium, respec- strate. This may be done with either gases,
tively, requiring resistance furnaces to produce vapor-phase epitaxy, or liquids, liquid-phase
the appropriate temperature zones. Other prob- epitaxy.
lems include the comparative difficulty in produc- Generally the first layer of a chip is silicon
ing stable adherent insulating layers for GaAs ICs dioxide, which does not conduct electricity and
and the slower hole mobility. The technology used therefore serves as an insulator. This layer is
in producing GaAs ICs is similar to that for applied in a diffusion furnace in an oxidizing
silicon-based ICs. The methodology and hazards atmosphere at a high temperature (Fig. 1).
involved in the production of single-crystal GaAs The wafer is now ready for patterning, or
has been described elsewhere (Harrison 1986), lithography. The first step in this process is “depo-
but clearly the potential consequences of mis- sition.” Conventionally, a coating of a viscous
handling or accidents involving elemental arsenic polymeric liquid, a photoresist, whose physical
cannot be overstated. properties alter on exposure to energy either in
It should be understood that silicon and GaAs the form of ultraviolet (UV) light, X-ray irradia-
are not the only semiconductor materials available tion, or as electron beam radiation, is applied to
today. The microelectronic industry is an evolving the surface of the insulated wafer. There are two
one, and research is constantly being undertaken types of photoresist, positive and negative. Posi-
into other semiconductor materials, some of tive photoresists weaken (become more soluble)
which are already in use. Some of the more impor- when exposed to energy; negative resists
tant substances in use are indium phosphide, alu- strengthen. Some photoresists require the addition
minum indium gallium phosphide, and mercury of other compounds, which act as photoinitiators
cadmium telluride, and there is also a great deal of or photostabilizers, before they will respond in the
interest in gallium on silicon technology. It should desired manner to incident energy. Further, since
be stressed that the discovery and use of these the dimensional stability of finished (fully devel-
exotic materials in most cases is outstripping the oped) resists is of vital importance (they must, for
ability to produce reliable toxicological data either instance, neither shrink nor swell during the later
Fig. 1 Silicon wafers on a

quartz tray about to enter a
furnace for deposition of
epitaxial layers on the
wafer’s surface
steps in the processing because their straight walls position another chip under the light. Today, more
and sides are essential to subsequent etching), the complex patterns are being transferred using step-
addition of still further ingredients is required to pers that move the wafer and the mask during
achieve these particular dimensional properties. exposure. These devices are known as scanners.
A spigot deposits a precise amount of photoresist On each chip, the parts of the photoresist layer
on the wafer surface. The wafer is then spun so that that were struck by the light become either sol-
centrifugal force spreads the liquid over the surface uble or insoluble and can be developed using
at an even thickness. This operation takes place on organic solvents, a process known as “etching.”
every layer that is modified by lithography. During etching, insoluble photoresist remaining
The second stage is “masking.” A photomask, on the surface protects the parts of the underly-
or mask, is the device through which the UV light ing layer from being removed by the acids or
shines, not dissimilar to an elaborate overhead reactive gases (wet and dry etching, respec-
projector film, to define the circuit pattern on tively) used to etch the circuit pattern on the
each layer of a chip. Because the pattern is intri- surface of the wafer. After etching is complete,
cate and must be positioned precisely on the chip, the protective layer of the photoresist is
the arrangement of opaque and transparent spaces removed, using solvents, to reveal electrically
on a mask must be done carefully during the conducting or electrically insulating segments
chip’s design stage. Masks are usually purchased in the pattern determined by the mask. Each
from other specialist companies who manufacture additional layer put on the chip has a distinctive
them to correspond to the desired computer-aided pattern of this kind. Solvent-based systems for
designed circuit as mentioned earlier. The mask the removal of photoresists are gradually being
image is transferred to the wafer using a replaced by plasma processing, removing some
computer-controlled machine known as a stepper. of the likelihood for worker exposure to sol-
It has a sophisticated lens system to reduce the vents. Plasma processes use chemicals in gas-
pattern on the mask (millimeters–centimeters eous form and take place in sealed chambers. As
diameter) to the microscopic dimensions of the a result, the use of compressed gases within the
chips circuitry. The wafer is held in place by the industry has increased.
stepper on a positioning table below the lens sys- Thus, in summary, photolithography involves
tem. UV light from an arc lamp or a laser (or X-ray using UV light shone through masks to transfer
irradiation or electron beam radiation) shines circuit patterns onto the surface of photoresist-
through the clear spaces of the mask’s intricate coated silicon chips. The weakened, or not hard-
pattern onto a single chip. The stepper table then ened, areas of photoresist may then be etched
moves the wafer the precise distance required to away to reveal a layer of circuitry.
Further masking and etching steps deposit pat- Table 1 Common photoresist, photoinitiators and stabi-
terns of additional material on the chip. These mate- lizers, etchants, and solvents used in photolithography
rials include polysilicon as well as various oxides Positive photoresists Novolak resin (phenol and
formaldehyde)
and metal conductors, such as aluminum and tung-
Polymethylmethacrylate
sten. On each layer of material, masking and etching Polybutene-1-sulfone
create a unique pattern of conducting and non- Polymethacrylamide
conducting areas. Together these patterns aligned Polymethylmethacrylate-
on the top of one another form the chip’s circuitry coethylacrylate
Negative photoresists Polyglycidylmethacrylate-
in a three-dimensional structure. The circuit is now coethylacrylate
ready for doping. Table 1 lists the commonly used Epoxidized polybutadiene
photoresistors, photoinitiators and stabilizers, etch- Bisarylazide
ants, and solvents used in the photolithographic Polyvinyl alcohol
process. As can be seen, many of the chemicals are Polyvinyl cinnamate
Vinyl benzene
plastics and therefore known skin irritants and sen-
Vinyl acetate
sitizers. Toxicological data may not be available for
Cyclized natural and synthetic
some of the more exotic compounds, whose pres- rubbers
ence may not even be indicated on the product label. Photoinitiators/stabilizers/ Quinones
It should again be pointed out, however, that as preservatives Anthrones
in many other industries, these processes are Diphenyls
Thiophenylmethane
almost entirely automated and occur in closed dyes
systems so that worker exposure to the chemicals Thiazolines
involved is likely to be minimal, except during the Trichloroacetophenone
processes of cleaning and charging the machines. Triarylselenium compounds
Owing to understandable secrecy within the Triarylarsenic compounds
Etchants
industry and to the vast number of different com-
Acids H 2SO 4
panies in the electronic industry, to produce an
HF
exhaustive list of all the chemicals used in this HCl
and other steps in semiconductor manufacture H 3PO 4
here would be impossible. The practicing CH 3COOH
dermatologist investigating a possible cause of HNO 3
occupational-related dermatosis will need to CrO 3
Solvents Xylene
closely investigate each individual separately, tak-
Cellosolve acetate
ing into account at precisely which stage in chip n-butyl acetate
manufacturing the patient works and what Deodorized kerosene
chemicals that patient’s particular company uses. Stoddard solvent
Aqueous NaOH
3.1.6 Doping Aqueous KOH
Tetramethylammonium
Doping deliberately adds chemical impurities to
hydroxide
parts of the silicon wafer to alter the way the silicon Methylethylketone
in each doped area conducts electricity. In electrical Isopropanol
terms, silicon can be either n-type or p-type, Glycol ethers
depending on the impurity added. The atoms in 1,1,1-trichloroethane
the doping material in n-type silicon have an extra Acetone
Naphthalene
electron that is free to move. Some of the doping
o-Dichlorobenzene
atoms in p-type silicon are short of an electron and Tetrachloroethylene
so constitute an electron “hole.” Where the two Phenol
types adjoin, the extra electrons can flow from the Freons
n-type to the p-type region to fill the holes.
The material at the base of the chip is p-type patterned using photolithography to create a sys-
silicon. One of the etching steps removes parts of tem of wiring that links all the chip’s transistors
the polysilicon and/or silicon dioxide masking and allows the flow of electrical current through
layers previously put on the silicon base, thus the circuit. Other common metals used for metal-
laying bare two strips of p-silicon. Separating lization are nickel, chromium, nichrome, gold,
them is a strip that still bears its layer of germanium, copper, silver, titanium, tungsten,
conducting polysilicon; it is the transistor’s platinum, and tantalum (Rohm 1990). A variety
“gate.” The doping material now applied to the of methods are available to affect metallization;
two strips of p-silicon transforms them into n-type filament evaporation, electron beam evaporation,
silicon. A positive charge applied to the gate flash evaporations, induction evaporation, and
attracts electrons below the gate in the transistor’s sputtering (Rohm 1990). Again, these methods
silicon base. These electrons create a channel all take place in enclosed systems.
between one n-type strip (the source) and the The metallized individual chips are now tested
other (the drain). If a positive voltage is applied to ensure that all their electrical connections work
to the drain, current will flow from the source to using tiny electrical probes. Next, a dicing
the drain. In this mode, the transistor is “on.” A machine cuts up the wafer into individual chips,
negative charge at the gate depletes the channel of and good chips are now separated from the bad.
electrons, thereby preventing the flow of current Prior to dicing, the wafers are often coated on
between the source and the drain. The transistor is either side with an adhesive plastic to facilitate
now “off.” It is by this means of switching on and the process. Wire bonders then attach metal leads
off that a transistor represents the array of 1 and to chips. The electrical contacts between the
0, commands that constitute the binary code, the chip’s surface and the leads are made with tiny
basis of function of all semiconductor devices and gold or aluminum wires. This wire bonding pro-
the language of computers. cess gives an opportunity for worker exposure to
The dopant materials in most common use gold dust during opening and recharging of the
today are arsenic, boron, antimony, and phospho- bonding machines.
rus. Today these materials are most usually added
to the wafer by the process of ion implantation, 3.1.8 Packaging/Encapsulation
but in the past, this was done by diffusion. Packaging of the chip portion of the chip/lead
Diffusion involves physical contact between combined unit into a plastic or ceramic container
dopant source, usually oxide of the elemental is a semiautomated process involving the use of
dopant, combined with organic solvent, and the epoxy resins, usually epoxy novolak resin forma-
wafer. The dopants are forced in by heating in a tions (Rohm 1990). These should be carefully
furnace. Ion implantation forces ions of dopant cured prior to use, but unreacted monomers may
into the silicon using a stream of high-energy be present, which can sensitize, as many other
ions produced in a machine similar to a mass diluents and flame-retardant materials, such as
spectrophotometer. Sources of dopants for this halogenated derivatives of bisphenol A, which
process are elemental arsenic and phosphorus, are added to resin prior to use. The completed
arsine, phosphine, diborane, and some boron devices are then laser marked in an enclosed sys-
halides. A more detailed description of doping tem and tested, again in an automated process,
procedures is beyond the scope of this text and prior to delivery for sale.
can be found elsewhere (Lewis 1986).
3.1.7 Metallization 3.2 Printed Circuit Board (PCB)

and Interconnections Fabrication and Assembly
This last step begins with further masking and
etching sequences that open a layer of electrical Completed chips and other electrical components
contacts between layers of the chip. A conducting are assembled onto the printed circuits on PCBs,
metal, most usually aluminum, is deposited and which are then packaged to make the finished
electrical product. The process of assembly of 4 Part 2: Cutaneous Hazards

components on to PCBs may be manual or auto- and Skin Disorders
mated as may the subsequent soldering. Far more in the Electronic Industry
workers are involved in this branch of the industry
than in the semiconductor manufacture, and the Despite the vast size of the electronic industry
jobs undertaken tend to be rather more manual, workforce, there is little information available in
particularly so in the final product assembly oper- the medical literature on precisely how common
ations, increasing the potential for skin contact occupationally related skin disorders in this indus-
with various hazardous materials. try are. In 1984, in California, only 260 occupa-
The manufacture of PCBs is less complicated tional illnesses were reported from a
than that of chips. There are basically two types of semiconductor workforce of 70,000, of which
PCBs, the cheaper phenol-formaldehyde-impreg- 30 (11%) were skin disorders (Adams 1986).
nated paperboards and the better quality epoxy These 260 illnesses are compared to a calculated
resin and hardener/fiberglass PCBs. In the later 637 expected illnesses for the same number of
types, the fiberglass acts as a reinforcement filler, workers employed in manufacturing as a whole,
and they are manufactured as described in the fol- based on the occupational illness rates for that
lowing sections (Goh 1994; Nethercott et al. 1982). area. In addition, traditionally 40–50% of all
Initially, the plain epoxy/fiberglass boards tend occupational illness cases are skin diseases,
to be bought in by electronic industries that mod- which would give a total expected number of
ify them further. The procedures involved are 104 cases of dermatitis compared to the actual
mostly automated, and again worker exposure is figure of 30 (Adams 1986).
most likely to occur during cleaning operations These figures would suggest that the incidence
and refilling of the machines. of occupational skin disease in the electronic
The desired circuit pattern is printed on the industry is significantly lower than in other
board using photolithographic methods, as manufacturing industries despite the heavy daily
described earlier. Acrylate resins, sensitive to use of hazardous chemicals. This has been
UV light, are used for the process and are spread assumed to be due to the near-complete degree
on the board. The desired circuit is imaged onto of automation in the industry, which makes skin
the board using a mask, and incident UVL will contact with hazardous substances less likely to
then cure the exposed parts of the resins. Uncured occur (Adams 1986), although it is acknowledged
resins are removed with solvents, and the frame- that there is likely to be a significant degree of
work of the electrical circuit has been imprinted underreporting of skin disease (Goh 1994) and the
on the board. In the past, and probably still in situation is complicated by misclassification of
some lower budget outfits today, epoxy resin- what processes exactly fall into the category of
based inks were used in the place of acrylates, the “electronic industry.”
and these were heat rather than UVL cured. Contrary evidence from Singapore (Goh and Soh
Other stages in manufacture include electro- 1984), where the electronic industry workforce is
plating with a thin coating of copper, and holes relatively large, would suggest that skin disease in
are later drilled at desired sites. Copper debris is this industry is more of a problem than is suggested
removed, and the board is cleaned with aqueous by the above figures. In a study (Goh and Soh 1984),
acid solutions. Drilled sites are metallized, and 55 of 377 (14.6%) cases of occupational contact
then a polyvinyl resin coat is applied to the etched dermatitis identified in an occupational dermatosis
circuit pattern, which then allows for copper plat- clinic were among workers in the electronic indus-
ing onto these areas, done in an electrolytic bath. try, putting it third in importance after the construc-
Unwanted vinyl coating is removed by dipping tion and engineering industries. Absolute numbers
the board into a bath of appropriate solvent. There of workers involved in each industry are not given,
then follows lead plating, using electrolysis, and and so the data cannot be compared to that from
etching away the excess copper coating to give the California, but these results do suggest that the sheer
completed PCB. size of the industry in some countries will mean that
it is likely to contribute a large number of cases of There is evidence that the appropriate authori-
occupational skin disease to the dermatologist. ties are responding to the scale of the problem of
Another more recent report (Koh et al. 2001) in skin disease in the electronic industry. One study
2001 from Singapore states a 14% prevalence rate (Ducatman et al. 1991) showed that in the United
of occupational dermatitis in prefabrication con- States in 1991, the computer, electronic, and sci-
struction workers based in a survey size of 272; of entific equipment manufacturing industries
the 38 cases, 42% were ACD to chromates and employed the largest number of occupational phy-
rubber chemicals. sicians per capita relative to occupational illness/
There is even more evidence (Shiao et al. 2004) injury/lost workdays per capita.
to suggest that the report from California is an It should be understood that in plants, particu-
underestimate of the incidence of contact dermatitis larly manufacturing plants, in which state-of-the-
in the electronic industry workers. In Taiwan, a art equipment is used, the hazards to production
survey was conducted in five electronic plants workers are likely to be minimal, but cleaning,
using a self-administered questionnaire on skin repair, and maintenance staff remain at special
symptoms; 302 of 3070 workers (9.8%) who com- risk (Adams 1986). Production staff involved in
pleted the questionnaire reported having symptoms chip manufacture work in remarkably clean envi-
compatible with contact dermatitis. Among those ronments which have to be virtually dust-free to
with reported hand dermatitis, 183 completed a prevent chip malfunction. This is achieved both
skin examination and patch testing, 65/183 by efficient air-filtering mechanisms and by the
(35.5%) were diagnosed as having ICD and 7/183 requirement that all workers wear special suits
(3.8%) ACD. The most important allergens were with boots and head coverings and wear gloves
nickel, cobalt, and phenylenediamine. In a study and surgical masks at all times (Fig. 2). Primarily
from Taipei (Sun et al. 1995), evidence of the rela- intended to protect the product and not the worker,
tive importance of the electronic industry as a cause there can be no doubt that the latter function is
of occupational skin disease is presented. Of a total also, to some degree, served. It should be remem-
of 164 patients seen at a tertiary referral center over a bered also that if the incidence of skin disease in
7-year period with occupational hand dermatitis the electronic industry is truly lower than that in
(OHD), 25 (15.2%) cases occurred among workers other industries as a whole, this may be due to the
from the electronic industry. This put the electronic fact that the industry is top heavy, with profes-
industry top of their list of occupations associated sional staff involved in design and product inno-
with OHD. vation who work in an office environment.
Further data from Singapore (Tan et al. 1997) Production and maintenance workers constitute
shows that of all the 633 cases of occupational only 31% and 2.5%, respectively, of the work-
dermatoses seen at an occupational dermatosis clinic force but contribute nearly 60% of reported injury
over a 5-year period from 1990 to 1995, and illness (Wald and Jones 1987; Meyer et al.
149 (23.5%) were from the electronic industry. Of 2000; Adams 1990).
these, 137 (91.9%) were due to contact dermatitis, Clearly, poorly maintained plants and lacka-
and data is given listing the commonest irritants and daisical working practices are likely to contrib-
allergens encountered. Again, this cannot be directly ute to increased risk of preventable skin disease
compared with previous figures, but the data does (Wald and Jones 1987). Improperly maintained
suggest that the figure of 14.6% from Singapore is filter and ventilation systems and ill-fitting fur-
on the increase. This study also showed a skewed nace exhaust pipes may increase the risk of
dermatosis incidence distribution with age, exposure to many chemicals and radiation haz-
suggesting that the young and inexperienced appear ards, and standard clean room ventilation sys-
to constitute a risk group. The authors state that tems will recirculate solvent vapors if they are
these workers may have experienced more occupa- not properly expelled (Wald and Jones 1987;
tional exposure because of their ignorance about Cone 1986). Such situations may arise in devel-
hazards of occupational chemicals. oping countries where there is often an absence
Fig. 2 The working

environment in the clean
rooms is extremely clean,
and protective clothing
must be worn at all times.
Here, a worker is dipping a
tray of wafers into an
aqueous acid bath for
pre-furnace cleaning of the
wafers. Note the wall-
mounted exhaust system
and that the fluid level of the
acid baths are considerably
lower than the workbench
itself
of regulations regarding health and environmen- 4.1 Specific Hazards

tal standards (Geiser 1986). An epidemiological
study (Rischitelli 2005), using a self-reported 4.1.1 Solvents
symptom survey, catalogued the character, pat- These multipurpose chemicals are used in many
tern, duration, and frequency of complaints and processes in the electronic industry. Many dif-
found good correlation with specific environ- ferent solvents are used, and Table 1 lists some
mental factors in the plant (temperature and of the more common ones. Solvents primarily
low humidity), which were likely causes of the cause ICD (Koh 1997; Tan et al. 1997; Adams
outbreaks. 1990; Koh et al. 1990), and it is suggested that
EPI-DERM is a reporting scheme in the United they may be overtaking soldering flux as the
Kingdom which has been in operation for 18 years most common cause of ICD in the industry
and whose purpose is the monitoring of occupa- (Tan et al. 1997). Solvents defat the skin, and
tional skin disease. Its data comes from clinical affected areas not surprisingly tend to be the
dermatologists and occupational physicians hands, but solvent vapors can lead to facial der-
throughout the country, who are asked to record matitis. The additives and other contaminants
and report all the details of any patients they sometimes found in solvents can also cause
investigate with suspected occupationally related ACD. Trichloroethylene (TCE) has largely
skin disease. EPI-DERM reports an average num- replaced Freon as a degreaser because it does
ber of 6 cases per 100,000 workers per year in the not deplete the ozone layer (Tan et al. 1997).
“manufacture of computer, electronics and optical TCE may affect the skin in several ways
products” and “manufacture of electrical equip- (Xu et al. 2009). Its vapor has been reported as
ment” between 2008 and 2016 (Health and Safety causing a bullous eruption (McBirney 1954).
Executive 2017).The Employment and Labour Inhalation of even small amounts of TCE
Market Review from the Office of National Sta- followed within an hour or two by consumption
tistics April to June 2017 gives the total number of of alcohol has been reported as resulting in a
workers employed as “electronic engineers,” pronounced facial and neck erythema called
“electrical and electronic technicians,” and “elec- “degreaser’s flush” (Stewart et al. 1974).
trical and electronic trades nec” as 150,000 Steven-Johnson syndrome resulting in the
(Employment and Labor market 2017). This death of one in five reported cases (Phoon et al.
therefore gives an estimated nine cases per year 1984) and toxic epidermal necrolysis also
in the United Kingdom. resulting in death (Tan et al. 1997) have also
A more detailed discussion of the main cuta- been reported and felt by the authors to be due
neous hazards in the electronic industry follows. to exposure to TCE. In addition, scleroderma
and scleroderma-like multisystem disease have 4.1.4 Fiberglass

been reported after exposure to various solvents, Fiberglass is often found as the reinforcement
especially TCE (Walder 1983; Yamakage and filling material of PCBs. Direct penetration of
Ishikawa 1982). fiberglass spicules into the skin may cause irritation
(Koh 1997), and larger diameter fibers (>4.5 μm)
4.1.2 Soldering Flux are likely to cause a dermatitis. Several studies (Tan
Soldering is frequently carried out in the elec- et al. 1997; Koh 1993; Koh et al. 1992; Koh and
tronic industry, particularly in assembly pro- Khoo 1994) have highlighted this problem. Clinical
cesses. Solder metals (usually tin/lead alloy) will signs may be few, but itch can be a prominent
not function properly unless oxide layers nearly symptom. Causation in one study (Koh and Khoo
always present on the surface to be soldered are 1994) was demonstrated by the finding of fiberglass
first removed (Rubin and Allen 1972). This is spicules in the skin of workers that were of a similar
achieved with soldering flux. ICD resulting from size to those found free in large quantities at the edge
exposure to liquid flux is probably roughly as of the particular PCB.
common as ICD resulting from solvent exposure A study (Hsieh et al. 2001) in Taiwan found
(Tan et al. 1997). ICD occurs because fluxes con- fiberglass dermatitis to be the most common occu-
tain aqueous solutions of acids. Fluxes may also pational dermatosis experienced by electronic
contain colophony. The flux is either in liquid industry workers. The study also concluded that
form where it would be squirted by the worker singular glass fibers with a sharp free end and a
onto the metal surface or it comes as a number of length of 50–150 μm are most likely to induce
cores incorporated into the solder wire (Courtney fiberglass dermatitis.
1983). Colophony in the flux has been reported to Free fiberglass in the workplace environment,
cause ACD and through its fumes, airborne con- released during the sawing of PCBs, has caused
tact dermatitis (Widstrom 1983; Liden 1984; generalized in exposed workers (Adams 1986).
Mathias and Adams 1984; Goh and Ng 1987),
and allergic contact urticaria (Rivers and Rycroft 4.1.5 Acids and Alkalis
1987). Aminoethylethanolamine and hydrazine, Various acids and alkalis are used at many stages
which may be present in fluxes, have been of the manufacture in several different areas
reported as causing ACD (Wheeler et al. 1965; within the electronic industry. They are chiefly
Crow et al. 1968). used for cleaning purposes. Hydrofluoric acid
Flux dermatitis typically involves finger pulps (HF) is a well-known offender and is reputed to
and periungual areas and, from contamination of be the most common cause of burns in the semi-
workbenches, the ulnar borders of the forearms conductor industry (Edelman 1986). Hydrofluoric
(Goh 1985; Yokota et al. 2004). It is important to acid, unlike other acids, often causes no immedi-
patch test to the patient’s own colophony in addi- ate burning sensation and so remains in prolonged
tion to that in commercially available batteries contact with the skin, eventually producing hor-
(Liden 1984; Mathias and Adams 1984). rific injuries. This effect may be enhanced by the
sweaty condition of the hands and fingers under-
4.1.3 Oils and Coolants neath the gloves often worn by workers, which
Oils and coolants have been reported as com- allows for easier penetration of the acid.
mon irritants in the electronic industry (Tan In recent years, the frequency of serious HF
et al. 1997). In the paper quoted, the precise burns has diminished due both to increased auto-
chemical culprits are not given. Historically, mation and to the introduction of plasma process
exposure to oil-based cutting fluids has been for wafer stripping and etching, which do not
considered to be associated with cutaneous require the use of HF (Adams 1990).
squamous cell carcinomata (Mastromatteo 1971; Many other acids and alkalis are used in the
Waterhouse 1971). industry, particularly in etching and megasonic
pre-furnace cleaning of wafers, and constitute most risk will be personnel involved in reactor
potential exposure risk, although again, automation and furnace maintenance and cleaning. To date,
and workplace design greatly minimize the risk. there are no reports of carcinogenesis or arsen-
Water and detergents have also been demon- ical dermatitis having occurred in the electronic
strated as a cause of ICD in the industry (Tan et al. industry, but there is a long latent period of
1997). 30–35 years following exposure before the emer-
gence of the lesions.
4.1.6 Metals
Metals are emerging alongside epoxy resins as the
chief cause of ACD in the electronic industry (Tan 4.1.7 Epoxy Resins
et al. 1997; Meyer et al. 2000, EPI-DERM, Centre Epoxy resins are frequent sensitizers in the elec-
for Occupational Health, University of Manchester, tronic industry (Tan et al. 1997; Tosti et al.
Personal Communication; Kiec-Swierczynska 1993; Leow et al. 1995; Yokota et al. 2000,
1988). Common sources of metal allergens include 2002). Their reactive diluents and hardeners
nickel-plated earthing straps worn by assembly may also cause problems. Epoxies are used or
workers to prevent damage to electrical compo- may be found in the electronic industry in var-
nents, which are extremely sensitive to static elec- ious situations including die attaching, chip
tricity, and nickel-plated tools and coolants (Tan encapsulation, ingot mounting prior to slicing
et al. 1997). Cobalt and platinum may also sensitize into wafers, tool handles, electrical insulation
(Adams 1986). Gold is also used in some processes material, resin molding systems, laminated
and, although only a rare sensitizer, may cause black sheeting, and PCBs (Koh 1997; Adams 1990).
dermographism and gold smudge (Rapson 1985). Various reports of allergy, including airborne
Dichromate solutions used in etching and slic- contact dermatitis, have occurred (Tosti et al.
ing of wafers are highly irritating and may cause 1998; Fischer et al. 1987; Nishioka et al. 1988;
perforation of the nasal septum and “chrome Jolanki et al. 1994).
holes” (Adams 1990).
Although less of an issue, in light of modern 4.1.8 Acrylates and Anaerobic Sealants
television screen technology, there have been a num- These chemicals harden between metal parts in the
ber of older reports (Stevenson and Morgan 1983; absence of air. They are resistant to shock and vibra-
Ali 1997) on the problem of chromate dermatitis in tion and are used for making locking threads of
the manufacture of television tubes. Ammonium screws and as sealants, as structural adhesives, and
dichromate is used for adhesion of phosphorescent as photoresists in photolithography. They are a fairly
pigments to color television screens in a flow coating common cause of sensitization in the electronic
process. Contact with the skin occurs during manual industry. Polyethylene glycol dimethacrylate is the
weighing of ammonium dichromate powder prior to most frequently reported sensitizer (Mathias and
mixing with distilled water from a burette. The Maibach 1984; Ranchoff and Taylor 1985; Patussi
authors also point out the importance of late reaction et al. 1986; Conde-Salazar et al. 1988). The acrylate
on patch testing; three of the nine positive patch-test sealants may also contain stabilizers, accelerators,
results were not seen until day 7. All nine also and other additives which can also cause ACD
showed positive patch-test reactions to potassium (Conde-Salazar et al. 1988).
dichromate although an opinion is not given as to
whether these were felt to represent cross-reaction. 4.1.9 Isocyanates
It has been demonstrated that arsenic can be Isocyanates are chemical used in the production of
released from wafers during implantation polyurethane. Polyurethane may be found in
(Ungers et al. 1985), and so potential for expo- the protective lacquer for circuit boards and is also
sure exists although all such reactions should used as an insulating material. A Finnish study
take place in closed chambers. Again those at identified 23 cases of isocyanate contact dermatitis
Table 2 Other skin hazards, allergens, and irritants in the electronic industry
Hazard Skin problem References
Physical
Low humidity Itch, burning sensation of face, Rycroft and Smith (1980)
scaling of face and neck
Facial itch, redness, and Guest (1991)
urticaria
Unpolymerized cyanoacrylate glue Irritant contact dermatitis (ICD) Calnan (1995)
in concert with low humidity
Heat (near furnaces) Rashes Koh (1995)
Mechanical pressure (screwdrivers) Palmar callosities Koh et al. (1995)
Chemical
Formaldehyde Erythema multiforme Nethercott et al. (1982)
exudativum
(PCB fabrication) solvent-containing Cold urticaria Bjorkner (1981)
contact sprays
Diphenylamine (additive in grease) Allergic contact dermatitis Bazin et al. (1986)
(ACD)
Polypropylene (capacitors) Contact urticaria Tosti et al. (1986)
Bishydroxyethyltallowamine ICD Bennett et al. (1988)
(BHETA); an oily antistatic agent
Rubber/rubber additive (gloves, ACD, contact urticaria Adams (1986) and Estlander et al. (1986)
finger cots)
Safety spectacles, safety shoes ACD Sonnex and Rycroft (1986) and
Foussereau et al. (1986)
Perchloroethylene (garment cleaner) ICD Redmond and Schappert (1987)
Risk of melanoma Nelemans et al. (1993) and Vagero and
Olin (1983)
X-rays, UV, microwaves, and Known potential effects Garabrant and Olin (1986), Cohen (1986),
radiofrequency radiation and Rudolph and Swan (1986)
over a 13-year period, 4 of whom worked in industry as regards cutaneous risks to its work-
the electronic industry. All four cases tested force (Adams 1990). Evidence is emerging that
positive to one particular monomer, MDA (40 4- as the industry grows in size that, despite this
diaminodiphenylmethane) (Aalto-Korte et al. 2012). high degree of automation, cutaneous disease is
There are a variety of other chemicals and nevertheless a reality among electronic industry
physical hazards, either potential problems or personnel, and that this is occurring from a
already reported, which may be encountered in diverse array of sources. Incidence rates of
the electronic industry. With the exception of rub- skin disease in this industry are lower than in
ber chemicals, these only rarely cause problems. most of the manufacturing industries, but in
These, their specific cutaneous consequences, and certain countries that have a very large number
other miscellany are listed in Table 2. of people working in electronics, significant
numbers of cases of work-related dermatitis
are likely to present to the physician.
5 Conclusions Both ICD and ACD appear to be important,
and the major hazards are solvents, metals,
In the recent past, the electronic industry has soldering flux, epoxy and acrylate resins,
been considered, owing to an enormous degree oils and coolants, fiberglass, and rubber
of automation within it, to be a relative safe chemicals.
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Paints, Lacquers, and Varnishes in
Occupational Dermatology 63
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
3 Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
4 Significant Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
4.1 Biocides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
4.2 Synthetic Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
Composition of Paints, Varnishes, and Lacquers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
A.1. Binders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 932
A.2. Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933
A.3. Pigments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
A.4. Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935
Abstract in contact with paints over a prolonged period,

Although the risks of allergies or irritation such as painters, people with more acute expo-
are highest for those who are most consistently sures such as residence dwellers in a newly
painted home may also be at higher risk. Even
public places where painting is being done
could potentially be a health hazard both for
R. M. Law (*)
School of Pharmacy and Faculty of Medicine, Memorial the workers and the general public. Water-
University of Newfoundland, St. John’s, NL, Canada based paints require important additives (e.g.,
Department of Dermatology, University of California San preservatives) which are often the cause of an
Francisco, San Francisco, CA, USA irritant or allergic reaction. Minute amounts of
e-mail: rlaw@mun.ca an additive may induce a potent allergic reac-
H. I. Maibach tion. Volatile paint ingredients, including pre-
Department of Dermatology, University of California, servatives of the isothiazolinone class and
San Francisco, CA, USA synthetic resins such as epoxy resins and

https://doi.org/10.1007/978-3-319-68617-2_61
920 R. M. Law and H. I. Maibach
isocyanates, may cause respiratory and other • The airborne nature of some volatile paint ingre-
nondirect contact symptoms of allergic der- dients may cause respiratory and other nondirect
matitis. As allergens, the most problematic contact symptoms of allergic dermatitis.
recent isothiazolinone is methylisothia- • Volatile allergens include preservatives of
zolinone (MI); others include methylchloroi- the isothiazolinone class. The most signifi-
sothiazolinone (MCI), octylisothiazolinone cant recent culprit is methylisothiazolinone
(OIT), benzisothiazolinone (BIT), and butylben- (MI). Others include methylchloroisothia-
zisothiazolinone (BBIT). The most problematic zolinone (MCI), octylisothiazolinone (OIT),
recent epoxy resin is diglycidyl ether of benzisothiazolinone (BIT), and butylbenzi-
bisphenol A resin (DGEBA-R); diglycidyl sothiazolinone (BBIT).
ether of bisphenol F (DGEBA-F) is also • Epoxy resins are also volatile. The most sig-
a significant allergen. Both aromatic nificant recent culprit is diglycidyl ether of
and aliphatic isocyanates may be volatile, bisphenol A resin (DGEBA-R). Diglycidyl
causing asthma, airway irritation, and hyper- ether of bisphenol F (DGEBA-F) is also
sensitivity pneumonitis; although poly- a significant allergen.
isocyanates based on hexamethylene-1,6- • Both aromatic and aliphatic isocyanates may
diisocyanate (HDI) are less volatile. Allergic be volatile, causing asthma, airway irritation,
reactions may take repeated exposures over and hypersensitivity pneumonitis. Aliphatic
months to years before symptom manifesta- polyisocyanates based on hexamethylene-1,6-
tion. Allergens are also found in other products diisocyanate (HDI) are less volatile and com-
(e.g., MI is commonly used as a preservative monly used in lacquers, coatings, and spray
in cosmetics). Cross-sensitization between paints.
products within the same class can occur, but • Some of the allergic reactions may take
co-existing reactions may be due to co-expo- repeated exposures over months or even years
sure and not cross-sensitization. before manifestation of symptoms.
• Allergic or irritant reactions are not always
occupation-related.
Keywords
• Allergic or irritant reactions are not always
Paint · Varnish · Lacquer · Isothiazolinones ·
from a paint, varnish, or lacquer. Many poten-
Methylisothiazolinone · MI ·
tial allergens are also found in other products
Methylchloroisothiazolinone · MCI ·
such as cosmetics.
Diglycidyl ether of bisphenol A resin ·
• Cross-sensitization between products within
DGEBA-R · Isocyanates · Hardeners · Curing
the same class (for example the iso-
agents · Biocides · Preservatives · Airborne
thiazolinones) can occur. However, co-existing
sensitization · Cross-sensitization
reactions may also be due to co-exposure
and not cross-sensitization.
1 Core Messages
2 Introduction
• Paint components and formulations change
over time. Paints and painted surfaces are ubiquitous. They
• Water-based paints have greater complexity are constantly encountered by persons in all walks
and require preservation as well as other paint of life from the wealthiest to the homeless. Not
additives which may be sensitizing. only are there painted walls and ceilings, we have
• Additives are often the cause of an irritant or painted/varnished furniture, floors, decks, and
allergic reaction. fences. We ride in painted cars, trucks, trains,
• Minute amounts of an additive may induce and airplanes. We use painted appliances and
a potent allergic reaction. other items such as lacquered bento boxes and
63 Paints, Lacquers, and Varnishes in Occupational Dermatology 921
lacquered toilet seats as used in Japan. We live or discuss allergens and irritants in paints, varnishes
work with paints and potentially live with freshly and lacquers (which from here on in will just be
painted environments around us. Although the called “paints” unless it is a discussion about
risks of allergies or irritation are highest for a specific varnish or lacquer), we must first briefly
those who are most consistently in contact with talk about paint components.
paints over a prolonged period, such as painters,
people with more acute exposures such as resi-
dence dwellers in a newly painted home may also 3 Composition
be at higher risk. Even public places where paint-
ing is being done could potentially be a health Besides pigments, paint components include
hazard both for the workers and the general binders, solvents, and a variety of different addi-
public. tives. The constituents of varnishes are very sim-
Paint constituents differ and may change over ilar to those of paints (e.g., binders, solvents, and
time. Liquid wall and ceiling paints have evolved additives), but varnishes lack pigments (Conde-
from mostly oil and solvent-based to primarily Salazar et al. 2007). Binders are the primary ingre-
water-based paints which have greater complexity dients in paints which keep pigments bound and
and many more component types in their formu- dispersed on the painted surface. Binders provide
lations. Paints may also be in powder form when hardness, flexibility, and influences drying speed.
applied to surfaces. Paint application may be via Solvents are used to modify paint viscosity. Sol-
brush, roller, spray, or other methods. vent-based paints contain about 50% organic sol-
It should be clarified that paints as discussed in vents which is volatile (Estlander and Jolanki
this chapter (as in the Painters chapter) do not 2014). Additives are usually present in small
include paints used by artists who produce paint- amounts but provide a significant effect or func-
ings and other works of art. Artistic paints may tion for the paint. Additives include catalysts,
have entirely different formulations. Issues relat- thickeners, hardeners/curing agents, stabilizers
ing to paints and varnishes as used by artists are (e.g., UV stabilizers), biocides to inhibit bacterial
not specifically discussed here. growth (e.g., preservatives), and others. Even in
Lacquer refers to a liquid coating typically minute quantities, additives are often the source
applied to wood or other materials that dries to a of the allergic or irritant dermatologic reaction.
hard and potentially shiny finish. There are natural In particular, preservatives such as the iso-
lacquers and others including synthetic lacquers. thiazolinones are major culprits. Since preserva-
Natural lacquer is a polymer collected as a sap tion is needed in water-based paints and most
from lacquer trees such as Rhus vernicifera in paints used today are water-based, this is a signif-
China, Japan, and Korea, Rhus succedanea in Viet- icant problem.
nam and Taiwan, and Melanorrhoea usitata in Natural lacquer constituents include lipid
Muanmar and Thailand. Thus, the constituents of components (60–70%), water (20–30%), plant
a natural lacquer differ, dependent not only on the gum (4–10%), lacase enzyme (1.5–2%), and
tree species but also the age, location, and season glycoprotein (3–5%). The major lipid components
(time of year) of sap collection (Ma et al. 2012). from the different trees are urushiol (Rhus
Today, there are also more complex lacquer formu- vernicifera), laccol (Rhus succedanea), and
lations include fast drying, hybrid, nano, and syn- thitsiol (Melanorrhoea usitata). All of these
thetic lacquers (Ma et al. 2012). The lacquer may be have a catechol ring structure with lipid side
clear or colored and dries by evaporation or a chains. For example, urushiol is a dihydric phenol
curing process that produces a hard, durable finish, with a side chain of 15 carbon atoms; however,
with the sheen from ultra matte to high gloss. the side chains can differ somewhat. It is the
Allergens and irritants in paints, varnishes, and catechol ring in natural lacquers which can
lacquers are many and may be ingredients from react and bind with proteins, causing the haptens
any of a number of components. Thus in order to (urushiol, laccol, thitsiol) to become antigenic
and induce an allergic dermatologic reaction (Ma 4.1.1 Isothiazolinones

et al. 2012). Synthetic lacquers may contain poly- Isothiazolinones include methylisothiazolinone
isocyanates, epoxy resins, or polyfunctional acry- (MI), methylchloroisothiazolinone (MCI),
lates; these can also induce allergic dermatologic octylisothiazolinone (OIT), benzisothiazolinone
reactions. (BIT), and butylbenzisothiazolinone (BBIT). MI
For an overview of paint, varnish, and lacquer was introduced as a stand-alone preservative in
components and additional details about binders, 2000 and was initially thought to be safer than
solvents, pigments, and additives, information MCI, which had been a known contact allergen
excerpted from the previous edition of this for years. In 2004, MI was assessed by the Scien-
chapter “Paints, Lacquers, and Varnishes” can tific Committee on Consumer Safety (SCCS) as
be found in Appendix A (Estlander and Jolanki a stand-alone preservative for cosmetics and was
2014). considered safe at 100 ppm (0.01%) including the
sensitization risk. By 2014, MI was the second
most frequently registered isothiazolinone in the
4 Significant Issues Danish Product Register Database (PROBAS),
with 884 different products registered, 471 of
What allergic issues do paint, varnish, and which were paints and varnishes. MCI/MI was
lacquer substances cause and of what significance the third most frequently registered with 611 prod-
is this as an occupational hazard? A PubMed ucts of which 363 were paints and varnishes. MCI
search of paints using the Mesh headings irritant was fourth with 474 products including 275 paints
dermatitis, irritation, photo irritant dermatitis, and varnishes. OIT was the fifth most common
photo irritation, allergic contact dermatitis, photo- (111 products with 60 paints and varnishes). The
allergic contact dermatitis, photosensitivity, and most commonly registered isothiazolinone was
contact urticaria yielded 256 citations from 1957 BIT (985 products with 544 being paints and
to 2017, with 60 from 2012 to 2017 of which 24 varnishes) (Frils et al. 2014).
citations were found to be relevant upon review. PROBAS is a Danish database where products
A specific search of lacquer using the same Mesh with potentially hazardous chemical entities are
headings yielded five other relevant citations, with registered. Products are registered if (a) product/
one from 2012 to 2017. Additional related articles substance is manufactured or imported for occu-
were also retrieved including earlier literature. pational use in quantities >100 kg/year; (b) if the
Some of the more relevant findings are product contains at least one registered harmful
highlighted here including those from older liter- chemical according to the Danish Ministry of the
ature; some other findings are briefly discussed. Environment and the Danish Working Environ-
Tables 1 and 2 provide a detailed listing of contact ment Authority (WEA); (c) if the product or mate-
allergens and irritants. rial contains >/= 1% of that chemical (but for
preservatives the limit is 0.1%); (d) if the product/
substance has an occupational exposure limit (set
4.1 Biocides by the WEA); and (e) if materials contain >/= 1%
of a substance that has been assigned an occupa-
Biocides inhibit bacterial growth and include tional exposure limit in the WEA list of limit
isothiazolinones, formaldehyde, and formalde- values for substances and materials. PROBAS
hyde releasers, methyldibromo glutaronitrile, is updated at the end of every odd year with data
and chloracetamides (less in use today). Among collected from manufacturers in even years (Frils
these types, the most significant allergens/irritants et al. 2014).
are the isothiazolinones. As mentioned, these are The frequency of use as per the PROBAS
preservatives in water-based paints; however, register is mirrored by the frequency of contact
they are also used in other areas such as the allergy. A retrospective study of consecutively
cosmetic industry for the same reason. patch tested contact dermatitis patients at
Table 1 Contact allergens. (Adapted/modified from Table Table 2 Contact irritants. (Adapted/modified from Table
178.1, Estlander and Jolanki 2014) 178.2, Estlander and Jolanki 2014)
Synthetic resins Epoxy chemicals: diglycidyl ether of Biocides Tributyltin oxide (TBTO)
bisphenol A resin (DGEBA-R): Isothiazolinones: MCI, MI, BIT,
Diglycidyl ether of bisphenol F OIT, BBIT
(DGEBF) Tetrachloroisophthalonitrile
Formaldehyde resins (chlorothalonil)
Acrylic paint Organic solvents Mineral or white spirits
Polyurethane resins: di- and tri- Xylene and toluene
isocyanates Alcohols
Polyfunctional acrylates and aziridine Esters
hardeners
Ketones
Cyclohexanone resins
Mixtures of solvents (thinners)
p-tert-butylcatechol
Citrus solvent (limonene)
Unsaturated polyester resins
Other solvents Glycols and glycol esters
Turpentine and Turpentine and irritants Monomers from binders, surface-
other natural Linseed oil, shellac, dammar, tung oil active agents
products Colophony Dusts (e.g., dry powder sprays, dust
Citrus solvent (limonene) from sanding paints) and abrasives
Preservatives/ Biocides Fiberglass fabrics
Biocides Isothiazolinones: MCI, MI, BIT, OIT, Fillers, putties, plasters
BBIT Cleaning agents: soaps, detergents,
Formaldehyde and formaldehyde caustic soda (sodium hydroxide)
releasers Amines, ammonia
Methyldibromo glutaronitrile Potash
Other additives Chloracetamides Paint and varnish removers, paint
Iodopropynyl carbamate strippers
Tetrachloroisophthalonitrile
(chlorothalonil)
N-(Trichloromethylthio)phthalimide
Chlorocresol Copenhagen University Hospital Gentofte (from
Butylated hydroxytoluene Jan 2009–Dec 2013) showed that MI was the
Other types of Epoxy hardeners/curing agents: (non- second most frequently registered preservative
additives standard) 1,3-benzenedimethanamine (n = 830 with n = 446 in paints and varnishes),
(1,3-BDMA) aka m-xylylenediamine MCI/MI was the third (n = 630 with n = 354 in
(MXDA), N-(2phenylethyl)
derivatives
paints and varnishes), and MCI was the fourth
Accelerators and polymerization (n = 407 with n = 252 in paints and varnishes).
inhibitors Formaldehyde was the preservative most fre-
Photoinitiators quently registered (n = 894 with n = 401 in paints
Surfactants (dioctyl sodium and varnishes) (Schwensen et al. 2017a). Based
sulfosuccinate) on frequency of use, the relative risk of sensitiza-
Metals and metal Zinc chromate tion has been described as MCI > MI > BIT >
salts Cobalt OIT (Mose et al. 2013). This ranking is consistent
Nickel with that reported in earlier literature (Aalto-Korte
Mercury derivatives
et al. 2007; Geier and Schmuch 1996). The rela-
Organic pigments (azo derivatives)
tive risk may change as frequency of use and/or
Paint and varnish Dibutylthiourea
removers allowed concentrations change.
Miscellaneous Rubber gloves (natural rubber latex) For allergy testing, MCI is part of the 50
Other preservatives (e.g., in barrier allergens in the baseline panel for patch testing
creams, hand lotions/creams/ identified by the North American Contact Derma-
ointments/cleansers) titis Group (Lachapelle and Maibach 2012). The
European baseline series (used, for example, by in the paints and the indoor façade renders,
the Danish Contact Dermatitis Group) has long which he had not directly touched as he
included MCI/MI (Mose et al. 2012); and since was the site foreman (Herry et al. 2016).
2013, MI has also been a recommended part of the 3. A 24-year-old woman with no history of atopy
European baseline series (Bruze et al. 2013). It had two episodes of acute facial dermatitis
has been advocated that the addition of MI to the separated by a 2 month timespan, with each
baseline series is warranted due to the large episode relating to similar water-based paints
number of patients testing positive to MI but not being used (at home and work). An intensely
MCI/MI (Uter et al. 2013). Currently, many base- pruritic facial rash with periorbital edema
line series in North America also include MI. followed by progression to neck and upper
MI has emerged as one of the most significant chest developed 3 days after the initial episode
contact allergens in water-based paints today. In and 2 days after the second. Each time the rash
the current PubMed search, 13 of the 24 relevant took several weeks to resolve. Patch testing
citations from 2012 to 2017 discussed MI. Ten identified MI, MCI/MI and less strongly OIT.
citations were specifically about MI with five The paint contained MI, MCI and BIT (Wright
being new case reports. There were two other and Cahill 2016).
more general articles and an additional case report 4. A 33-year-old woman had three episodes of
about the isothiazolinones which included MI facial dermatitis with generalized spread over
(Aeerts et al. 2017; Amsler et al. 2017; Bregnbak a 10 year span, with the last episode temporally
and Johansen 2013). The case reports were all coinciding with a residential move. Thus the
related to the airborne nature of MI (and MCI/ patient had a strong suspicion of the interior
MI) and are summarized below: wall paint she just used with no protective
clothing during painting, even though the
1. A 23-year-old non-atopic previously healthy referring dermatologist suspected photoallergy
woman developed facial dermatitis with peri- due to the distribution and her history of tan-
orbital edema progressing to vesicular derma- ning bed use. Patch testing at day 5 showed a
titis. She had a burning sensation on her strong reaction to MI (+++) and a mild reaction
cheeks, malaise, and dizziness after working to MCI (+) with BIT negative. Paint samples
for 2 months in a new restaurant where the applied to her arm had positive results at 48 h
walls were newly painted. Patch testing identi- in three of four samples, while nine volunteers
fied MCI/MI and MI as potential causes and (controls) had negative results at 96 h which
when re-exposed to MI in a new facial cleans- ruled out irritancy. The four paint samples were
ing product she experienced marked aggrava- then analyzed by HPLC for the presence of MI,
tion of facial dermatitis (Kaae et al. 2012). MCI, BIT, and BBIT. MI and BIT were found
2. A 26-year-old man with no history of asthma in all four samples but in varying concentra-
or atopic dermatitis developed a persistent dry tions ranging from 50–100 ppm (MI) and
cough and rhinitis (despite use of antihista- 290–340 ppm (BIT). Neither BBIT nor MCI
mines and a steroid/beta2-agonist inhaler) were detectable. The patient was able to stay in
followed within days by an eczematous erup- her current home and at 3 months’ follow-up
tion on the face, eyelids, chest, nape of neck, her skin was clear (Goodier et al. 2017).
and folds of elbows with respiratory signs 5. A 53-year-old woman with no atopic or allergy
(PFTs showed a 19% reduction in FEV1 upon story presented with severe respiratory symp-
methacholine challenge) after working for toms, facial erythema and periorbital edema
2 years for a construction company specializ- 2 days after her apartment was painted. Patch
ing in renovation work where water-based testing identified MI (+) and the paints were
paints and pulverized indoor façade renders preserved with MI (confirmed by paint manu-
were commonly used. Patch testing identified facturer but not noted on the paint container)
MI and MCI/MI. MI and MCI were both found (Lundov et al. 2013).
6. An otherwise healthy 3-year-old boy presented especially leave-on cosmetics with an almost
with a recurrent itchy and erythematous rash fourfold significant increase ( p < 0.001, total
(this time in the popliteal fossa and on the n = 14,104). Freshly painted rooms was also a
dorsal surfaces of his hands) which had significant risk factor although the numbers were
been treated as atopic dermatitis by a local small ( p = 0.043, total n = 100), with paints/
dermatologist for about 2 years before being lacquers showing a trend ( p = 0.166, total
referred for further investigation. During the n = 403). Painters headed the list of occupations
medical history review, it was noted that at with a 14% crude (unadjusted) prevalence rate of
about 3 months of age, his family moved to MI sensitization (14.14%, 95% CI of 9.61–19.79)
a freshly painted house and it was about a (Uter et al. 2013).
month later that his first itching rash occurred. Regulation is needed for paint manufacturers
A recurrence occurred during a family visit to to identify the presence of MI (or other iso-
his aunt’s house, which had also been newly thiazolinones) on paint container labels. In
painted. Patch testing was done with the Euro- March 2016, a recommendation was made by
pean baseline series supplemented by the stan- the Committee for Risk Assessment (under the
dard child series; patch and photo patch tests European Chemicals Agency) that MI be classi-
were done with the sunscreen series and with fied as a potent skin sensitizer (group 1A) with
the child’s personal products used. Patch tests a concentration limit of <0.0015%, i.e., any prod-
were positive for MCI/MI (++) and MI (++). ucts containing MI > = 0.0015% (15 ppm) shall
MI and MCI/MI were found in the child’s have a warning about the risk of sensitization,
shampoo, soap, and sunscreen. The conclusion either on the product label or on the safety data
was that the child has atopic dermatitis which sheet. EU regulation is still in progress: EU
was either triggered or worsened by his severe Member States are in the process of formally
allergy to MI and MCI/MI. The authors con- adopting the recommendation, and the regulation
sidered this case noteworthy both because of is expected to be in force by Summer 2018 (Edi-
the age of the child when sensitized (3 months) torial 2016). Currently, efforts are being made by
and the level of exposure (Bregnbak and some paint manufacturers to produce paints with
Johansen 2013). zero to low amounts of isothiazolinones, and
some manufacturers have already begun to volun-
Airborne sensitization and presentation of aller- tarily label their paint products as containing such.
gic contact dermatitis due to the continuous evap- Octylisothiazolinone (OIT) or more specifi-
oration of isothiazolinones (MI, MCI/MI) over cally 2-N-octyl-4-isothiazolin-3-one was a fungi-
days to weeks/months constitute an important cide initially developed specially for latex and oil
health risk. This risk has been confirmed by emis- paints but has been more widely used in adhe-
sion testing of 19 different water-based paints, with sives, wood preservatives, metalworking fluids,
MI being found in all 19 paints (concentration stains, cleaning agents, and others including tex-
range 10–300 ppm), BIT in 16 (concentration tiles such as mattress textiles (Aalto-Korte et al.
range 1.5–360 ppm), and MCI in 4 (concentration 2007). Occupational allergic contact dermatitis
range 2–14 ppm) (Lundov et al. 2014). Given the has been reported in painters and in workers in
volatile nature of MI, it has been estimated that paint factories. A 56-year-old man developed
75% of MI paint-related allergic reactions are sec- acute eczema on the face, hands, and arms from
ondary to airborne exposure (Lundov et al. 2012). using latex paint containing OIT (Oleaga et al.
An increase in MI sensitization has been occur- 1992). A 29-year-old female technician in a fac-
ring worldwide. A study assessing risk factors for tory mixing paint ingredients for roof sheets
MI contact sensitization over a 4-year period developed eczema on the right wrist that spread
(2009–2012) identified freshly painted rooms to the face and extremities with generalized
and paints/lacquers as risk factors for the increase lymphadenitis in 10 days; patch testing using
although the greatest risk factor was cosmetics OIT 1% in olive oil was positive to OIT. A 48-
year-old male worker took over the previous 29- concomitant allergic reactions concluded that,
year-old technician’s work while she was on sick in almost half of their cases, OIT reactions were
leave, and after 3 days of mixing the paints, a better explained by cross-sensitization to MI and/
severe contact dermatitis developed with rapid or MCI than by specific exposure to OIT (Aalto-
spread from hands to arms, thighs, and face; again Korte and Suuronen 2017). This differs from
patch testing using OIT in olive oil was positive the author’s own earlier observations of separate
(Thormann 1982). A 31-year-old man developed sensitizations to these chemicals (Aalto-Korte et
recurrent episodes of hand dermatitis beginning al. 2007) and a 1996 study which concluded
6 weeks after working in a paint factory even that no cross-sensitization existed between MCI/
though he was wearing gloves – as the occasional MI, BIT, and OIT (Geier and Schmuch 1996).
splash on exposed skin resulted in dermatitis. His Additionally, a recent study in mice has shown
work required him to add a mildewcide (Skane M- cross-sensitization between MI, BIT, and OIT
8) into the paint mixer. Patch testing using diluted (Schwensen et al. 2017b).
concentrations of Skane M-8 were positive. Skane
M-8 contains OIT (Mathias et al. 1983). A review
of 202 painters working in eight paint companies 4.1.2 Formaldehyde and
identified 3.6% of painters who developed ery- Formaldehyde Releasers
thema while hand painting with water-based paints Formaldehyde and formaldehyde-releasing pre-
and additional investigations identified OIT was servatives were once widely used in water-
one of the culprits (Fischer et al. 1995). containing products such as metal-working
fluids and occupational sensitization was com-
Photo-aggravation mon in machinists who handled them, as well as
A 2017 retrospective study of airborne allergic other occupations including cosmetologists
contact dermatitis caused by water-based paints and painters. Contact allergy to formaldehyde
containing MCI/MI or MI was conducted by releasers without formaldehyde allergy is rare
the Dermatology and Allergy Group of the French (Aalto-Korte et al. 2008). As of March 2009,
Society of Dermatology, and 44 cases were iden- paints, lacquers, and varnishes were the most
tified between 2012 and 2016. In three of the 44 frequently registered products containing formal-
patients who reacted positively to MCI/MI, photo- dehyde in PROBAS (Estlander and Jolanki 2014).
aggravation of dermatitis occurred after exposure Examples of formaldehyde and some formalde-
to sunlight. Only one of the three patients was hyde-releasing biocides and other products in
tested with MI alone, with a positive result paints, lacquers, and varnishes include: Form-
(Amsler et al. 2017). aldehyde, 2-Bromo-2-nitropropane-1-3-diol,
Dimethylol urea, Melamine/formaldehyde resin,
Co-Exposure and Cross-Sensitization Methanamine, N-methylolchloracetamide, Poly-
Cross-sensitization between isothiazolinones can oxymethylene urea, Tetramethylol acetylenediurea,
occur but a distinction would need to be made Tris(hydroxymethyl)-nitromethane, and Tris(N-
between cross-sensitization and co-exposure with hydroxyethyl) hexahydrotriazine.
simultaneous reactions. A 2013 study found that
all patients with concomitant positive patch test 4.1.3 Other Biocides
results to MCI/MI, OIT, and BIT were painters, 3-iodo-2-propynyl-butylcarbamate (IPBC) is
suggesting co-exposure with concomitant sen- a fungicide added to paints and wood treatments
sitization and not cross-sensitization (Mose et to prevent fungal decay of wood (and used in
al. 2013). A 2015 study also found that simulta- other industries such as cosmetics). It can cause
neous reactions between MI and BIT as well as airborne allergic contact dermatitis. A case report
between MI and OIT resulted from co-exposure described a 34-year-old woman with a history of
and not from cross-sensitization (Geier et al. atopic dermatitis who had been working in a
2015). However, a more recent study assessing paint factory for 6 years before developing
dermatitis on the hands, neck, scalp, and face epoxy resin monomer was seen in 1% (n = 275)
upon transfer to the section of the factory where and the frequency was higher in males (1.9%)
the ingredients of wood-preservation products versus females (1%). A follow-up job inquiry
were mixed. Patch test results to 0.1%, 0.03%, questionnaire was returned by 188 patients who
and 0.01% IPBC were all positive (Jensen et al. identified painting as the third highest job cate-
2003). gory (6.9%, n = 13), again with a male predom-
Methyldibromo Glutaronitrile (MDGN) is inance (11.4% M, n = 10 vs. 3% F, n = 3). Paint
a potent contact allergen which was once widely was identified as the second most frequent
used then became mostly found in cosmetics and source of epoxy resin exposure in the workplace
hand soaps (Zacharia et al. 2003). But MDGN (30.1%, n = 28) (Bangsgaard et al. 2012).
has since been banned from both leave-on and Non-occupational exposure and sensiti-
rinse-off cosmetic products in the European zation is also not uncommon, especially since
Union, since 2005 and 2008, respectively; the epoxy resins are volatile. A 10-year study
however, it may still be used in occupational of 6042 general dermatology patients patch
products. tested with DGEBA-R identified non-occupa-
tional sensitization in 35% (21/59) of patients
with 65% (38/59) being occupational cases
4.2 Synthetic Resins (Majasuo et al. 2012). Eyelid dermatitis is asso-
ciated with allergic sensitization due to the
Synthetic resins include the following: Epoxy resins’ volatile nature, and cases have been
chemicals: diglycidyl ether of bisphenol A resin reported: (1) In a housewife who had occa-
(acronyms are DGEBA-R or less commonly sional contact to hobby varnishes for 3 years
BADGE – bisphenol A diglycidyl ether), formal- and prior contact to epoxy glues and varnishes
dehyde resins, acrylic paint, polyurethane resins: in her father’s carpenter workshop, where sim-
di- and tri-isocyanates, polyfunctional acrylates, ilar eczema had occurred for the first time
and aziridine hardeners, cyclohexanone resins, (Ozkaya 2012); and (2) In a middle-aged
p-tert-butyl catechol, and unsaturated polyester woman who paints (canvases not walls) as a
resins. A recent PubMed search provided many hobby and was subsequently found to be aller-
relevant new citations between 2012 and 2017 gic to DGEBA-R (Lolatgis and Nixon 2015).
plus case reports, confirming that this is a current Airborne contact dermatitis (AirbCD) assessed
issue. Earlier relevant citations were also retrieved via a retrospective analysis of 201,344 consec-
and discussed here. utively patch tested patients from 1994 to 2013
identified 1,203 AirbCD cases of which 8%
4.2.1 Epoxy Resins (95%CI 6.8–10.3) were positive to epoxy
Epoxy resins, in particular diglycidyl ether of resin based on BADGE, i.e., DGEBA-R 1.0%
bisphenol A resin (DGEBA-R), and secondly (Breuer et al. 2015).
diglycidyl ether of bisphenol F (DGEBF), are
most often the contact allergens in epoxy paints. 4.2.2 Isocyanates
Resins derived from diglycidyl ether of Isocyanates are low molecular weight compounds
bisphenol A (DGEBA-R) is considered the with reactive ▬N〓C〓O groups, making them
most important sensitizer in epoxy systems excellent cross-linking agents to produce resins
and a significant occupational hazard for pain- such as polyurethane. They can be classi-
ters. In 209 cases of occupational contact fied based on the number of reactive groups,
allergy to epoxy chemicals, the largest occupa- i.e., monoisocyanates, diisocyanates, and poly-
tional group was painters (n = 41) (Aalto-Korte functional or multifunctional isocyanates (Frick
et al. 2015). In a study where patch testing was et al. 2003). Most commonly, di- or tri-
performed in 20,808 consecutive patients from isocyanates react with various multifunctional
2005 to 2009, a positive patch test reaction to alcohols to make polyurethane resins.
Isocyanates are widely used in the manufactur- she presented to the emergency room with ery-
ing of rigid and flexible foams, fibers, and coat- thema and pruritus affecting her face, ears, arms,
ings such as paints, lacquers, and varnishes. abdomen, and legs. Vesicles were also present on
Isocyanates are either aromatic or aliphatic. her arms. She required IV corticosteroids and
Aromatic isocyanates include toluene was discharged on a tapering course of predni-
diisocyanate (TDI), diphenylmethane-4,4- sone. She was patch tested with the North Amer-
diisocyanate (MDI), and isophorone ican Standard Screening Series, an
diisocyanate (IPDI). Aromatics are widely isocyanate series, and CHEM-Dec 808 iso-
used since they are cheaper; however, they cyanate 1% in petrolatum. At day 7, she had a
may discolor when exposed to light +++ reaction to Chem-Dec 808 isocyanate
and moisture. Thus aliphatic isocyanates 1%, and a ++ reaction to the aromatic isocy-
are often used to produce polyurethanes for anate MDI 0.1% in petrolatum was also seen.
coatings (Donovan et al. 2009). For example, The manufacturer would not release the com-
aliphatic polyisocyanates based on hexa- plete ingredients in Chem-Dec 808; however it is
methylene-1,6-diisocynate (HDI) are com- known that the primary ingredient was
monly used in lacquers, coatings and spray dicyclohexylmethane-4,40 -diisocyanate (DMDI),
paints (Aalto-Korte et al. 2010). (Refer to an aliphatic isocyanate. She was considered to
Appendix A for further description.) have had an uncommon cross-reaction to the
Isocyanates are known contact irritants aromatic isocyanate MDI as she had no previous
and allergens. They can induce respiratory symp- MDI exposure (Donovan et al. 2009).
toms including asthma, airway irritation, and 2. A 2017 study highlighted issues and identi-
hypersensitivity pneumonitis. In particular, the fied preventative measures with methylene
monomeric HDI, IPDI, and TDI are highly vola- bisphenyl isocyanate (MDI), used during
tile at ambient temperatures. Polyisocyanates spray-on-truck bed-lining (STBL) processes.
based on HDI have higher molecular weights Acute exposure to MDI during STBL tasks
thus less volatile and were initially introduced have resulted in fatalities due to acute asth-
to reduce respiratory symptoms (Aalto-Korte matic reactions. Ventilation system and pro-
et al. 2010). Contact dermatitis is less common cess characteristics were assessed during 18
but can result in a rash, itching, hives, swelling of site visits to 9 STBL companies. Results
extremities, and irritation or serious burns to indicated that increases in ventilation charac-
the eyes (Schaal et al. 2017). Below are illustra- teristics (airflow, face velocity, capture
tive cases, reports, and studies of allergic contact velocity, etc.) had the greatest effect on
dermatitis to various isocyanates: reducing MDI exposures and would be use-
ful preventative measures to put in place
1. A 27-year-old woman developed a severe (Schaal et al. 2017).
eczematous eruption within 4 days of begin- 3. MDI is also found in lacquers. An out-
ning employment as a nameplate laminator break of allergic contact dermatitis occurred
where she was required to apply a polyurethane among workers after a water-repellent lacquer,
resin coating to nameplates placed upon a board based on MDI, was introduced at a laminate
at waist level. Her work included mixing Chem- flooring manufacturing plant. Five out of
Dec 808 isocyanate (a urethane prepolymer) with twenty workers had a contact allergy. Of the
Chem-Dec polyol and using a foot pedal to five workers patch tested, four reacted
deliver the mixture via a penlike device onto to the lacquer or a diisocyanate including
the nameplates. Her sole protection was a pair MDI. This lacquer was a one-component poly-
of gloves which only reached her wrists. She was urethane lacquer composed of 80% poly-
seen by her family physician, but despite initial meric diphenylmethane diisocyanate (MDI)
treatment with antihistamines and a 4-day course according to the product safety sheet; however,
of prednisone, 6 days after the initial eruption, the manufacturer indicated that it actually
contained about 20% each of the mono- swelling. Patch test results were positive to
meric isomers diphenylmethane-2-4-diisocynate Desmodur N3300 with additional reactions
(2,4-MDI) and diphenylmethane-4,40 - to three other hardeners, all of which
0
diisocyanate (4,4 -MDI) (Frick et al. 2003; contained polymeric HDI.
Aalto-Korte et al. 2010). (d) A 33-year-old female laboratory worker in
4. Aliphatic polyisocyanates based on hexa- a paint factory developed dermatitis on
methylene-1,6-diisocyanate (HDI) are used her face, backs of hands, and forearms
in lacquers and paints. The aliphatic poly- after working for 2 months. When she left
isocyanates hexamethylene 1,6-diisocyanate her job, the dermatitis healed. Patch test
biuret, hexamethylene 1,6-diisocyanate iso- results were positive to Desmodur N3300
cyanurate, and hexamethylene 1,6-diisocyanate initially and on subsequent testing also
trimer, asymmetrical are used in hardeners of positive to Desmodur N3900 and N3200.
two-component polyurethane paints and are
among the new contact allergens identified
between 2008 and 2015 (respectively in a 4.2.3 Polyfunctional Acrylates
packer working in a paint factory; a painter Some lacquers may contain 85–90% of poly-
and an office worker working in a paint fac- functional acrylates, which can cause allergic
tory; and a laboratory worker working in a contact dermatitis.
paint factory) (de Groot 2015). These were
the four cases of occupational contact allergy 1. Occupational contact dermatitis from ultravio-
to HDI-based aliphatic polyisocyanates in let-cured lacquer for painting wood, containing
hardeners of two-component polyurethane dipropylene glycol diacrylate (DPGDA), has
paints seen at the FIOH from 2000 to 2009. been reported (Estlander et al. 1998).
The authors of the paper believed that theirs 2. A case of disseminated allergic contact
was the first report of contact allergy to ali- dermatitis occurring in a screen process
phatic polyisocyanates in humans (Aalto- printer, caused by ultraviolet-cured transparent
Korte et al. 2010). lacquer containing multifunctional acrylates
(a) A 37-year-old female packer in a paint (methylpropane triacrylate and pentaerythritol
factory developed facial dermatitis twice triacrylate), has also been reported. This was
while packing a hardener with a constituent a 54-year-old man with no history of atopy
(Desmodur N75 MPA/X) that contained who developed disseminated skin changes
75% HDI-based aliphatic polyisocyanate. (upper and lower extremities, face, neck and
(b) A 53-year-old female office worker in a upper chest) which included erythema with
paint factory spilled some samples of vesicles and papules accompanied by severe
three hardeners for industrial paints on pruritus. As per the material safety data sheet,
her left forearm and thigh and subse- the lacquer contained 85–90% multifunctional
quently developed allergic dermatitis on acrylates and 10–15% photoinitiators and sur-
the same areas 1½ weeks later. Patch factants. Patch tests using the acrylates and the
test results were positive to Desmodur lacquer were all highly positive (++/+++)
N3390 BA (which contained 90% of an (Kiec-Swierczynski et al. 2006).
isocyanurate-type HDI trimer), Desmodur
N3300, and Desmodur N3200. Varnishes may contain acrylates. Four cases of
(c) A 38-year-old male with a history of mild sensitization to acrylates in people who work with
atopic dermatitis worked as a painter in an varnishes were reported in 2007 (Conde-Salazer
aircraft repair workshop. His primary job et al. 2007).
was grinding of surfaces painted with two-
component paints. He developed new skin 1. A 33-year-old woman with no prior skin dis-
symptoms on his thighs and feet and facial ease presented with a history of erythematous
itching, exudative lesions followed by scaling was negative. An ophthalmologist had considered
affecting the flexor surfaces of her forearms, his conjunctivitis as probably allergic in nature.
abdomen, right thigh, and both cheeks 10 days Patch testing with the European baseline series,
after working with new varnishes at her work the paint (0.2%, 0.1%, and 0.05% in petrolatum),
place. The varnishes contained tripropylene and a (meth)acrylate series showed posi-
glycol diacrylate, 203 acrylate, and glycerol tive reactions to trimethylolpropane triacrylate
propoxy triacrylate. She stopped handling the (TMPTA) and pentaerythritol triacrylate however
varnish and was treated with topical corticoste- only TMPTA was present in the paint. It was
roids and the lesions disappeared 2 weeks later. interesting to note that he had a focal flare of
Patch testing results were positive for several his conjunctivitis concurrent with the positive
acrylates including tripropylene glycol patch tests to TMPTA (Mancuso and Berdondini
diacrylate. 2008).
2. A second case involved a 41-year-old man
with no prior skin disease who presented with
eczema 15 days after starting work at a varnish 4.2.4 Polyester Resins
plant and patch testing was positive for Polyester resins are condensation products
dipropylene glycol diacrylate. of difunctional or polyfunctional monomers.
3. A third case was a 40-year-old man with no Unsaturated polyester resins are made by con-
prior skin disease who presented with eczema a densing a di- or polyhydric alcohol with a di- or
few days after casual contact with new var- polybasic organic acid or anhydride. The curing
nishes – patch test results were positive for reaction occurs when an unsaturated cross-
various acrylates. linking monomer (e.g., styrene or methyl meth-
4. A fourth case was a 28-year-old man with no acrylate) and an oxidizing catalyst (e.g., benzoyl
prior skin disease who presented with a 15-day peroxide) are mixed together (Tarvainen et al.
history of erythema. He used a new varnish 1993). Contact allergy to raw materials or com-
which contained diipropylene glycol diacrylate ponents of polyester resin systems is considered
and tripropylene glycol diacrylate. quite rare but has been reported. Six cases of
allergic dermatitis from car-repair painting due
Paints may contain acrylates. A UV-cured to unsaturated polyester resin cements were
paint containing acrylates induced an occupa- reported in 1993. All six cases had eczema on
tional conjunctivitis with it being the sole mani- their hands with one whose eczema was limited
festation of the contact allergy. With no history to fingertips injured by cyanoacrylate glue (after
of atopy, a 28-year-old man who worked as a wrenching his fingers too vigorously out of the
screen-printer presented with a 2-month history dried glue). Four of the six also had eczema on
of itching of both eyes with conjunctival ery- airborne areas (wrists, face, neck), and it was
thema. Symptoms started a month after he began concluded that they developed skin symptoms
using a screen-printing process with a UV-cured from the sanding dust of the finished product.
paint, to print onto plastic bottles. He wore cotton All cases healed on sick leaves and relapsed in a
gloves with no other protective measures but day or two after returning to work (Tarvainen et
except for the eyes there were no other skin man- al. 1993). An analysis of patients from the Finn-
ifestations. His eyelids would swell after a work- ish Institute of Occupational Health (FIOH)
ing day, and a mild hyperemia of the bulbar and between December 1993 and February 2015
tarsal conjunctivae without papillary or follicular identified 11 cases of occupational contact
hypertrophy would be noted. Symptoms would allergy caused by components of polyester
improve on the weekends and would disappear resins. Six of the 11 were painters (three car
when away from work for a week. A conjunctival painters, a painter of cabins of mining machines,
scraping showed moderate lymphocytic reaction a painter of tractor cabins, and a spray painter of
with increased eosinophils, and a bacterial culture bicycles) (Aalto-Korte and Suuronen 2016).
4.2.5 Others Production of powder paints (nanoparticles)

Epoxy hardeners/curing agents in particular can cause skin irritation either topically or via
the nonstandard 1,3-benzenedimethanamine (1,3- inhalation, for example, during the powder han-
BDMA), also known as m-Xylylenediamine dling or packaging stages (Aitken et al. 2006).
(MXDA), is a newer epoxy hardener; and N- Biocides may be skin irritants. In particular, the
(2phenylethyl) derivatives resemble MXDA and antifouling agent tri-butyltin oxide (TBTO) is
are used as curing agents to harden epoxy paints a biocide used in marine paints and others.
and coatings. A report in 2016, which appeared TBTO is a strong skin irritant with corrosive prop-
to be the first case series of contact allergy to erties. A 39-year old shipwright developed pruri-
derivatives of 1,3-BDMA, described six patients tus, erythema, and vesiculation on both wrists
examined at the Finnish Institute of Occupational and forearms with a few lesions on the abdomen
Health between 2013 and 2015. Patch tests with after using an antifouling paint for wooden blocks,
one of two hardener ingredient mixtures, each where his skin was oversprayed by the paint. The
of which contained derivatives of 1,3-BDMA, skin irritation was noted within about an hour,
were positive for all six patients, five of whom with erythema and ulceration noted on the second
were painters and one was a floor layer. All pre- day. The paint contained 10–11.7% TBTO and
sented with symptoms of eczema with varying was labelled as irritant or corrosive. Other constit-
locations but most consistently on the forearms, uents included xylene, cuprous oxide, and copper
wrists, face, and eyelids. Two of the patients also thiocyanate. A prior exposure to a TBTO
tested positive to DGEBA-R (Pesonen et al. 2016). containing paint 2 months previously also resulted
in a similar dermatitis on both wrists, and at least
four other workers performing similar tasks also
4.3 Irritant Contact Dermatitis developed dermatitis on that prior occasion. The
authors noted that TBTO has a strong irritant
Although the focus of this chapter has been on potential, which can be manifested by merely
allergic contact dermatitis from paints/varnishes/ brushing a contaminated arm across the mouth or
lacquers, prolonged skin irritation resulting by wearing shoes contaminated with TBTO some-
solely in an irritant dermatitis may also occur. A time earlier (Lewis and Emmett 1987).
case-controlled study in dockyard painters in the
United Kingdom versus in China showed that
irritant symptoms from skin, eyes, or nose were 5 Summary
higher in all painters versus controls, and that the
relative risks for skin, eye, and nasal irritations There are many potential contact allergens and
were all higher in Chinese painters when com- irritants in paints, varnishes, and lacquers. People
pared to British painters. It appeared that there with anticipated frequent exposures such as pain-
was a direct correlation between duration of ters should take protective measures (e.g., gloving
exposure and irritant symptoms (Chen et al. and masking as needed) to reduce the possibility
2001). of a dermatologic reaction.
Important causative agents for irritant dermati-
tis include organic solvents, paint dusts, and rem-
nants of biocides. Organic solvents used as paint
Appendix A
thinners or for cleaning brushes and spray guns
are common causes of irritant dermatitis. Simi- Composition of Paints, Varnishes, and
larly, skin irritation can occur if clothing becomes
Lacquers
soaked by accidental splashes of solvents and the
soaked clothing is allowed to remain in contact Excerpted from Estlander T, Jolanki R. Chapter 61
with the skin for a prolonged period. This speaks Paints, Lacquers, and Varnishes
to the painter’s hygiene and painting style. Kanerva’s Occupational Dermatology 2nd ed. 2014
A.1. Binders reaction of the binder with the oxygen in the air
(Fischer and Adams 1999; Estlander et al. 2000).
Binder is the main ingredient in paints, lacquers, Epoxy resin compounds. Paints, varnishes, and
and varnishes. It is the actual film-forming agent lacquers based on epoxy resins are used
in paints. It keeps the pigments bound and per- in various industrial applications because of
manently dispersed on the painted surface, and it their strength and durability. A hardener must
provides the most important properties of the be added to two-component epoxy paints that
coating: hardness, flexibility, and speed of dry- cure at ambient temperature before their
ing. Binders include synthetic or natural resins application. The paint hardeners include polyamines,
and oils, alkyds, epoxy resin compounds, form- e.g., diethylenetriamine, triethylenetetramine, tri-
aldehyde resins, acrylic resins, polyurethane methylhexamethylenediamine, isophoronediamine,
resins, water-dispersible polymers and other and 1,3-xylylene diamine and often also a catalyst,
synthetic resins, polystyrene resins, and cyclo- such as 2-,4-,6-tris(dimethylaminomethyl)phenol
hexanone resins (Rose and Vance 1997; Fischer (tris-DMP).
and Adams 1999; Estlander et al. 2000). One-component epoxy powder paints that
Natural resins and oils originate from trees, are heat-cured contain a hardener which can
plants, fish, and insects. Dammar, Japanese lac- only be activated by heating. Polyfunctional aro-
quer, and shellac are suitable for lacquers and matic amines, solid polyamides, and organic
varnishes because they dry quickly, although anhydrides can be used as curing agents (Jolanki
the film formed is brittle. Copal is a fossilized 1991; Estlander et al. 2000; Ponten 2006). See
resin which is used in varnishes. Natural oils, ▶ Chap. 52, “Epoxy Resins” for additional
such as flaxseed or linseed oil, perilla, tung and information.
pine (tall) oils, soybean and ricin oils are all used Formaldehyde resins. Urea, melamine, phe-
in oil-based paints. Since the 1980s, synthetic nol, or substituted phenols can be modified with
alkyd resins have widely replaced natural binders formaldehyde to produce corresponding resins.
(Fischer and Adams 1999; Estlander et al. 2000). An excess of free formaldehyde must be removed
Alkyds or alkyd resins are condensation prod- in order to prevent interference with the film-
ucts of poly-alcohols; e.g., glycerol, penta- forming properties of paint. These resins can
erythritol and sorbitol, and polycarboxylic acids also be used to cross-link alkyd resins. The curing
or corresponding anhydrides such as phthalic takes place by heating. Phenol formaldehyde
anhydride, adipic acid, and maleic acid. Common resins (PFRs) remain stable in temperature varia-
alkyd binders are formed after modification with tions and are resistant to moisture, acids, and
oils containing unsaturated fatty acids. These solvents (Fischer and Adams 1999; Estlander
include linseed, soybean, sunflower, cottonseed, et al. 2000). For more information, refer to
and pine oil. Linseed oil and similar drying oils ▶ Chap. 53, “Contact Allergy to Phenol-Formal-
can be combined with colophony (rosin) to pro- dehyde Resins” in the textbook.
duce a paint resistant to climatic conditions while Acrylic resins. Multifunctional acrylates
also having good color retention. are used in the formulations of UV-curable coat-
Polyester resin binders are alkyds containing ings. The most commonly used multifunctional
no modifying oils. Styrene and vinyl toluene are acrylates in industrial UV-curable acrylate paints
used as cross-linking agents for these alkyds. and coatings are trimethylolpropane triacrylate
Epoxidized alkyd resins are alkyds modified (TMPTA), pentaerythritol triacrylate (PETA), or
with epoxidized oils which are formed by reacting hexanediol diacrylate (HDDA). A photoinitiator
double bonds in unsaturated fatty drying oils with system is also needed.
oxygen to form an epoxide ring. Multifunctional acrylates can be combined
Paints based on alkyd resins need no hard- with polyfunctional aziridine (PFA) cross-linking
eners. They are hardened by the evaporation of agents. Commercially available PFA cross-
organic solvents or water, followed by the linking agents are usually synthesized from
ethyleneimine or propyleneimine and TMPTA or Cyclohexanone resin can be added to increase

PETA. A PFA cross-linker is added to the aqueous the hardness and water resistance of any paint but
acrylic component before its use. The cross- is most often used in floor paints. Paint may con-
linking reaction is self-curing, but heat or UV tain 5% cyclohexanone resin. Various manufac-
radiation may be used to enhance the reaction, turers make cyclohexanone resins (Bruze et al.
resulting in faster drying of the products. 1988).
PFA is also used to cross-link water-based
polyurethane emulsions, such as lacquers and top-
coats. (Kanerva et al. 1995; Fischer and Adams A.2. Solvents
1999; Estlander et al. 2000; Bjorkner 2006). For
more information, refer to ▶ Chap. 51, “Acrylic Paint solvents include water and organic solvents.
Resins” chapter. They are used to modify the paint viscosity
Polyurethane resins. Polyurethane coatings required for the application methods of brushing,
are formed by the reaction of isocyanate groups rolling dipping, and spraying. Solvents are chosen
with hydroxyl groups of polyalcohol compo- for their solvency, evaporation, and suitability for
nents. The polymerization reaction is usually cat- product use (Leira 1997; Estlander et al. 2000).
alyzed by tertiary amines. Mainly di- or Solvent-based paints contain about 50%
triisocyanates, e.g., toluene diisocyanate (TDI), organic solvents, which is the volatile component
isophorone diisocyanate (IPDI), hexamethylene of paints, Until the 1970s, turpentine was the
diisoxyanate (HDI), or their trimers are used in most often used solvent in many countries in
the reaction. Unmodified polyurethane resins can construction paints, but it was later replaced by
be formulated in one- or two-component sys- aliphatic and alicyclic hydrocarbon solvents, such
tems. They can be modified with natural drying as white spirits. Paints used for other purposes
oils, resulting in coatings which dry in the air and may also contain xylene, toluene, alcohols (e.g.,
are polymerizable, like alkyl resins. Polyure- n-butanol and isopropanol), and ketones. The use
thane resins are durable, heat resistant, and flex- of D-limonene, the principal component of the oil
ible (Fischer and Adams 1999; Estlander et al. extracted from citrus fruit rinds, has expanded
2000; Frick 2006). For more information, refer dramatically. It may also be used in paints and
to ▶ Chap. 54, “Polyurethane Resins” in the other coatings (van Faassen and Borm 1991;
textbook. Wieslander et al. 1994; Rose and Vance 1997;
Water-dispersible polymers and other Estlander et al. 2000).
synthetic binders mostly include polyvinyl ace- Solvent-based paints dominated the construc-
tate, polyacrylate, copolymers of vinyl acetate and tion paint market until the 1970s (Hansen et al.
acrylate, and copolymers of styrene and acrylate. 1987). New environmental regulations and con-
These are used in water-based latex paints. The sumer demand have led to the development of low
latexes may contain small amounts of ammonia VOC and zero VOC paints and finishes. The first
(0.3% w/w), formaldehyde (0.06% w/w) or other latex-type water-based paint was introduced in
biocides (e.g., mixture of isothiazolinones), sur- 1957 (Rose and Vance 1997; Wieslander et al.
factants and polymerization inhibitors (e.g., 1994).
hydroquinone or benzyl peroxide), and even Water-based paints contain water-dispersible
traces of monomers, e.g., mono(meth)acrylates polymer binders. They can also contain alkyl
(Hansen et al. 1987; Fischer and Adams 1999; resin and a mixture of polyacrylate and polyure-
Estlander et al. 2000). thane binders. Although water is the main solvent
Polystyrene resins are made from polymerized in these types of paints, comprising about 30–85%
styrene and have good insulating power. Synthetic of the raw materials, up to 10% organic solvents
rubber, known as styrene-butadiene or chlorinated may be used to improve the film-forming proper-
rubber latex, can be used in paints for floor ties of the paint. Totally solvent-free paints and
coverings or tank linings (Fischer and Adams 1999). varnishes (VOC less than 0.1%) for decorate
finishes are available. Powder paints are also free pigments and have a significant impact on
from solvents (Wieslander and Norback 1997; the overall characteristics and performance of the
Fischer and Adams 1999; Estlander et al. 2000; paint, including durability, scrubbability, and the
Kaukiainen 2005). retention of color. Extender pigments are mainly
made from clay, silica, talc, and chalk (Fischer and
Adams 1999; Estlander et al. 2000).
A.3. Pigments
Pigments are fine ground powders dispersed A.4. Additives

throughout the paint to give it a color. They also
have other properties: they can alter paint flow Additives are used in paints in small percentages
and provide corrosion resistance. Pigments also to ensure, e.g., their stability, quality, and desired
have limited solubility to water and solvents, and application properties. Additives include bio-
good color fastness. They must be opaque but cides, driers, emulsifiers or surfactants, thixotro-
may be either inorganic or organic (Rose and pic agents (thickeners), plasticizers, stabilizers,
Vance 1997). antioxidant antiskinning agents, photoinitiators,
The most commonly used inorganic pigment and corrosion inhibitors.
is white titanium dioxide, which can be used in Biocides are used to prevent growth of microbes
combination with zinc oxide. Titanium dioxide is (bacteria, fungi) mainly in water-based paints. They
also one of the most broadly applied nano- are used for conserving the binder and the paint
materialsand is used in numerous other commer- during production and storage. Biocides are effec-
cial products (Aitken et al. 2006). Other white tive even after the paint has dried, and thus prolong
pigments include lithopone white (mainly its life. Oil-based paints do not usually contain anti-
consisting of zinc sulfate and barium sulfate), microbials, but some exterior paints can contain an
zinc oxide, and antimony trioxide. The use of antimildew agent. A great number of biocides are
white lead (basic lead carbonate) has been banned available for use in paints. Antifouling agents are
in most countries because it can cause lead poi- used in marine paints and are usually toxic to under-
soning, although paint with significant lead con- water organisms. These include copper, organic tin,
tent may still be used in industry and by the tetramethylthiuram disulfide (TMTD), and zinc car-
military. Red pigments include iron oxides bamates (Estlander et al. 2000).
and Cadmium Red (containing cadmium sulfide Driers can feature one or more metal salts, e.g.,
and cadmium selenide). Yellow pigments include cobalt, manganese, iron, lead, zinc, and tin
lead chromate, strontium chromate, zinc chro- naphthenates, oleates, octoactes, and resonates.
mate, and lead chromate. Chrome Green Emulsifiers or surfactants include sodium pyro-
(containing lead chromate and ferric ferrocya- phosphates, dioctyl sodium sulfosuccinate, sodium
nide) and chromium oxide are examples of green lauryl sulfate, and non-ionic detergents. They help
pigments. Blue color is obtained using, e.g., to maintain pigment-particle dispersion in water-
a certain iron oxide, and violet color with, e.g., based latex emulsions. Antifoaming agents prevent
manganese ammonium pyrophosphate. Carbon the formation of foam during the manufacturer and
black is the most commonly used black pigment application of water-based latex paints.
(Rose and Vance 1997; Fischer and Adams 1999). Thixotropic agents (thickeners) such as poly-
Organic pigments are used for special pur- amides are added to oil-based paints, whereas
poses. They are generally purer but more expen- cellulose derivatives are used for the same pur-
sive. Examples include Para Red, Lithol Reds, pose in water-based latex paints.
Pigment Red 170, Toluidine Red, Phthalocyanine Plasticizers are added to paints to increase the
Green and Blues, and Dioxazine Violet. flexibility of the resinous film. They include
Extenders are fillers used in paint pigment. dibutyl and dioctyl phthalates, adipic and sebacic
They do not provide as much cover as primary acids, and their esters, polyester resins, and castor
oil. Coalescing agents include pine oil, butyl in the UK and global trends. In-depth review. Occup
cellosolve, and tributyl phosphate; these are vola- Med 56:300–3006
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Coatings
64
Carmen Maria Sălăvăstru, Letiţia Bucur, Gheorghe Bucur, and
George-Sorin Ţiplica
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
3 Metallic Coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
3.1 Chromium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
4 Plastic Coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
5 Paint Coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
5.1 Skin Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
6 Printed Coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
7 Natural Gums . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
8 Waxes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
8.1 Skin Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Keywords
Gheorghe Bucur: deceased. Coatings · Aluminium · Chromium · Gold ·
C. M. Sălăvăstru (*) Nickel · Platinum · Silver · Contact dermatitis ·
Colentina Clinical Hospital, “Carol Davila” University of Urticaria
Medicine and Pharmacy, Pediatric Dermatology,
Bucharest, Romania
e-mail: galati1968@yahoo.com
L. Bucur 1 Core Messages
Department of Occupational Health, Belsana Grup LLC,
Bucharest, Romania • Different object properties are enhanced by
e-mail: letitia.bucur@gmail.com coating: hardness, durability, longevity, elas-
G. Bucur ticity, appearance, corrosion resistance, etc.
Bucharest, Romania • Metallic coatings are frequently used. Nickel,
G.-S. Ţiplica chromium, mercury, and antimony have
Colentina Clinical Hospital, “Carol Davila” University important sensitizing properties.
of Medicine and Pharmacy, Dermatology 2, Bucharest,
Romania • Plastic and paint coatings have a wide range of
e-mail: george.tiplica@umfcd.ro applications. Direct or airborne contact with

https://doi.org/10.1007/978-3-319-68617-2_62
940 C. M. Sălăvăstru et al.
several polymers can induce irritant or allergic monitored, and the industry is taking measures to
skin dermatitis, contact urticaria, mucosal irri- limit and control all possible risks and hazards. A
tation or allergy, scleroderma, etc. good example is the use of lead pigments in the
• Printed coatings are revolutionizing the print- USA: first replaced when possible (1930s), then
ing industry. Allergic dermatitis was described limited in use (1950s), and banned for use (1978).
in workers using different dyes. There are different coating processes that need
• Other coatings (natural gum, waxes) are to be known by the physician treating an occupa-
mainly present in the food industry and in the tional dermatosis: vapor deposition (chemical or
drug industry. Some components can induce physical), chemical and electrochemical tech-
allergic reactions (arabic gum, beeswax), acne niques (including plating), spraying, roll-to-roll
(organochloride compounds), etc. coating, and physical coating processes.
A complete coating system may include a
primer (to improve adhesion and to level imper-
2 Introduction fections of the substrate), the base coat (for color-
ing and effects), and a top coat (for coloring and as
Coating is a covering, a thin liquid, gas, or solid protective layer against weathering, solvents, and
film applied on a substrate (the surface of an scratching) (Nanetti 2006). Sometimes an addi-
object – film, foil, paper, fabric, sheet stock), to tional clear coat can be applied (also for protec-
improve the qualities of the substrate by pro- tion). Most frequent used are metallic coatings,
tecting, preserving, or beautifying it. Coating is plastic coatings, and paint coatings.
enhancing the value of the coated object far Coating classification includes:
beyond the direct costs. Historically, coating
was used by humans from early times in all – Industrial coatings: applied at the time of prod-
their activities (cave wall decoration, pottery, uct manufacture
waterproofing, archaic metallurgy, etc.). Clay, – Architectural coatings: applied after the
animal fat, plants, bee wax, ox blood, lime, and manufacture in order to protect or beautify
ochre were among the first used in the coating the product
process. From the initial purpose of beautifying – Special purpose coatings: applied “on-site”
and protection of the substrate, the coatings later and not in an industrial setting.
evolved in gaining functional properties (Nanetti
2006): electronic properties (e.g., passivity or There is hardly any industry that does not
conduction), low surface energy coatings (e.g., use some form of coating for one purpose or
PTFE coatings), magnetic properties (e.g., cas- another. However, the risk of developing occupa-
sette tapes and floppy disks), melt-adhesive prop- tional dermatoses is reduced as the coating pro-
erties (e.g., heat seal or vacuum seal), optical cesses are mainly automated and preventive
properties (color, tint, holographics, anti- measures are identified.
reflection, etc.), photosensitivity, scent proper-
ties (e.g., scratch and sniff stickers and labels),
self-adhesive properties (e.g., labels, tapes, etc.), 3 Metallic Coatings
water-proof coatings (e.g., paper, fabrics,
watches, wood surfaces), mechanic properties Metallic coating uses a large variety of techniques
(e.g., hardness, sturdiness, durability, longevity, and types of metals and other chemicals sub-
smoothness, elasticity), etc. stances. Plating is a surface covering in which a
In the modern world, coatings are indispens- metal is deposited on a conductive surface. Met-
able and cover virtually every object from house- allizing refers to coating metal on nonmetallic
hold appliances, buildings, cars, ships, and objects (Nanetti 2006). It is hundreds of years
airplanes to computers and microchips. The old technique but also a very modern one. Objec-
impact of coating on environment and health is tives of plating are the following:
64 Coatings 941
– Appearance enhancing (as in silver, gold, occupational context is suggestive, skin lesions
platinum finishing of jewels) can be induced by arsenic traces found as impuri-
– Conductivity altering ties (Kim et al. 1999).
– Corrosion inhibition Arsenic is very toxic. May be fatal if inhaled,
– Decoration swallowed, or absorbed through the skin. Arsenic
– Friction reduction is also known as human carcinogen. Different
– Hardening types of allergic lesions have been described
– Improving of solderability, wearability, and (Degreef and Roelandts 1974):
paint adhesion
– Nanotechnology – Allergic eruption localized to the face and
– Radiation shielding folds, mimicking atopic dermatitis. The clini-
cal aspect can be acute with papules, vesicles,
In the process of metallic coating, the workers’ and pustules. Follicular papules can be observed
skin and mucosa can be exposed to different sub- on the neck or limbs. There are cases where the
stances with harming potential. Acids (chromic aspect is of chronic eczema.
acid, nitric acid, oxalic acid, phosphoric acid, – Urticarial lesions persisting more than
sulfuric acid) can induce severe skin irritation 2 weeks. Lesions are located on the exposed
(corrosive dermatitis). areas, skin folds, and regions exposed to minor
Aluminum is apparently not hazardous for trauma and are induced by contact with dust or
the skin, but pure aluminum with sodium vapor. In time, the erythema changes to hyper-
fluoride (NaF) forms aluminum fluoride (AlF3). pigmentation from café-au-lait color to brown
Fluorides cause severe skin burns (rash, corrosive, or ochre. Some authors consider that arsenic
itching dermatitis). Contact sensitivity to alumi- melanodermia is produced by toxic effects
num is extremely rare, and sensitization occurs (Ayerza 1918).
if aluminum-containing antiperspirants are fre- – Toxidermic-like erythema with local or gener-
quently used or if vaccines containing aluminum alized distribution can be associated with pur-
adjuvants are injected. Patch test used for diagno- pura and ecchymoses. At the palmoplantar
sis is aluminum sulfate 10% aq or aluminum level, there can be bullous lesions which later
acetate 10% aq (Böhler-Sommeregger and develop to keratoderma. Skin hyperkeratosis
Lindemayr 1986). can also have other location. Some of them
An evaluation of dermal toxicity of flake-like are precancerous lesions, especially in the scro-
α-alumina (the most stable form of aluminum) was tal region (Andrews et al. 1991).
conducted on human skin cells, also in vivo on – Exfoliative erythroderma can appear in
mouse model, and in vitro on porcine skin (Kwon neglected cases of chronic evolution or in per-
et al. 2015). No significant injury to the cell viability sons with excessive sensitization. The skin is
up to 24 h and no dermal inflammation as assessed covered by large scales, and general symptoms
by histology of epidermal architecture, hyperplasia, are also present: fever, chills, fatigue, and loss
or the expression of interleukin-1β and cyclooxy- of appetite. Diffuse alopecia can also occur.
genase-2 were observed. Therefore α-alumina may Sometimes the evolution is fatal, as in the
be considered safe for use as a coating pigment. syphilis cases with secondary erythrodermia
Antimony (stibium) can induce skin induced by the treatment with arsenic (Centeno
irritation with erythema, vesicles, and pruritus. et al. 2002).
Frequently lesions occur on the cephalic extrem- – Irritative lesions also can occur as typical
ity, especially periorbital, peribucal, and peri- lesions of contact dermatitis. Skin ulcers and
nasal. Sometimes lichenoid eruption can occur in perforation of the nasal septum were also
several weeks after exposure. Patch test used for described (Scierski et al. 2007). Often, the
diagnosis is stibium chloride (SbCl2) 2% aq. If the first lesions developed are of orthoergic
SbCl2 patch testing is negative but the eczema as most combinations of arsenic have
an irritating action. Only in a second phase the 3.1 Chromium

allergic dermatitis is developed. Investigation
of arsenic exposure should take into account Metallic chromium is not a sensitizer (Alfonzo
that arsenic compounds are often primary irri- 1979; Avnstorp 1992; Huriez et al. 1969) (see
tant. Testing with high concentrations can also ▶ Chap. 44, “Chromium”). The chromium
induce false positive tests (irritation), and insis- hexavalent form (present in chromic oxide, chro-
tently repeating the tests can lead to patient mic acid, chromates, and dichromates) is soluble,
sensitization. The most accurate patch test and therefore it is the only form able to penetrate
substances for arsenic allergy are sodium the skin. Once in the skin, often via sweat glands
arsenite 1% aq. and potassium arsenite 1% (dissolved in sweat), chromium undergoes reduc-
aq. (Fowler’s solution). tion to the valence 3+ which can act as a haptene. It
binds with certain skin protein to form the com-
Brass, an alloy of copper (66%) and zinc plete antigen and thus initiate the allergic cascade
(33%), is not sensitizing when pure. Skin irritation, (Dooms-Goossens et al. 1980; Peltonen and Fräki
pigmentary disorders, systemic poisoning, and 1983; Thormann et al. 1979), sometimes accom-
respiratory mucosal irritation can occur, mostly panied by sarcoid-type infiltration. The presence of
due to some secondary components (as vapor dur- chromium in various materials is tested with the
ing the technological process) or to impurities: reaction of diphenyl carbazide, 1% alcoholic solu-
antimony, nickel, cadmium, manganese, arsenic, tion, which turns violet in the presence of chro-
and aluminum. Professional musicians (brass mium (Foussereau and Laugier 1966). It is possible
players) can have their lips and skin affected by to challenge the chromium allergy by oral inges-
the contact with the instrument (Bork 1993). tion of one tablet containing 2.5 mg of potassium
Bronzes are formed by mixing copper with tin dichromate. A reactivation and/or an extension of
and with small quantities of other elements: alumi- the skin rash will be observed in the case of a
num, zinc, antimony, phosphorous, and lead. Skin positive reaction (Fregert and Gruvberger 1973;
irritation and sensitization can be induced by copper, Pirila and Förström 1966). Hexavalent chromium
but the most irritating and sensitizing bronzes are has a significant irritant capacity. It can have caus-
those containing mercury, arsenic, and antimony. tic action with skin ulcer formation (“dove eye”
Also noxious can be the substances used to apply characteristic aspect) and nail dystrophy. Hexa-
bronze on wood, stone, paints, and even textiles: valent chromium can be toxic and mutagenic
acetone, ammonium sulfate, antimony sulfate, ben- (Van Ketel 1984a; Wahba and Cohen 1979).
zene, methanol, turpentine, synthetic resins, and EU adopted the limit of 3 mg/kg for hexavalent
varnish. This provides a range of decorative wood, Cr in consumer and occupational leather
metal, paper, textiles, clothing, household items, and products. The prevalence of chromium allergy
paper dyes. In metallurgy where bronze alloys are in European adult population is approximately
poured in forms and in workshops where bronzes 1–3% (Mathiason et al. 2015).
are used, there can be encountered cases with aller- Sensitized subjects to hexavalent chromium
gic or orthoergic contact dermatitis. Toxic accidents may have also allergic reactions to trivalent chro-
can also appear with mucosal signs (stomatitis, gin- mium (Moretto 2015). Both hexavalent and triva-
givitis with teeth, and gum staining green), green lent chromium are released from leather goods.
color of hair, green sweat, and systemic poisoning Even if the content of hexavalent chromium in
(Apostoli 1998). leather is regulated in European Union, trivalent
Cadmium is known for its potential of induc- chromium compounds are also used for leather
ing skin irritation and sensitization, photoallergic tanning, and more important is the rate of release
reactions, and allergic conjunctivitis. Dermatitis of both forms of chromium for allergic skin reac-
frequently manifests periocularly and periorally tions. A Danish study was performed on 155
(Motolese et al. 1993). Patch test for diagnosis is dermatitis patients with positive patch tests to
using cadmium chloride (CdCl) 1–2% aq. potassium dichromate and 621 matched patients
64 Coatings 943
with other dermatitis from a control group. The limits for humans and no emergency medical
study showed that 66% of the chromium-allergic guidelines for treatment of gallium poisoning
patients were sensitized from leather exposure. In (Ivanoff et al. 2012).
the chromium allergy group, the quality of life Germanium can induce skin irritation (Kaplan
was significantly lower ( p < 0.001), the preva- et al. 2004).
lence of dermatitis during the last year was higher Gold (Aurum) very rarely can induce skin irri-
( p = 0.008), the use of medication during the past tation, sensitization (allergic contact papulous rash,
12 months was higher ( p = 0.001), and the prev- contact urticaria), conjunctivitis, or discromia (see
alence of sick leave was higher ( p = 0.007) than also ▶ Chap. 46, “Gold”). Due to its resistance to
those in patients from the control group oxidation and other special chemical properties, it
(Bregnbak et al. 2014). is used in jewelry industry, watches, paint, furnish-
Patch test is performed with potassium dichro- ings, and artwork, as well as some special technol-
mate 0.5% pet. An alternative diagnostic test for ogies (including space industry). Sensitizing to
chromium-allergic contact dermatitis was devel- gold is exceptional; some cases are actually given
oped by Brazilians Martins LE and Reis VM by other metals or elements present as impurities.
(2013). They observed that in allergic patients, Gold salts can be sensitizers: gold trichloride (used
chromium increased the production of IFN-y, in photography) and gold cyanide (used in glass
IL-5, and especially that of IL-2 and mainly and porcelain industry). Gold cyanide can induce
IL-13 who had a sensitivity, specificity, and accu- allergic contact dermatitis of the hands and face,
racy of about 80% in 2-day culture but even better allergic conjunctivitis, and irritative lesions
in 6-day cultures. (including discromias, necrotic erosions, nail
Cobalt can induce skin irritation and also sen- lesions) (Elgart and Higdon 1971). Other gold
sitization. Photoallergic reaction, urticarial rash, salts are particularly irritating, having an acid pH
and sarcoid infiltrate were also described (Manciet and inducing even violent reactions, sometimes of
et al. 1995). Skin lesions are clinically identical to acantholytic type. Skin lesions can also be minimal
those induced by nickel. as hypopigmented spots. Most contact dermatitis
Copper (Cuprum) rarely acts as a sensitizer to gold salts appears to dental technicians and
and can induce immunologic contact urticaria, jewelers using, in fact, a number of alloys with
allergic contact dermatitis, systemic allergic reac- gold. The most sensitizing alloys are red gold (an
tions, and contact stomatitis. Copper is widely used alloy of gold with copper) and yellow gold (an
(e.g., coins, intrauterine devices, decorations), but alloy of gold with nickel 20%). Skin rashes to
reports of sensitization to the metal are extremely gold salts and gold alloys are papular and some-
rare. Some persons allergic to copper may have times with infiltrative aspects as in insect bites or in
cross-reactions to nickel. For patch test, CuSO4 pseudolymphomas. If sensitization is due to dental
1% aq is used (Hostynek and Maibach 2004). prosthesis, the allergic lesions are of eczematous or
Gallium is a skin sensitizer and also an irritant urticarial type (Comaish 1969).
(Tsai et al. 2005). There is a case report of a Gold was named Contact Allergen of the Year
college student accidentally exposed to gallium 2001. Positive patch test reactions to gold have
halide complexes that developed acute gallium relatively low clinical relevance, and its
poisoning initially presented as dermatitis but pathogeny is not yet well understood (Chen and
which then rapidly progressed to tachycardia, Lampel 2015). An unusual case of gold allergy
tremors, dyspnea, vertigo, unexpected blackouts, from a new pigment used in tattooing was
and finally irreversible cardiomyopathy. Workers reported in 2011 by Tammaro et al.
involved in the production of semiconductors Patch test is performed with potassium
may be accidentally exposed to gallium, as dicyanoaurate (0.002% aq. or 0.001 in ethanol)
also are the dentists who use gallium alloys to or gold chloride (0.5–2% aq.) or potassium
replace mercury-containing amalgam. There bromaurate (0.1% aq.) or sodium chloraurate
are no threshold limit values and exposure (0.1% aq.).
Indium is apparently not hazardous for the maintained, reactivated, and demonstrated by
skin. food rich in nickel (herrings, oysters, beans,
Iron (ferrum) is inducing skin irritation peas, corn, spinach, onions, tomatoes, mush-
and rarely is a sensitizer. Skin lesions also rooms, pears, margarine, mayonnaise, tea, coffee,
include discromia or “occupational tattoo” (skin cocoa, chocolate). Food processing and storage in
enclavation of iron particles) (Zugerman 1985). vessels and objects coated with nickel lead to the
Lead (plumbum) is irritating and can induce enrichment of foods with this metal (Pirila and
nail dystrophy. Lead can be absorbed through the Förström 1966). Objects containing nickel are
skin. Sensitization is very rare, sometimes with permanently leaking a very low quantity of this
bullous-type rash (Slodownik et al. 2008). metal sufficient to sensitize susceptible individ-
Magnesium dust may cause mechanical irrita- uals (Kieffer 1979). Nickel is released from laptop
tion. Particles embedded in the skin may cause computers in concentrations that may elicit
“chemical gas gangrene” with symptoms of per- allergy and contact dermatitis (Hamann et al.
sistent lesions, inflammation, and gas bubbles 2013a). In another study, it was demonstrated
under the skin. Patch test is magnesium peroxide that 39% of 31 laptops from five brands released
10% aq (Santucci et al. 1995). nickel, and 6% released cobalt, as it was showed
Manganese is apparently not hazardous for the by spot tests and tests in artificial sweat (Midander
skin. et al. 2016).
Mercury alloy is named amalgams. The most It is estimated that a diet low in nickel pro-
sensitizing amalgams are those containing nickel motes the healing of the allergic contact dermati-
and antimony. Other combinations include gold, tis, whereas excess in dietary nickel worsen the
silver, zinc, tin, cadmium, copper, and strontium. disease in 39–90% of investigated patients. It was
Also other sensitizing factors used are solvents, also noticed that the use of nickel prostheses
resins, oils, and pigments. Amalgams are used in causes sudden exacerbation of eczema. Ordinary
industry in the manufacture of mirrors, cutting keys may constitute sources of nickel leakage,
knives, electronics, and aerospace industry possibly responsible for sensitizing predisposed
(Epstein 1991). Dental amalgam has the following daily users. Fifty-five keys with enamel coatings
composition: silver, 69.4%; tin, 26.2%; copper, were tested (Hamann et al. 2013b), and 80% had a
3.5%; zinc, 0.8%; and sometimes gold or plati- strong positive nickel spot test after 30 insertions,
num. Sensitization can occur not only in patients because the coatings chipped at the portion
but also in dentists and dental technicians. Patch inserted into the lock, while the handles didn’t
test is done with ammonium mercury 1% pet. or release nickel not even after 60 insertions. Cobalt
phenylmercuric nitrate 0.01% pet. was not released. Nickel-allergic users should not
Molybdenum is not hazardous for the skin. use keys with nickel leakage.
Nickel is a sensitizer in pure condition, but Nickel is widely used in coins. A study was
most allergies are caused by its salts: NiO, conducted on 850 coins from 52 countries and
NiCl2, NiSO4, and Ni(OH)2. Airborne allergies of 362 denominations. The coins were analyzed
were also described (Alfonzo 1979; Foussereau with nickel and cobalt spot tests and X-ray fluores-
and Laugier 1966; Pedersen et al. 1974a) (see also cence spectrometry for metal leakage. Two hundred
▶ Chap. 43, “Nickel”). Nickel is the most fre- thirty-nine of them (28%) released nickel, and none
quent sensitizer worldwide, both in terms of occu- released cobalt (Hamann et al. 2013c). About 40%
pational allergen (9%) and nonprofessional of global coinage do not release nickel.
allergen (15–20%). It is admitted today that A study was performed on 61 dental tools, and it
about 60% of nickel sensitization of men and was demonstrated that 20% released nickel and 23%
45% of women are induced at work and that released cobalt. Of 21 dental tools and 5 dental
5–10% of the entire western population shows alloys immersed in artificial sweat, all tools released
positive patch tests to Ni (Dooms-Goossens et 0.0047–820 μg/cm2/week of cobalt, 0.0051–10 μg/
al. 1980; Cronin 1980). Nickel allergy can be cm2/week of nickel, and 0.010–160 μg/cm2/week
64 Coatings 945
of chromium; all alloys released 0.0010–17 μg/ – Prurigo chronic presents with very itchy
cm2/week of cobalt and also nickel and chromium papulovesicular lesions. Lesions are localized
in lower concentrations (Kettelarij et al. 2014). mainly on the extensor surfaces of the limbs
These metals may induce contact allergy of the but may also spread. Histological examination
patients’ mouth and dentists’ hands. shows vasculitic lesions (Atasoy et al. 2009).
For diagnosis purpose, oral challenge test can be – Contact urticaria can evolve with typical
performed using 25 mg of nickel sulfate (Barranco lesions or may associate papulovesicular
and Solomon 1972) or 10–20 mg nickel leading to eczematiform lesions (Magen et al. 2011).
worsening of the skin rash in 60–80% of cases. To – Granulomatous dermatitis was also described
observe the release of nickel at the surface of after contact with nickel-plated objects
objects, the dimethylglyoxime test (Fisher’s test) (Capriotti et al. 2009).
can be performed (Peltonen 1979). The application – Eczematous dermatitis is the most frequent
of a few drops of dimethylglyoxime (1% alcoholic manifestation of nickel contact allergy. Patch
solution) and ammonia (10%) on the tested surface test is performed with NiSO4 5% pet.
is producing a pink-red precipitate as insoluble salts
of nickel. To reduce the contact with nickel, the Nickel alloys with iron, copper, chromium,
European Committee for Standardization issued magnesium, manganese, beryllium, and molybde-
the Nickel Directive 94/27/EC in 1994, prohibiting num are also inducing contact eczema. Frequent
the manufacture and sale of household articles in cases were reported in the industry of watches and
which Ni individual releases are more than 0.5 μg/ clocks (Bucur and Bucur 2006).
cm2/week (the maximum capacity detection of Nickel as a coating in contact with skin has
nickel with Fisher’s test). already been regulated by the nickel EU directive
Hands are the most common site for the devel- [94/27/EC] since 1994.
opment of allergic contact dermatitis to nickel. Niobium (columbium) can induce skin irrita-
It was found that 15–20% of hand eczema in the tion. Niobium is used mostly in alloys. Niobium-
general population are caused by sensitization to containing superalloys are used in rocket engines.
nickel and 44% in hairdressers (Cronin 1980). Niobium is used also in superconducting alloys in
Overall percentage of sensitization is higher in combination with titanium and tin (e.g., in MRI
women due to the massive use of unprofessional scanners). Other applications include electronics,
detergents, cutlery, jewelry, and other fashion optics, numismatics, and jewelry (Vilaplana and
accessories containing nickel. Romaguera 1998).
Different clinical forms of skin diseases Palladium in contact with the skin induces
induced by nickel were described (Li and both irritation and sensitization (Kalman 2007).
Wang 2002): Phosphorus is a direct irritant of the skin
inducing skin burns (Bucur and Bucur 2006).
– Combination of the direct skin contact with Platinum is used as photodeveloper (the pho-
nickel ingestion produces eczematous derma- tographic paper contains potassium chloroplatinate),
titis with disseminate lesions and pompholyx as catalyst in the chemical industry, as precious
(manifested with large, pearly vesicles on the metal in the jewelry industry, dentistry, and space-
fingers and palms). The lesions have a chronic craft industry. Platinum used in jewelry contains
evolution and are treatment resistant (Boscolo 90% platinum and 10% iridium. Platinum can
et al. 1999). induce irritant contact dermatitis. Tetra- and hexa-
– Nummular eczema manifests with clear-cut chloroplatinates (PtCl6 and PtCl4) are very reactive
plaques, distant from the contact place (Krupa sensitizers. Platinosis is an allergy-like reaction at
Shankar and Shrestha 2005). exposure to the platinum-soluble salts (Santucci et
– Neurodermitis evolves with well-defined al. 2000). The symptoms of platinosis may include
plaque lesions that expand slowly and are dif- dermatitis, asthma, dyspnea, conjunctival vasodila-
ficult to heal (Eberhartinger et al. 1969). tation, and rhinopharyngitis (Parrot et al. 1967). The
symptoms are progressive, sometimes appearing Allergic reactions can be induced by some of its
after years from exposure. Platinosis is usually asso- alloys (zinc, copper, cadmium) especially in
ciated with workers in industries related to platinum jewelers. Silver nitrate and silver oxide (Argirol)
production (Parrot et al. 1963). Cases with urticaria, can induce eczema to pharmacists and healthcare
Quincke’s edema, and anaphylaxis were also professionals. The risk of immediate reactions
described (Roberts 1951). (urticaria, Quincke’s edema) was also described
A 52-year-old female laboratory technician with in sensitized patients. Silver chloride sometimes
atopic dermatitis since adolescence developed work- induces allergic eczema in photographers. Some-
related hand eczema, cough, and runny nose after times the allergy is in fact due to the traces of
12 years of working at a precious metal refinery. She nickel that exists in silver (Ţiplica 2006). Argyria
had a negative skin prick test to sodium hexa- – developed after chronic exposure to silver –
chloroplatinate but positive patch test to ammonium evolves with gray coloration of the eyelids and
tetrachloroplatinate after 24, 48, 72, and 96 h. Inha- nail free edge and then expands to the entire
lation challenge with sodium hexachloroplatinate surface of the eyelid, cheeks, fingers, hands, and
yielded cough, mild breath shortness, significant forearms and also to the radiocarpal joints (similar
increases of exhaled nitric monoxide, sputum eosin- to the photoexposed areas) (Ţiplica 2006). In time
ophils, and a maximal decrease of FEV1 of 8% from the skin gradually becomes blackish in color with
baseline 24 h after the challenge (Merget et al. 2015). metallic reflections and does not respond to any
It should be noted that the latter are more treatment. It is an embarrassing stigma, some-
frequent as unprofessional exposure (chemother- times perceived as a social handicap. Nail dystro-
apy with cis-diamino-dichloro-platinate). Contact phies can also be induced. Patch testing is
eczema was occasionally observed in platinum performed with AgNO3 1% aq or silver fulminate
jewelry (Dastychova and Semradova 2000). 0.1% pet (White and Rycroft 1982).
Rhodium (alloy of gold and platinum) is used Stainless steel (alloy) may contain carbon, man-
in jewelry and high-fidelity audio cables. Rarely ganese, phosphorus, sulfur, silicon, titanium, cobalt,
skin allergies were described in workers, mainly tantalum, nickel, chromium, columbium, wolfram,
due to platinum. Platinum combinations with ali- molybdenum, selenium, and copper with their spe-
phatic amines or ammonium are not sensitizers. cific skin effects (Bucur and Bucur 2006).
Rhodium is slightly hazardous in case of skin Sulfur is reputed for inducing skin irritation
contact (corrosive, irritant, permeator) and in (skin burns) (Bucur and Bucur 2006).
case of eye contact. Liquid or spray mist may Tantalum can develop skin irritation (Bucur
produce tissue damage particularly on mucous and Bucur 2006; Romaguera and Vilaplana 1995).
membranes (eyes, mouth, and respiratory tract). Tin (stannum) is apparently not hazardous for
Skin contact may produce burns (Santucci et al. the skin, but direct contact should be avoided. It
2000; Dastychova and Semradova 2000; Koch rarely can induce allergy (de Fine et al. 1993).
and Baum 1996). Patch test may be performed with SnCl2 0.5 or
Selenium is apparently not hazardous for the 1% in petrolatum.
skin. Titanium (in laser-deposited titanium diboride
Silicon is known to be irritative. Silicon pow- coating) can induce skin irritation (low hazard for
der may induce silicon granuloma. Silicon spray usual industrial handling). Its salts (especially irri-
and silicon adhesives may induce contact derma- tating is titanium tetrachloride) are used as mor-
titis (Beyer and Belsito 1997). dant in dyes and dyes industry, including those
Silver is used as an industrial and artisanal used for rubber (e.g., nickel titanate) (Bucur and
noble metal for jewelry and decorations, work of Bucur 2006).
art, electrical appliances, industry of glass and Vanadium is apparently not hazardous for the
porcelain, photography, dental alloys, pharma skin.
industry, etc. (Ţiplica 2006). Silver as pure metal Wolfram (tungsten) induces skin irritation
is very rarely a sensitizer (Pedersen et al. 1974b). and rarely acts as sensitizer. Contact eczema
64 Coatings 947
was described in metallurgy where alloys following: acrylics, alkyds, amino resins, cya-
contain chromium and cobalt-chromium-tung- nate esters, epoxies, furanes, phenolics, polyes-
sten. Sodium tungstate is used in the dyes industry ters, polyimides, polyurethanes, silicones, and
and bronze tungsten in the ceramics industry vinylesters. Types of thermoplastic resins:
(Bucur and Bucur 2006). acetals, polyamide (Nylon), polybutylene tere-
Zinc has irritating properties and can induce phthalate (PBT), polycarbonate (PC), polyethyl-
skin ulcerations. It rarely occurs in skin sensitiza- ene (PE), polyethylene terephthalate (PET),
tion or skin granuloma through skin enclavation polyphenylene ethers, polypropylene (PP), poly-
of zinc particles (Isaksson et al. 2002). Sometimes tetrafluoroethylene (PTFE), and polyvinyl chlo-
acneiform eruption and respiratory irritation can ride (PVC).
occur after zinc exposure. Zinc electroplating is a There are different technical processes for plas-
procedure that protects the metal by forming an tic coating, many of them requiring heating the
insoluble layer of zinc compounds with protective plastic polymer: chemical vapor deposition, phys-
properties. In electroplating sections, where zinc ical vapor deposition, chemical and electrochem-
is melted at 475 C, zinc vapors are released. ical techniques, spraying, dip coating, epitaxy,
Exposure to this vapors can cause fever (“fever polymer coatings (e.g., Teflon), powder coating,
of metal fumes”), general acute intoxication, and roll-to-roll coatings. In this process, the
chills, headache, nausea, etc. Symptoms are workers are exposed to monomers and also to
malaria-like and are accompanied by respiratory additives existing in the plastic recipe. Direct con-
events (Lindahl et al. 1998). Patch test is using tact or airborne contact can induce irritant or aller-
zinc 2.5% pet. gic skin dermatitis, contact urticaria, mucosal
irritation or allergy, scleroderma, skin cancer, etc.
4 Plastic Coatings
5 Paint Coatings
Plastic coatings are versatile and can have
a wide range of applications: corrosion protection, Paints, lacquers, and varnishes are used as
impact resistance, chemical protection, electrical coatings for most industrial products, performing
insulation, nonstick coating, decorative not only an esthetic role but many others as well
finishes, anti-squeak, antibacterial coatings, (see also ▶ Chaps. 63, “Paints, Lacquers, and
sterilizable coatings, UV resistance, weather resis- Varnishes in Occupational Dermatology”, ▶ 207,
tance, dry lubrication, impact resistance, wear “Polyvinyl Resins”, and ▶ 51, “Acrylic Resins”).
resistance, flexibility, noise reduction, heat resis- Various plastics are present in different types of
tance, low-temperature resistance, anti-vandalism paints, lacquers, and varnishes, in order to
resistance, and “warm to the touch” feel (see also increase their qualities.
▶ Chaps. 56, “Other Plastics”, ▶ 207, “Polyvinyl Paint coatings can be waterborne (such as
Resins”, ▶ 51, “Acrylic Resins”, and ▶ 52, acrylics and vinyls) or solvent-borne (such as
“Epoxy Resins”). enamels and thinners). Waterborne products will
Plastic (resins) may be thermosets or thermo- normally be of lower risk and may even be non-
plastics. Thermoplastics are the plastics that do hazardous. Some of the waterborne paints still
not change their chemical composition when have acute or chronic toxicity or corrosive hazards
heated and can be molded again and again. Ther- and possibly be combustible. Solvent-borne prod-
mosets can melt and take shape once; when ucts have acute or chronic toxicity and corrosive
heated they develop a tridimensional network and flammable hazards and are used extensively
generating a rigid material. By cross-linking the in the industry (solvents, thinners, and tinters).
polymer chains through chemical additives, Varnish is a hard, protective film used in wood
ultraviolet radiation, electron beam, or heat, the and other materials finishing. Varnish is tradition-
resin is cured. Types of thermoset resins are the ally a combination of a drying oil (linseed oil, tung
oil, walnut oil – all of which contain high levels 6 Printed Coatings
of polyunsaturated fatty acids, alkyds), a resin
(amber, balsam, benzoin, copal, dammar, elemi, Printing is a process for reproducing text and
kauri gum, mastic, rosin, sandarac, shellac, lac- images (see also ▶ Chap. 58, “Inks and Dyes”).
quers, phenolic resins, waxes, etc.), and a thinner Classical printing involves ink, paper, and a print-
or solvent (turpentine, alcohol, white spirit, “mining press. In the modern era, the substrate can be
eral spirit,” “paint thinner”). Varnish has little or represented by a wide range of plastics, aluminum
no color, is transparent, and has no added pigment foil, etc. Inks had also evolved to a complex
(like paints do). Varnish hardens either directly medium, composed of solvents, pigments, dyes,
after the solvent has fully evaporated, either resins, lubricants, solubilizers, surfactants, etc.
through curing via sunlight, ultraviolet light, or There are different printing processes: screen
heat. Types of varnishes are the following: violin, printing, rotogravure, offset printing, letterpress
shellac, alkyd, spar varnish (marine varnish), dry- printing, inkjet printing, flexography, electropho-
ing oils, polyurethane, lacquer, acrylic, etc. tography, and digital printing.
Painters and lacquerers are exposed to a broad Screen printing on fabric, ceramics, wood,
spectrum of allergens. Powder coatings are paper, glass, metal, and plastic is more versatile
applied chiefly in engine and tool construction, than the traditional pressure printing techniques.
electrotechnology, and vehicle manufacturing and Allergic dermatitis was described in workers
less frequently in optics and precision mechanics. using different dyes (Jolanki et al. 1994). Roto-
Dispersion paints are used almost exclusively by gravure uses a rotary printing press. Rotary gra-
house painters. Radiation-curing systems are used vure presses are the fastest and widest presses in
mostly in the timber industry (Hillen et al. 2004). operation, printing everything from narrow labels
to wide rolls of vinyl flooring. Offset printing is a
5.1 Skin Problems printing technique used at large scale. In this
process, the inked image is transferred from a
Varnish can be tested as such. It can induce aller- plate to a rubber blanket and then to the printing
gic, irritant, and mixed dermatitis. surface. The skin of printers is vulnerable during
Solvents are primary irritants, but some can contact with washing and cleaning agents for
also induce sensitization. printing machines, paints, or other possible irri-
Colophony (rosin) can induce allergic contact tants such as alcohols or isocyanates (Jolanki et al.
dermatitis (including airborne type) and immuno- 1994; Korinth et al. 2003). Inkjet printing is a type
logical contact urticaria. Colophony contains of computer printer that creates a digital image by
more reactogens: dehydroabietic acid – the main propelling droplets of ink onto paper. Inkjet
antigen – pimaric acid, isopimaric acid, abietic printers are the most commonly used printers.
acid, and neoabietic acid (Karlberg and Wahlberg Workers contact with the ink is minimized. Elec-
1988). Colophony can cross-react with balsam of trophotography (xerography) is a dry photo-
Peru, abietol, and wood tar. For patch test: copying technique. Digital printing is a method
of printing from a digital-based image directly to a
White spirit 25% in olive oil variety of media. Digital printing has a higher cost
Colophony 20% pet per page than more traditional offset printing
Dehydroabietic 10% pet methods. There is a reduced contact of the
Pimaric acid 10–20% pet
workers with the unfinished printed substrate.
64 Coatings 949
7 Natural Gums – Vegetable waxes (carnauba wax, from Car-

nauba palm; castor wax, from castor oil; jojoba
Natural gums are polysaccharides of natural ori- oil, from the seeds of the jojoba bush)
gin. Their main characteristic is the capability to – Mineral waxes (Ceresin waxes, ozocerite –
increase the viscosity in solutions. Natural gums found in lignite beds)
are used in various ways: thickening agents, emul- – Petroleum waxes (paraffin wax, petroleum
sifying agents, adhesives, binding agents, crystal- jelly)
lization inhibitors, flocculating agents, swelling
agents, etc. Examples of natural gums are the Examples of synthetic waxes:
following: agar, alginic acid, carrageenan, gum
arabic, gum ghatti, gum tragacanth, karaya gum, – Polyethylene waxes – based on polyethylene
guar gum, mastic gum, tara gum, and xanthan – Polymerized α-olefins
gum. Some of the natural gums can be used in
edible coatings (a thin layer of material that covers In the industry for aluminum, steel, and metal
the surface of the food and can be eaten as part of alloys, all metallic surfaces are treated with a
the whole product). The composition of edible protective coating against rusting and corrosion.
coatings is established in EU by European Direc- It is a temporary protective coating usually made
tives (ED 1995, 1998). Ingredients that can be by lanolin. Sailors also use lanolin to create a
incorporated into the formulation of edible coat- slippery surface on their propellers and stern
ings include arabic gum, karaya gum, pectins, and gear to which barnacles cannot adhere. There are
shellac. Components of protective coatings rare cases reported with allergic dermatitis on
applied to fresh fruits and vegetables can be lanolin (Calnan 1979).
morpholine, polydextrose, sorbitan monostearate, Beeswax is used as a coating for cheese, to
sucrose fatty acid esters, cocoa butter, and castor protect the food as it ages. Beeswax is also used
oil (Vargas et al. 2008). In rare occasions, the as a component of shoe polish and furniture
edible coatings can induce allergic dermatitis. polish. It can be mixed with colophony to make
Several authors reported cases of sensitivity to an adhesive. It is also used by percussionists on
gum arabic (Ilchyshyn and Smith 1985; van Ketel the tambourine surfaces. Beeswax can act as a
1984b). Other ingredients that could cause allergic sensitizer. Due to the very complex composition,
reactions are the following: milk, soybeans, fish, it is difficult to indicate the causative ingredient.
peanuts, nuts, and wheat. Therefore, the presence Epicutaneous test with beeswax is recommended
of a coating with a known allergen on a food must be in this situation (Camarasa 1975).
also clearly labeled (Franssen and Krochta 2003). Enteric coatings are foils applied to the oral
medication to control the drug absorption in the
digestive system or to avoid adverse reactions.
8 Waxes
Enteric coating is stable in the stomach and
is destroyed in the basic environment of
Wax refers to a class of chemical compounds that
the small intestine. Materials used for enteric
are malleable at ambient temperatures. Waxes are
coatings include fatty acids, waxes, shellac, plas-
insoluble in water but soluble in organic, nonpolar
tics, and plant fibers (e.g., methyl acrylate-
solvents. All waxes are organic compounds, both
methacrylic acid copolymers, cellulose acetate
synthetic and naturally occurring.
succinate, hydroxypropyl methyl cellulose
Examples of natural waxes:
phthalate, polyvinyl acetate phthalate, methyl
methacrylate-methacrylic acid copolymers,
– Animal waxes (beeswax, produced by honey
sodium alginate, and stearic acid). No systemic
bees; lanolin, from the sebaceous glands of
adverse effect with skin manifestations was
sheep; shellac wax, from lac insect; sperma-
reported.
ceti, from the sperm whale)
Synthetic waxes are made from chlorona- in leather: a questionnaire study. Contact Dermatitis
phthalene and chlorodiphenols and are used as 71(6):338–347
Bucur G, Bucur L (2006) Profesiuni şi locuri de muncă cu
insulators in power capacitors and in the paints dermatoze profesionale întâlnite şi reactogenii
and varnishes industry. Synthetic waxes also can implicaţi. In: Bucur G, Bucur L, Sălăvăstru C,
contain ozokerite (a naturally occurring odorifer- Ţiplică GS (eds) Dermatoze profesionale. Niculescu,
ous mineral wax), and it is used in the varnishes Bucharest, pp 367–410
Calnan CD (1979) Lanolin in protective metal coatings.
industry. Contact Dermatitis 5(4):267–268, 01051873
Camarasa G (1975) Occupational dermatitis from bees-
wax. Contact Dermatitis 1(1):124
8.1 Skin Problems Capriotti K, Lee JB, Hyde P (2009) Allergic contact gran-
uloma: an uncommon reaction to pierced earrings in a
child. Pediatr Dermatol 26(5):620–621
Synthetic waxes induce very rarely allergic con- Centeno JA, Mullick FG, Martinez L, Page NP, Gibb H,
tact dermatitis. Most common are reported cases Longfellow D, Thompson C, Ladich ER (2002) Pathol-
with chloracne induced by organochlorine com- ogy related to chronic arsenic exposure. Environ Health
Perspect 110(Suppl 5):883–886
pounds (Falandysz 2003). Chen JK, Lampel HP (2015) Gold contact allergy: clues
and controversies. Dermatitis 26(2):69–77
Comaish S (1969) A case of contact hypersensitivity to
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Organic Solvents
65
Sibylle Schliemann, Anders Boman, and J. E. Wahlberg
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 954
2 Adverse Effects Resulting from Skin Exposure and Epidemiology . . . . . . . . 955
2.1 Acute Skin Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957
3 Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959
4 Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959
5 Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
6 Generalized Dermatitis, Steven-Johnson Syndrome, and Flushing
from Trichloroethylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
6.1 Flushing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
6.2 Whitening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
7 Cumulative Skin Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
7.1 Chronic Irritant Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
8 Patch Testing with Solvents: Feasibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963
9 Percutaneous Absorption: Systemic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963
10 Penetration-Enhancing Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
J. E. Wahlberg: deceased.
S. Schliemann (*)
A. Boman
Department of Occupational and Environmental,
Karolinska Institutet, Institute of Environmental Medicine,
Occupational and Environmental Dermatology,
Stockholm, Sweden
e-mail: bomananders@gmail.com; anders.boman@ki.se
J. E. Wahlberg
Stockholm, Sweden

https://doi.org/10.1007/978-3-319-68617-2_63
954 S. Schliemann et al.
11 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
11.1 Reduced Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
11.2 Appropriate Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
11.3 Protective Gloves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
11.4 Barrier Creams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
11.5 Individual Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
12 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
Keywords mainly treated as a group due to their general prop-

Acute irritant contact dermatitis · Allergic erties, solvents are chemically diverse (Fig. 1). Sol-
contact dermatitis · Contact urticaria · vents can be classified into different categories
Dermatoses · Occupational exposure limit according to their physico-chemical character-
values (OELs) · REACH Regulation · istics, such as volatility, water, and lipid solubility
Scleroderma · Steven-Johnson syndrome · (Table 1). Lipid solubility is expressed as the loga-
Turpentine · Whitening rithm of the partitioning coefficient between octanol
and water (log Po/w), where a high value represents a
high lipid solubility.
1 Introduction In 1996, the European Agency for Safety and
Health at Work was set up to collect, analyze,
Industrial solvents are volatile organic liquids and promote information regarding occupational
commonly used to dissolve other organic mate- safety and health in Europe. The agency provides
rials such as oils, fats, resins, rubber, lacquers, occupational exposure limit values (OELs)
waxes, perfumes, and plastic. They have a very from different EU member states on their web
wide variety of uses, including: site (http://osha.europa.eu/en/topics/ds/oel/mem
bers.stm/). Important components of regulation
• Analytical chemistry of chemicals in the EU are the REACH Regula-
• Carriers and intermediates in organic synthesis tion and the CLP Regulation. The CLP regulation
• Dyeing of paper, plastics, fabrics requires manufacturers to classify chemical sub-
• Dry cleaning stances, categories with special interest to derma-
• Floor laying tologists that may apply to solvents are skin
• Fuels, gasoline (Contestable 2017) corrosion (Hazard statement H314: Causes severe
• Graphic industries, rotogravure printing skin burns and eye damage), skin irritation (Haz-
• Maintenance and machinery repair, mechanics ard Statement H 315: Causes skin irritation), and
(Warshaw et al. 2017) skin sensitization (Hazard Statement H 317: May
• Media for extraction processes cause an allergic skin reaction), all replacing the
• Metal degreasing Painting former well-known-R-phrases, recently reviewed
• Paint manufacturing by Elsner (2018).
• Production of glass-fiber-reinforced polyester Over the years, steadily increasing knowledge
• Professional cleaning (Gerster et al. 2014) of the various adverse effects seen in humans and
• Spotting agents in experimental animals has resulted in a gradual
• Shoe manufacturing (Febriana et al. 2014) decrease in OELs and threshold values, for
• Surface coating example, with respect to methylene chloride. It
has been claimed that the relative importance of
Technical-grade organic solvents are reasonably the percutaneous route of absorption of solvents
inexpensive; considerable volumes are used yearly has increased as result of these regulatory
and numerous workers are exposed daily. Although activities concerning inhalation of solvents.
65 Organic Solvents 955
Fig. 1 Chemical structure Organic solvents

of selected solvents
Aliphatic Aromatic Alcohols

CH3
CH3(CH2)4CH3 CH3CH2OH
n-Hexane Ethanol
Benzene Toluene CH3CHOHCH3
iso-Propanol
Halogenated CH3 CH=CH2
aliphatics CH3CH2CH2CH2OH
CH2CI2 n-Butanol
CH3
Methylenechloride Xylene Styrene
CHCI3
Chloroform
Ketones Ethers
CCI4
CH3COCH3 CH3CH2OCH2CH3
Carbon tetrachloride
Acetone Diethyl ether
CHCI=CCI2
Trichloro ethylene CH3COCH2CH3
Methylethyl ketone Esters
CCI2=CCI2
Tetrachloro ethylene CH3COCH2CH2CH2CH3 CH3COOCH2CH3
Methyl-n-butyl ketone Ethyl acetat
CCI3CH3
Methyl chloroform
Miscellaneous Glycol ethers Petroleum

solvents distillates
CH3CH2OCH2CH2OH
CS2 Gasoline
Carbon disulphide Ethoxyethanol
White Spirit
HCON(CH3)2
Dimethyl formamide
Awareness of environmental and human effects respective textbooks and are beyond the scope of
has also led to a change from chlorinated sol- this chapter on skin effects.
vents to biologically degradable solvents with
altered risk spectra.
Health problems caused by solvent exposure 2 Adverse Effects Resulting from
can be acute or long term, and some substances Skin Exposure and
may have cumulative effects, depending on the Epidemiology
route, dose, and specific source. The systemic
adverse effects of solvents (carcinogenicity, The various signs, disorders, diseases, and other
teratogenicity, miscarriage, nephrotoxicity, hepa- effects seen as a result of skin exposure to solvents
totoxicity, neurotoxic and neuropsychiatric disor- are summarized in Table 2. Regarding systemic
ders, hematological, cardiovascular, respiratory, effects, it has been demonstrated that some sol-
and gastrointestinal effects) are reviewed in vents have specific target organs, e.g., the liver by
Table 1 Informations regarding vapor pressure and water solubility of commonly used solvents arranged according to
chemical groups
Examples Vapor pressure (25.0 C, kPa) Water solubility (mg/100 ml water) Log Po/wa
Aliphatic
n-Hexane 16 Insoluble 3.6
Aromatic
Benzene 10 180 2.13
Toluene 2.9 82 2.6
Xylenes 0.6–1.1 16–18 2.77–3.68
Styrene 0.6 Insoluble 2.95
Halogenated aliphatic
Methylene chloride 45 1,320 1.25
Chloroform 21 820 1.97
Carbon tetrachloride 12 50 2.83
Trichloroethylene 8 100 2.29
Tetrachloroethylene 1.9 40 2.60
Methyl chloroform 13 50 2.49
Esters
Ethyl acetate 10 9,000 0.73
Ketones
Acetone 25 1 –0.24
Methyl ethyl ketone 9 80,600 0.29
Methyl-n-butyl ketone 0.4 1,400 0.29
Alcohols
Ethanol 6 1 –0.31
Isopropanol 4 1 0.05
n-Butanol 0.6 7,800 0.88
Glycol ethers
2-Ethoxyethanol 0.5 1 –0.54
Miscellaneous
Carbon disulfide 40 230 2.16
Dimethylformamide 0.4 1 –1.01
Petroleum distillates
White spirit <0.7 Insoluble –
a
Logarithm of the partitioning coefficient between octanol and water
dimethylformamide (DMF) and the bone marrow general, toxicology is related to concentration,
by benzene. Adverse effects are sometimes dose, and duration of exposure. It has been demon-
caused by the solvent itself, sometimes by its strated (Klauder and Brill 1947) that the low-boil-
metabolite(s). Solvents may be transformed into ing-range (<250 C) petroleum solvents have the
reactive metabolites that are more toxic than the greatest defatting action and induction of dermatitis
parent compound. That metabolites might be the potential. Irritant action such as defatting action
principal offending agents causing skin effects is decreases as the boiling range increases. A worker
at present just a hypothesis. is rarely exposed to just one solvent; more often he/
In addition to irritancy, various other adverse she is exposed to mixtures of several solvents with
effects (Table 2) can often be linked to a particular a varying degree of purity. Mineral spirits, kero-
solvent. However, the main side effect in the skin – sene, gasoline, and thinners are examples of widely
different degrees of defatting clinically linked to used, though often poorly standardized, mixtures.
skin dryness and fissuring – is uniform and, in From a clinical point of view, it is hard to
Table 2 Adverse effects of solvents on skin exposure of solvents in epidemiological studies. Men were
Subjective irritation found to be significantly more likely to have oils
Irritancy and coolants and solvent exposures as causes of
Contact urticaria their occupational ICD in an Australian retrospec-
Flushing, generalized dermatitis and Steven-Johnson tive study (Cahill et al. 2016).
syndrome – from trichloroethylene
Whitening
Irritant contact dermatitis 2.1 Acute Skin Effects
Chemical burns
Allergic contact dermatitis
2.1.1 Subjective Irritation
Scleroderma
The affected workers report a stinging, tingling,
Dermatoses from higher boiling petroleum distillates
and/or burning sensation from a skin area exposed
Percutaneous absorption – systemic toxicity
Enhancing absorption of other toxic chemicals
to a solvent or to a mixture of solvents, especially
after intense or prolonged contact. The site may
look normal to the naked eye or show redness.
demonstrate the relative importance of one ingre- This phenomenon is not restricted to solvents
dient in a mixture of solvents. In a Swiss study that only; it has been reported, for example, from
analyzed hazardous substances in frequently used skin exposure to lactic acid (“the stinging test”).
professional cleaning products, 16% of all products It is caused by secretion of neurotransmitters from
contained solvents with varying concentrations free nerve endings of unmyelinated c-fibers in
from 0.1% to 75% (Gerster et al. 2014). the lower epidermis and papillary dermis as dem-
With the exception of generalized dermatitis onstrated in animal experiments with solvents.
and Steven-Johnson syndrome from trichloroeth- Important neurotransmitters in this context are
ylene (see below), the occupational skin effects substance P (SP) and calcitonin-gene-related
caused by solvent exposure are considered to peptide (CGRP), a potent vasodilatator (Iyadomi
be of lower dimension, compared to wet work et al. 1998). In general aromatic solvents, such
and detergent exposure, and epidemiologic data as cumene or toluene, penetrate the epidermis
regarding contact dermatitis caused by solvents more rapidly than aliphatic hydrocarbons, such
are underrepresented in the scientific literature. as octane and nonane (Kim et al. 2006; McDougal
In a Danish publication of notified occupa- et al. 2000). Cumene compared to octane caused a
tional eczematous diseases 1984–1991 (Halkier- higher degree of transient erythema, as measured
Sorensen 1996), exposure to solvents was the by laser doppler flowmetry, and more intense
cause in 991 cases (3.6%) and was placed fifth in subjective irritation, as quantified by a visual ana-
the ranking list. Higher frequencies were found logue scale, in a simultaneous occluded short-time
for water (13.9%), detergents (11.6%), nickel exposure experiment in healthy individuals. After
(5.4%), and hand cleansers and soaps (3.9%). repeated contact to both irritants, the intensity of
In a surveillance report on occupational skin subjective irritation decreased gradually over time
diseases in the UK, solvents accounted for 8% of (Schliemann et al. 2011), a phenomenon also
cases of irritant dermatitis and ranked fourth observed after repeated topical application of
behind soaps (22.0%), wet work (19.8%), and capsaicin in humans (Green and Shaffer 1993).
petroleum products (8.7%) (Meyer et al. 2000).
In an epidemiologic update from Singapore, 2.1.2 Acute Irritant Contact Dermatitis
wet work/detergents, oil/grease and solvents Solvents that quickly evaporate from the skin if
were the commonest irritants (Lim and Goon not occluded are not as likely to damage the skin
2007). However, in professions dealing with as solvents that do not evaporate, i.e., they will
solvents, employees are usually co-exposed to act for a longer period of time. Erythema, edema,
other water-soluble, chemically different irritants, and drying are the most common acute side effects
which makes it difficult to estimate the true impact seen from single or repeated exposures to
solvents. These signs are sometimes transient or blood flow. The most potent solvents were
may develop into cumulative irritant contact der- dimethylsulfoxide and trichloroethylene, while
matitis (see below). The course is related to the 15 min of exposure in excess to methyl ethyl
type of solvent (Table 1), concentration, dose, and ketone, propylene glycol, ethanol, and water did
exposure time. Direct handling of jet fuel without not influence skin blood flow. The results may be
appropriate glove protection is one example of more intense after occluded skin exposure.
intense skin exposure to solvents that may lead Aromatic solvents induce higher skin blood
to contact dermatitis as illustrated by a case flows compared to aliphatic solvents due to their
report observed in the US military environment different penetration potential after occluded
(Contestable 2017). short-time administration (Fig. 2) (Schliemann et
al. 2010). This immediate erythema observed after
2.1.3 Erythema skin contact to solvents is transient and subsides
In attempts to study and differentiate the erythema- spontaneously within 30–60 min.
inducing capacity of solvents in man, the objective
laser-Doppler technique was used to measure skin 2.1.4 Edema
blood flow (Schliemann et al. 2010; Wahlberg Edema caused by prolonged or repeated
1984a). This technique is three or four times more skin exposure to solvents can be quantified
sensitive than the naked eye (Wahlberg 1989). with a rather unsophisticated device: the caliper
In a series of experiments, 0.1 ml of the neat (Wahlberg 1984b). Results of measurements of
solvent was applied with a pipette to the forearm skin-fold thickness of experimental animals treated
skin of healthy subjects and was allowed to spread once daily with neat solvents are summarized in
freely. As can be seen from Table 3, only one Table 4. Trichloroethylene and dimethylsulfoxide
solvent (dimethylsulfoxide) caused an increase seem to be potent edema-inducing solvents as well
in skin blood flow. The sites looked normal as influencing skin blood flow in man (Table 3).
to the naked eye. In the second series of experi- However, daily open treatments with solvents
ments, the neat solvents were applied in excess (neat) for 10–18 days on human volar forearms
(1.5 ml/3.1 cm2) using a glass ring as a reservoir did not cause any increase in skin-fold thickness
and attached with rubber bands to the forearm. (Wahlberg 1993). Transient erythema immediately
Three different exposure times were used (1, 5, after the administration of toluene was observed in
and 15 min) and, as can be seen from Table 3, the a few cases. The absence of edema-inducing effects
solvents varied greatly in their effects on skin in man compared with rabbits and guinea pigs is
Table 3 Increase in skin blood flow from exposure to solvents (neat) as an expression of irritancy – objectively recorded
by laser Doppler flowmetry (Wahlberg 1984a)
0.1 ml pipetted Whitening after rubbing with cotton Duration in min required
Solvent onto the skin (exposure in excess of 1.5 ml/3.1 cm2) to get an increase
Dimethylsulfoxide Increase No 1
Trichloroethane No increase Yes 1
n-Hexane No increase Yes 5
Carbon tetrachloride No increase Yes 5
Toluene No increase Yes 5
1,1,1-trichloroethane No increase Yes 5
1,1,2-trichloroethane No increase Yes 5
Dodecane No increase Yes 15
Methyl ethyl ketone No increase Yes No increase
Propylene glycol No increase No No increase
Ethanol No increase Yes No increase
Water No increase No No increase
Fig. 2 Cutaneous blood laser Doppler flowmetry

flow as measured by Moor 900
laser Doppler Imaging ***
(MLDI) at baseline and 800
immediately after occluded
exposure to n-octane, an 700
MLDI flux (relative units)

aliphatic solvent, compared
600
to cumene, an aromatic
solvent (median flux, 500
conservative 95%
confidence intervals) 400
300
200 ***
100
0
octane cumene
Baseline After 8-min.exposure
Table 4 Ranking of edema-including capacity of solvents with 100% toluene and 100% xylene, 50% solu-
(neat) on skin exposure in experimental animals. Method: tions did not cause any cellular inflammation
skin-foldthickness measurements (Wahlberg 1984b)
(Saito et al. 2009).
Solvent Guinea pig Rabbit
Trichloroethylene 1 1
Toluene 2 1
1,1,2-trichloroethane 3 1 4 Contact Urticaria
Carbon tetrachloride 4 2
1,1,1-trichloroethane 4 2 Some solvents, e.g., alcohols, have been
Dimethylsulfoxide 5 Not tested shown to cause immunological as well as non-
n-Hexane 6 4 immunological contact urticaria (Ophaswongse
Methyl ethyl ketone 7 3
and Maibach 1994; Rilliet et al. 1980). In the latter
Ethanol 7 5
case, a racial predisposition (Wilkin and Fortner
1985) was suggested. There are also case reports
probably due to evaporation of solvents immedi- on, inter alia, methyl ethyl ketone (Varigos and
ately after administration to man, while solvents Nurse 1986), naphtha (Goodfield and Saihan
partly adhered to the animals’ fur. 1988), dimethyl sulfoxide, polyethylene glycol
(Fisher 1978), and xylene. However, there is
some confusion in the literature – is a macular
3 Histopathology erythema sufficient for the diagnosis of contact
urticaria? (Gollhausen and Kligman 1985). The
The histopathological picture after epicuta- general aspects of contact urticaria are reported
neous administration of solvents to guinea pigs elsewhere in this volume (see ▶ Chaps. 209,
also demonstrated great variation in potency “Contact Urticaria Syndrome: Occupational
(Kronevi et al. 1981). Various concentrations Aspects” and ▶ 210, “Nonimmunologic Contact
of toluene and xylene, dissolved in acetone, Urticaria”).
were applied once a week for 5 weeks to the From a clinical point of view, it is important to
ear skin of mice. Whereas slight invasion of know that oral provocation with alcohol can elicit
inflammatory cells was observed in ears painted anaphylaxis (Ophaswongse and Maibach 1994).
5 Testing
To diagnose immunological contact urticaria,

open tests with gas-chromatographically pure
ethanol (“as is”) are recommended (Ophaswongse
and Maibach 1994). With other solvents, for
which data are lacking, it is recommended to use
graded concentrations as well as a great number of
controls to verify the specificity.
6 Generalized Dermatitis,
Steven-Johnson Syndrome,
and Flushing from
Trichloroethylene
Exposure to trichloroethylene has been Fig. 3 Skin whitening immediately after exposure to a
associated with cases of generalized dermatitis glycol ether 1-methoxy-2-propanol (propylene glycol
monomethyl ether), applied in a test chamber for 10 min
(Bauer and Rabens 1974) and of Steven-Johnson
syndrome (Phoon et al. 1984). Several of the
patients had signs of liver dysfunction (toxic decrease in skin blood flow – evaluated by laser-
hepatitis) and one fatal case was reported Doppler flowmetry – was found, indicating that the
(Nakayama et al. 1988). From the case reports, whitening is not due to vasoconstriction. The sol-
however, it is somewhat hard to judge what vents that caused whitening were also able to extract
route of absorption – inhalation or percutaneous lipids from human stratum corneum. However, three
absorption – had dominated. solvents (dimethylsulfoxide, propylene glycol and
water) did not cause whitening and did not extract
lipids either (Wahlberg 1984a). The phenomenon
6.1 Flushing of whitening is not understood yet. It is speculative
whether it is caused by transient changes
There are some case studies in which exposure in light refraction of the stratum corneum.
to trichloroethylene and to DMF followed by Further solvents that cause skin whitening
ingestion of alcohol resulted in generalized are acetone, cumene, and some glycol ethers such
flushing of the skin (“degreasers flush”) and as 1-methoxy-2-propanol (Fig. 3; personal
nausea (Stewart et al. 1974). Based on findings communication).
from an experimental study, it was suggested
that the underlying mechanism is interference
of trichloroethylene with the metabolism of 7 Cumulative Skin Effects
alcohol in the liver.
7.1 Chronic Irritant Contact
Dermatitis
6.2 Whitening
There is a general agreement that solvents are
When some solvents are applied to human skin important skin irritants and that repeated expo-
followed by gentle rubbing with, for example, cot- sure may develop into irritant contact dermati-
ton, the site will turn white (“whitening”). In a com- tis. As previously mentioned, there is a great
parative study, this phenomenon was observed for variation in the degree of irritancy produced
nine solvents (Goldsmith et al. 1988) (Table 3). No (Tables 3 and 4); in addition, concentration,
aromatic content, duration of exposure, occlu- dryness, scaling, fissures, and edema are the
sion, temperature, humidity, and individual fac- most common features, but oozing can also be
tors, such as atopic diathesis, history of contact seen (for chemical burns, see below). The clinical
dermatitis and barrier function, are thought to picture is the same as for other causes of irritant
interact and contribute to irritant contact derma- contact dermatitis and is of no help when differ-
titis. Examples of predisposition and individual entiating from other irritants or when evaluating
susceptibility to irritant contact dermatitis are the relative contribution of the solvent exposure.
presented in Table 5. However, most of these Experimental irritant contact dermatitis and bio-
examples were derived from investigations with engineering methods have been used to study the
water-soluble irritants and have not been a mat- irritant potential of solvents. The cumulative irri-
ter of investigation whether these criteria apply tant potential of various solvents in parallel has
to solvent-induced irritation to the same extent. been a matter of interest in a limited number of
Individuals with past or current atopic dermati- human in vivo studies. In an occluded human
tis are more susceptible to irritants; among those repetitive irritation test with twice daily exposure
irritants, solvents and wet work are considered on 11 subsequent days, the cumulative irritation
to be of greatest importance in causing relapses potential of six neat chemicals including aliphatic
and deterioration. Preemployment examination and aromatic solvents and two glycol ethers
and vocational guidance are recommended for was compared. The irritant potential according to
individuals in these categories (Table 6). a clinical irritation score at day 12 was
A commonly affected site is the hands n-octane > nonane > toluene > cumene >
and especially the back of the hands and the 1-methoxy-2-propanol diethylene glycol mono-
finger webs, but any skin site contaminated by butyl ether (personal communication). The glycol
solvents can develop an irritant contact dermatitis. ethers exhibited only very mild irritation potential
When the face is affected, vapors are suspected as according to visual scoring. Both caused a decrease
well as contamination by the hands. Erythema, of the stratum corneum hydration, albeit to a lesser
extent than any other irritant. In another repetitive
Table 5 Individual susceptibility on skin exposure to irritation test in healthy volunteers, twice-daily
organic solvents occluded exposure to cumene and n-octane over 4
History of atopic Predisposition/increased days induced clinical irritation as assessed by a
dermatitis susceptibility cumulative irritation score and decrease of stratum
History of Not settled corneum hydration as measured by corneometry.
asthma/rhinitis
Cumene was a weaker irritant than n-octane and
History of contact Dry or senile skin; considerable
dermatitis variation, even in non-atopics caused only minimal visual irritation, if any,
Recommendation Pre-employment examination, “Stingers” who had been identified by a lactic
vocational guidance acid stinging test beforehand, were more suscepti-
ble to cumulative irritation from both solvents com-
pared to “nonstingers” (Schliemann et al. 2010).
Table 6 Adverse effects of skin exposure to solvents and
some preventive measures
Combined exposure to both solvents and deter-
gents is more irritating than exposure to either of
Reduce exposure
the irritants alone, which is of relevance for primary
Select appropriate solvents; solvents exhibit great
variations in potency (irritancy, percutaneous and secondary prevention measures in the occupa-
absorption, systemic toxicity) tional setting where mixed exposure profiles may
Gloves provide some protection, as do sleeves dominate. An over-additive irritant potential of an
Barrier creams provide questionable protection; their alternating exposure to toluene and SLS compared
usefulness is still a matter for debate to twice-daily exposure to either toluene or SLS
Consider the individual’s susceptibility alone was found in a repeated irritation test
Skin-care programs, cleansing, moisturizers, etc. (Wigger-Alberti et al. 2000), and recently, similar
Legislation, labelling, information, and education results were obtained both with cumene, another
aromatic solvent, and octane, in combination with irritation, especially on the legs, wrists, and neck.
SLS (Schliemann et al. 2014). Jet propellant-8 (JP- It has been suspected that this residue may cause
8) jet fuel is a complex mixture of primarily ali- or contribute to chemical burns.
phatic (but also aromatic) hydrocarbons. There is
potential for dermal exposure to jet fuels
with personnel involved in aircraft refueling (Con- 7.2 Allergic Contact Dermatitis
testable 2017). The cutaneous effects mainly
derived from animal studies have been recently 7.2.1 Solvents as Contact Allergens
reviewed (McDougal and Rogers 2004). There are rather few case reports on allergic contact
dermatitis to solvents, considering their extensive
7.1.1 Scleroderma use and the size of the exposed population. This
There are an increasing number of case reports may be due partly to the inherent problems encoun-
on scleroderma related to exposure to various sol- tered when patch testing with solvents (see below),
vents (Bottomley et al. 1993; Czirjak et al. 1994; but also to ignorance or lack of suspicion by the
Walder 1983; Yamakage and Ishikawa 1982). In examining physician and partly due to the solvents’
two metaanalyses, the relative risk to acquire relative chemical inertness.
scleroderma was higher for men than for women
after occupational exposure to solvents (Bovenzi et 7.2.2 Turpentine
al. 1995; Kettaneh et al. 2007), a finding that has The principal contact allergen in turpentine is
been confirmed in other studies meanwhile (Marie Δ-3-carene (Hellerstrom et al. 1955, 1957).
et al. 2014). It is not clear whether the main route of It was a frequent cause of allergic contact der-
exposure is percutaneous or by inhalation, and it matosis among painters in Scandinavian countries,
can be assumed that both routes contribute. but after its replacement with petroleum-derived
alternatives (white spirit, “mineral turpentine”) the
7.1.2 Dermatoses from Higher-Boiling frequency decreased. A frequency of positive reac-
Petroleum Distillates tions of 1.6/1.8% was found when turpentine was
Petroleum distillates obtained at temperatures included in the standard series in southeastern
above 315 C are mainly oils (lubricating, spindle, Europe (Rudzki et al. 1991). However, evaluation
transformer, machine, and cutting oils) and have of patch test data 45,005 patients tested between
less defatting but more keratogenic action. They 1992 and 1997 in 30 dermatological centers associ-
can cause comedones, acne, photosensitivity, ated with the German-Austrian Information Net-
melanosis, keratoses, and epitheliomas. work of Departments of Dermatology (IVDK) of
showed an increase in positive patch test reactions
7.1.3 Chemical Burns to turpentine from 0.5% during the years
Extensive and prolonged skin exposure to 1992–1995, up to 1.7% in 1996, and 3.1% in 1997
solvents – especially under occlusion – may (Treudler et al. 2000).
cause severe skin damage including blisters, bul-
lae, oozing, or necrosis. Solvent-soaked clothing 7.2.3 D-Limonene
in direct and prolonged contact with the skin is D-Limonene-containing products were launched
an often-mentioned cause of these burns. Solvents to replace environmentally persistent chlorinated
that have been implicated are, according to the hydrocarbons and chlorofluorocarbons as solvents.
literature, tetrachloroethane, trichloroethylene, The main allergens are oxidation products created
methylene chloride, carbon disulfide, Stoddard when D-limonene is air exposed, e.g., limonenoxide,
solvent, gasoline, kerosene, benzene, and toluene, L-carvone, and limonene hydroperoxides (Karlberg
but probably many more have this potential if et al. 1991, 1992). The oxidation can be prevented
the exposure conditions (concentration, duration, by the addition of butylated hydroxytoluene (BHT)
occlusion) are unfavorable for the worker. (Karlberg et al. 1994). Limonene has many other
Perchloroethylene used in dry cleaning may, to uses (Karlberg and Dooms-Goossens 1997), and
some extent, remain in clothing and cause skin there is then a possibility of cross reactions. The
worker has been sensitized via other D-limonene- negative test results (Vail and Letter 1974).
containing products and can have a relapse due to It was therefore recommended to medicate the
contact at work when limonene is used as a solvent. patch immediately before the test is applied on
A test preparation (dipentene) is available from sup- the patient to minimize evaporation and to use
pliers of patch-test allergens. filter papers. Since several solvents are potent
skin irritants even after short exposure times
7.2.4 Dioxane (Table 3), it is thus probably impossible to dem-
A worker who used dioxane for degreasing metal onstrate allergenicity by the conventional patch-
parts developed hand eczema (Fregert 1974). He test technique.
was patch-test positive to 0.5% dioxane in water. Information regarding test concentrations and
vehicles are rarely available – for the examining
7.2.5 Alcohols dermatologist, the testing is a question of trial and
Case reports of allergic contact dermatitis error. If a “positive” reaction is obtained, it is
from alcohols were previously reviewed crucial to carry out serial dilution tests and at
(Ophaswongse and Maibach 1994). In addition, best to test a sufficient number of controls. So
cross reactivity and oral provocation were far, provocative use tests, such as the repeated
addressed. An individual with a type-IV allergy open application test (ROAT), do not seem to
may cross react to other alcohols on patch testing. have been used to clarify the relevance of a
In a few cases, oral provocation with alcoholic “positive” patch-test reaction to a solvent.
beverages was positive, but it is unclear whether Ethanol, methyl ethyl ketone, and acetone are
there was a coexistence of type I and type IV in recommended vehicles for patch tests of mate-
some patients. There are presumably metabolic rials and products brought to the physician by
dose-response relationships and individual sus- patients, indicating that vast experience has
ceptibility factors that operate as risk factors in demonstrated these solvents to be only marginal
predicting one’s propensity to develop systemic irritants (Wahlberg 1995). Propylene glycol has
contact dermatitis due to oral provocation. It has irritant properties under occlusion and is consid-
been recently speculated in one publication ered a weak contact allergen only occasionally
whether isopropyl alcohol may be an overlooked causing occupational allergic contact dermatitis
contact allergen. Allergic patch test reactions were (Lessmann et al. 2005; Noiles et al. 2010;
found in 44 out of 1450 patients patch tested with Wahlberg 1994). Isopropyl alcohol has been
isopropyl alcohol during the period 1992–2011 in described as contact allergen (Garcia-Gavin et
Belgium, and four cases presented as occupational al. 2011); however, its potency is still under
hand eczema (Garcia-Gavin et al. 2011). debate and it is often difficult to discriminate
truly allergic from irritant (toxic) reaction, espe-
7.2.6 Styrene cially if patch test concentration is not limited to
Styrene is a skin irritant. At least one case of contact 10% (Loffler et al. 2012).
allergy has been reported (Sjoborg et al. 1984).
9 Percutaneous Absorption:
8 Patch Testing with Solvents: Systemic Toxicity
Feasibility
Systemic toxicity may result from percutaneous skin
The irritant properties and volatility of some absorption of solvents. A defective skin barrier is
solvents make patch testing highly problematic. considered to facilitate percutaneous penetration.
For example, in a comparative study with tetra- In an experimental study in guinea pigs (Boman
chloroethylene, it was found that a positive reac- and Mellstrom 1989), however, it was demon-
tion was obtained when it was applied as a 1% strated that induced skin damage (stripping,
solution in olive oil using ordinary patch-test tech- needle and sand paper abrasion, delipidization)
niques, while open application (neat) produced caused a considerable increase in the absorption
rate n-butanol (a water-soluble solvent), while be balanced against the technical requirements of a
the absorption of toluene and 1,1,1-tri- solvent. It is self-evident that those with the most
chloroethane (lipophilic solvents) decreased. favorable toxicity profile should be chosen.
Thus, skin damage does not automatically lead
to increased percutaneous absorption; instead,
the lipophilic and hydrophilic properties of a 11.3 Protective Gloves
particular solvent seem to be crucial.
Gloves, if selected according to recommenda-
tions, may provide protection which allows for
10 Penetration-Enhancing Action direct contact with solvents for several hours.
The basis for this recommendation is data gath-
Alcohols and propylene glycol are used in many ered in technical testing or in vitro studies
topical medicaments and are supposed to have (Mellström et al. 1994; Chao et al. 2004) (see
several functions, including facilitating penetra- also ▶ Chap. 115, “Protective Gloves,” by
tion of other ingredients. Irritancy is occasionally Crepy, Boman, Zimmermann). The varying effi-
reported by patients using corticosteroid prepara- cacy of gloves and barrier creams and the impor-
tions containing these solvents. Solvents are tance of using proper skin protection when
often blamed, but other ingredients should also working with a solvent with low vapor pressure
be considered. Certain solvents, such as DMF, and high skin absorption conditions was clearly
dimethyl sulfoxide, and pyrrolidones, have a demonstrated for DMF. During the first week,
profound absorption-enhancing effect and may gloves were used as skin protection, and some
facilitate the absorption of toxic substances at absorption of DMF was found. During the sec-
concomitant exposure. ond week, a glycerol-based barrier cream was
used instead and this was obviously less protec-
tive than the gloves (Lauwerys et al. 1980).
11 Prevention In another study, the efficacy of various
protective equipment in protecting the skin
The preventive measures are summarized from exposure to styrene, a solvent with
in Table 6. They were previously reviewed physico-chemical properties different from those
(Wahlberg and Boman 1996). of DMF, was investigated (Brooks et al. 1980).
For this solvent, absorption takes place mainly via
inhalation. Respiratory protection (a mask) was
11.1 Reduced Exposure crucial, and the additional protection provided by
gloves was minimal.
Reduced exposure is of great importance due
to the considerable systemic toxicity of some
solvents. As a result of increasing awareness of 11.4 Barrier Creams
their adverse effects, skin exposure has been
reduced by automation, enclosed manufactur- Barrier creams should only be recommended
ing systems, and avoidance of direct contact in under exceptional circumstances when handling
many industries at least in the developed solvents as they are generally considered to be far
countries. less protective than gloves in reducing the pene-
tration of solvents. Barrier creams actually failed
to offer protection against solvents in several
11.2 Appropriate Selection human studies using bioengineering techniques
to assess skin reactions (Frosch and Kurte 1994;
Quantitative data on skin-irritant properties (Table 3), Schliemann-Willers et al. 2001; Wigger-Alberti et
percutaneous absorption, and systemic toxicity must al. 1998). In addition to lack of efficacy, it was
demonstrated that inappropriate barrier creams References

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Cutting Fluids
66
Michael F. Koller and Iain S. Foulds
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970
2 Definition and Functions of Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971
3 Composition of Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971
3.1 Base Oil (Fluid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
3.2 Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
3.3 Impurities or Secondary Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
4 Classification of Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
4.1 Neat Oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
4.2 Soluble (Emulsifiable) Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
4.3 Semisynthetic Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
4.4 Synthetic Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975
5 Preservation and Monitoring of Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . 975
6 Metalworking Fluid-Induced Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
7 Skin Problems Associated with Metalworking Fluids . . . . . . . . . . . . . . . . . . . . . . . . 976
7.2 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978
7.3 Common Allergens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979
7.4 Investigation of Metalworking Fluid Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
7.5 Prevention of Metalworking Fluid Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
7.6 Prognosis of Metalworking Fluid Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
M. F. Koller (*)
Division of Occupational Medicine, Suva, Lucerne,
Switzerland
e-mail: michael.koller@suva.ch
I. S. Foulds
Institute of Occupational and Environmental Medicine,
University of Birmingham, Birmingham, UK
e-mail: Isfoulds@hotmail.com

https://doi.org/10.1007/978-3-319-68617-2_64
970 M. F. Koller and I. S. Foulds
8 Other Benign Skin Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984

9 Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
10 Infections and Injuries of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
Abstract cancer · Polycyclic aromatic hydrocarbon ·

Most metal-cutting operations require the use of Infection · Inury
cutting (or metalworking) fluids for cooling and
lubricating and for the removal of metal fines.
Such fluids are complex mixtures of a base oil, 1 Core Messages
additives and substances that develop during use.
The most common diseases caused by met- • Most metal-cutting operations require the use of
alworking fluids are skin diseases; problems of metalworking fluids for cooling and lubricating
the respiratory tract and other disorders occur and for the removal of metal fines. Such fluids
much less frequently. Irritant contact dermatitis are complex mixtures of base oil (mineral,
is the most common skin disease in workers vegetable, animal, marine or synthetic oil), addi-
who come into contact with cutting fluids, tives (biocides, corrosion inhibitors, anti-
followed by allergic contact dermatitis. The foaming substances, etc.), and substances that
mainly responsible sensitizers are additives develop during use (metal chips, nitrosamines,
such as biocides. microorganisms, etc.). Metalworking fluids may
Other skin disorders like squamous cell can- be classified into water-insoluble neat oils and
cer, oil acne, hyperpigmentation, granuloma or water-soluble fluids (emulsifiable soluble fluids,
infections are rarely seen today due to better semisynthetic fluids, and synthetic fluids).
metalworking fluids and working conditions. • In this chapter, we describe skin diseases, which
are the most common diseases caused by metal-
working fluids. Problems of the respiratory tract
Keywords and other disorders occur much less frequently.
Metalworking fluid · Cutting fluid · Cooling · • Irritant contact dermatitis is the most common
Lubricating · Removal of metal fines · Mineral skin disease in workers who come into contact
oil · Additive · Anti-aging substance · with metalworking fluids, followed by allergic
Oxidation inhibitor · Anti-wear additive · contact dermatitis. Between 7% and 27% of all
Detergent · Dispersant · Emulsifier · Pressure metalworkers develop eczema, with 50–80% of
additive · Fragrance · Deodorant agent · Foam these cases being irritant contact dermatitis.
inhibitor · Friction inhibitor · Metal Metalworking fluid-induced dermatitis occurs
deactivator · Corrosion inhibitor · Viscosity mainly on the back of the hands and web spaces
index improver · Secondary component · Neat between the fingers, but is also seen in many
oil · Soluble oil · Emulsifiable fluid · other parts of the body that are exposed to
Semisynthetic fluid · Synthetic fluid · metalworking fluids and contaminated clothes.
Bacteria · Yeast · Fungi · Biocide · Skin • Risk factors for developing contact dermatitis
disease · Respiratory disease · Contact include additives, alkalinity, frequent hand
dermatitis · Irritant contact dermatitis · Allergic cleaning, use over long periods, solvents,
contact dermatitis · Photosensitization · microtrauma, heat, as well as host factors
Formaldehyde-releasing biocide · Non- such as increasing age, skin type, skin disease,
formaldehyde-releasing biocide · improper hand care and personal hygiene,
Isothiazolinone · Patch test · Hand protection hobbies pursued, etc.
plan · Prognosis · Oil acne · • Mineral oils themselves are weak sensitizers;
Hyperpigmentation · Granuloma · Skin there are additives such as biocides
66 Cutting Fluids 971
(formaldehyde-releasing and non-formalde- Table 1 Functions of cutting fluids

hyde-releasing biocides) that are mainly respon- Cooling the workpiece
sible for sensitization. However, not every Reducing frictional heat between tool and chip
sensitization is of clinical relevance. Patch test- Removing swarf
ing can be helpful in finding the triggering Increasing the surface finish of the workpiece
allergen, though not in all cases. There are sev- Prolonging tool life
eral procedures for performing patch testing. Reducing power consumption
• Squamous cell cancer of the skin develops due to
carcinogenic polycyclic aromatic hydrocarbons unacceptable product. Without cooling fluids,
(e.g., benzo(a)pyrene), which are found in temperatures in excess of 1,300 C may be gen-
unrefined or mildly refined mineral oils. The inci- erated at the tool head, and the chips of metal
dence of such skin cancers declined from the removed from the workpiece may then weld to
1970s when industries switched to the exclusive the tool head, resulting in deformation, cracking,
use of highly refined mineral oils without PAHs. and reduced tool life. Cutting fluids are therefore
• Oil acne, folliculitis, hyperpigmentation, and applied primarily to the point of contact between
granuloma are induced by neat oils. These the tool head and the workpiece in order to
disorders are rarely seen today due to better achieve maximum cooling.
working conditions and a decreased use of 2. Lubricating: By providing lubrication in
neat oils. Skin infections may occur, especially addition to cooling at the tool head, metalwork-
when contaminated metalworking fluids come ing fluids will reduce frictional forces, allo-
into contact with damaged skin (e.g., irritant wing the tool to pass more cleanly through
contact dermatitis). the metal and resulting in a smoother finish.
• An individual hand protection plan is of great Lubrication also has the advantage of reducing
importance in preventing skin diseases. power consumption. The lubricating effect is
achieved by the basic oil or fatty soap content
of the metalworking fluid (Geraut et al. 2011).
2 Definition and Functions of 3. Removing metal fines: Chips of metal (often
Metalworking Fluids referred to as swarf) are removed by the con-
stant flow of cutting fluids over the workpiece.
Metalworking fluids are often referred to as cut- Depending upon the type of metal being
ting fluids, machining fluids, lubrication fluids, machined, the size of the metal chips may
cooling emulsions or oils, metalworking coolants, vary from a fine dust to large spiky fragments.
or drilling fluids. They are used in most metal- The metal chips may cause physical damage to
cutting operations. Metalworking fluids are liq- the skin, making it more susceptible to the
uids that flow or are sprayed over metal that is potential irritant effects of the cutting fluids.
altered in some physical way. This may be by
direct cutting through the metal, drilling, reaming,
boring, grinding, milling, tapping, drawing, or 3 Composition of Metalworking
rolling. Metalworking fluids have several func- Fluids
tions (summarized in Table 1) as follows:
The advantages of metalworking fluids have been
1. Cooling: As the machine tool cuts into the metal known for hundreds of years. Originally, water
(the workpiece), the pressure between the newly was used as a coolant for processes such as
formed chip and the tool head produces frictional reaming out gun barrels, but it had the disadvan-
heat. This heat is transferred to the workpiece, tage of corroding the workpiece and provided
resulting in thermal expansion of the metal. As a little in the way of lubrication. Over the years,
result, the workpiece may lose its dimensional cutting fluids were gradually developed to
accuracy on cooling, resulting in a technically improve efficiency. It was in the end of the
nineteenth century that soaps were first used as Table 2 Additives (modified according to Brinksmeier
lubrication fluids in metal machining processes et al. (2015))
(Geraut et al. 2011). Soap was later replaced by Additive type Examples of substances
vegetable, animal, and finally mineral oils with Antiaging substances, Aromatic amines, organic
fats and additives. Nowadays, metalworking oxidation inhibitors sulfide, zinc
dialkyldithiophosphate
fluids consist of base oil, additives, and substances
Anti-wear additives Phosphoric acid ester, zinc
that develop or are added during use. dialkyldithiophosphate
Biocides Phenol derivatives,
formaldehyde releasers,
3.1 Base Oil (Fluid) isothiazolinones
Detergents, Sulfonates, phenolates,
dispersants salicylates
The base oil is either a mineral (base) oil; an oil of
Emulsifiers Petroleum sulfonate,
vegetable, animal, or marine origin; or a synthe- potassium or alkanolamine
sized fluid: soaps, carboxylic acid soap,
fatty alcohol ethoxylate, fatty
1. Mineral (base) oils are formed by the decom- acid amide, quaternary
ammonium salt, colophony
position of animal and vegetable matter over a (tall oil)
period of millions of years within the earth’s Extreme pressure Chlorinated paraffine,
crust. Traditionally, the most commonly used additives sulfurous ester, phosphoric
mineral oils are naphthenic or paraffinic hydro- acid ester, polysulfides,
overbased sodium, or calcium
carbons refined from crude petroleum oils. In
sulfonate
the European Union, mineral base oils are
Fragrances, deodorant Pine oil, perfumes, balsam of
often divided into three groups depending on agents Peru
the grade of refinement (SCOEL 2011): Foam inhibitors Silicone polymer, tributyl
1. Unrefined or mildly refined oil phosphate
2. Highly refined oil Friction inhibitors Glycerol monooleate, whale
3. Other lubricant oil with high or low PAH oil, natural fats or oils,
synthetic esters
content
Metal deactivators Heterocycles, diamines,
2. Base oils may also be of animal origin (e.g., triarylphosphite
lard oil and skin grease, and fish oils), or of Corrosion inhibitors Sulfonates, organic boron
vegetable origin (e.g., rapeseed oil and castor compounds, amines, amine
oil), or of marine origin (e.g., tallow, fish oil). phosphates, zinc
dialkyldithiophosphate, tall oil
3. Synthetic fluids consist of polyalphaolefines, fatty acids, ethylenediamine,
polyalkylene glycols, synthetic esters (e.g., made epoxides
from vegetable oils or animal fat), or other sub- Viscosity index Polymers
stances. Synthetic fluids have well-defined char- improvers
acteristics and a high purity; they have a high
boiling point and evaporate slowly, while their 3.3 Impurities or Secondary
viscosity and tendency to aging is low. Components
Impurities or secondary components appear or

3.2 Additives develop while cutting fluids are used. These are:
Additives are added to the base oil to modify 1. Reaction products such as nitrosamines and
specific characteristic. There are countless types polycyclic aromatic hydrocarbons (PAH)
of additives (Table 2). In contrast to many mineral 2. Decomposition products of additives
base oils, additives may cross the skin barrier and 3. Contaminants such as metal splinters, dirt,
lead to systemic toxicity. hydraulic or tramp oil, dirt, dust, and solvents
4. Bacteria and fungi and their decomposition castor oil, are of vegetable origin. Synthetic oils
products. can be used as neat oils as well (INRS 2008).
Normally, neat oils are not diluted with water
Some of these secondary substances are (NIOSH 1998; OSHA 1999), but they may con-
discussed below in detail. tain additives that inhibit corrosion, allow high
pressure performances, improve lubrication, etc.
One of the advantages of neat oils is that they are
4 Classification of Metalworking less likely to become rancid, and therefore adding
Fluids germicidal agents may not be required. The per-
centage of additives is often less than 10%, but
There are several ways of categorizing metal- can be as high as 40%.
working fluids. They may be classified either as Today, neat oils are less common than water-
water-insoluble neat or straight oils or as water- soluble fluids. They are (or have been) used prin-
based fluids (Table 3). Water-soluble oils may be cipally as lubricants for moderate- to heavy-duty
subdivided into synthetic, semisynthetic, and the machining and therefore do not tend to be very
so-called soluble or emulsifiable oils. Synthetic efficient coolants.
fluids are either organic or inorganic solutions, In heavy machining operations, pressures gen-
semisynthetic fluids are finely dispersed emul- erated between the tool head and metal workpiece
sions, and soluble fluids are milky emulsions. can be very great, which tends to force out a film
The main effect of water-insoluble fluids is of lubricating oil. This can be overcome by the
lubrication; the more water-soluble a cutting addition of extreme pressure additives. The “EP”
fluid is, the better it functions as a coolant. in oil brand names such as “Castrol EP 501”
indicates the inclusion of extreme pressure addi-
tives. Traditionally, these additives have been
4.1 Neat Oils based on sulfur, chlorine, and phosphorous,
which – at the high local temperatures generated
Neat oils, straight oils, or non-soluble oils are between the metal surfaces – form metal sulfide,
usually based on mineral base oils, i.e., severely chloride, and phosphate bonds that then act as a
solvent-refined petroleum oils. However, with solid lubricant that prevents direct metal-to-metal
increasingly stringent requirements for environ- contact. However, with current pressures to elim-
mentally friendly disposal of mineral oils, more inate chlorine on environmental grounds, new
oils of animal, vegetable, or marine origin are now classes of EP additives based on highly overbased
being used. These include oils such as lard oil, sulfonates are being introduced.
tallow, skin grease, and fish oils. Most neat oils Sulfonates also have the benefit of reducing
now being developed, such as rapeseed oil or corrosion of the workpiece. Corrosion of the
Table 3 Classification of metalworking fluids

Water-
Type of oil based Appearance Use Dilution
Neat/straight oils No Fluid to viscous oils, waterless Lubrication, heavy-duty material, Not
corrosion inhibition required
Soluble/ Yes Oil-in-water emulsion, milky Coolant/lubrication, corrosion Yes
emulsifiable color, aqueous inhibition
fluids
Semisynthetic Yes Translucent, finely dispersed Coolant/less lubrication Yes
fluids emulsion, aqueous
Synthetic fluids Yes Transparent aqueous Excellent coolant, minimal Yes
lubrication
metal being machined can be an unacceptable Corrosion is further reduced by the addition of
problem, and corrosion inhibitors that may cause corrosion inhibitors that allow the oils to be used
skin sensitization problems are not infrequently at a greater dilution. Sodium nitrite is still a popular
added to neat oils. Epoxy compounds may also be corrosion inhibitor, as are aliphatic amines such as
added to scavenge any free radicals, and these triethanolamine. The use of older corrosion inhib-
may also cause sensitization reactions. itors such as sodium mercaptobenzothiazole and
Mineral base oils by themselves are not sensi- benztriazole has largely been discontinued because
tizing; they do not – or not significantly – cross the of their sensitization potential.
skin barrier and thus do not cause systemic toxicity. Soluble (emulsifiable) oils, like neat oils, also
However, until 1975, mineral oils were unrefined contain extreme pressure additives. They may
or mildly acid-refined and therefore contained car- also contain dyes and deodorants (fragrances) to
cinogenic PAHs. Nowadays, only highly refined improve their worker appeal, as oil left unused
oils with negligible PAH content are used. may become stagnant (resulting in what is often
Neat oils are usually easy to recognize as they referred to as a “Monday morning smell” follow-
look and smell like oil and usually have a translu- ing a weekend shutdown).
cent brown color. If mixed with water, they float If the oils contain carboxylic acid soaps as
on the surface as insoluble globules. emulsifiers, they have a tendency to foam – in
which case, anti-foaming agents such as silicone
or waxes may be added to reduce foaming.
4.2 Soluble (Emulsifiable) Fluids A fully formulated oil contains a multitude of
additives, some of which are oil-soluble (e.g., EP
Soluble (emulsifiable) fluids mainly consist of additives) and some water-soluble (e.g., corrosion
base oils (concentration 30–85%; oil-in-water inhibitors). Therefore, a coupling agent may also be
emulsion) that require nonionic and anionic emul- added to act as a solvent between the water and the
sifiers to enable the oil to blend and other addi- oil phases to produce a single stable emulsion. These
tives such as corrosion inhibitors, extreme may be based on phenolics (e.g., p-chloro-m-
pressure additives, anti-foaming substances, or xylenol), which impart a disinfectant odor to the oil.
biocides. Supplied neat, soluble oils have an oily It can therefore be seen that a fully formulated
appearance but, on dilution with water, they take soluble (emulsifiable) oil is a highly complex
on a characteristic milky color and are sometimes mixture (Table 4).
referred to by the workforce as “suds.”
Common emulsifiers used with soluble oils are
sodium or potassium alkyl-benzene sulfonates, 4.3 Semisynthetic Fluids
organic acid salts, and ethanolamines (Geraut et al.
2011). Semisynthetic fluids contain base oils of concen-
If petroleum sulfonates are used alone as emul- trations varying between 5% and 20%. They pro-
sifiers, then the pH of the soluble oil tends to lie vide more lubrication than synthetic oils. The thin
between 7 and 8, which although more acceptable oil-in-water emulsion is translucent, opalescent,
to the skin, tends to promote the growth of micro- or opaque when used.
organisms. In practice, therefore, a mixture of To enable the base oil to blend with water and
petroleum sulfonates and carboxylic acids is used, remain in a finely dispersed state requires the
sometimes with the addition of caustic soda to raise addition of emulsifiers. These are often based on
the pH to a preferred level of 8.5–10.5, which petroleum sulfonates, which are produced by the
reduces bacterial growth – one of the main prob- sulfuric acid treatment of spindle oils to produce
lems of soluble (emulsifiable) fluids. The addition white oils and carboxylic acids.
of germicidal agents is therefore necessary. Monoethanolamine, together with boric acids,
This more alkaline pH, although more irritating low molecular fatty acids, and citric or tartaric acid,
to the skin, reduces corrosion to the workpiece. are often used as biocides (Geraut et al. 2011).
Table 4 Composition of a soluble (emulsifiable) cutting water and are responsible for “Monday morning
fluid stink,” increased metal corrosion, development of
Lubricants (mineral oil) rust, loss of cutting fluid function, and emulsion
Emulsifiers/surfactants breakdown (Foulds and Koh 1990; de Groot et al.
Corrosion/antistain inhibitors 2010).
Extreme pressure additives Well-maintained cutting fluids contain less than
Coupling agents 1,000 bacterial colony-forming units/ml, while
Biocides poorly maintained metalworking fluids have more
Anti-foaming agents
than 1,000,000 colony-forming units/ml (HSE
Reodorants
2006).
Yeasts that may grow in metalworking fluid
4.4 Synthetic Fluids include Candida albicans (de Groot et al. 2010).
There are also mold fungi such as Aspergillus
Synthetic fluids have the advantage that they contain niger, Cephalosporum sp., and Fusarium sp.
no mineral oil and are totally water-based solutions (INRS 2008; de Groot et al. 2010). Most bacteria
of synthetic substances such as polyalphaolefines, that grow are nonpathogenic and may originate
polyalkylene glycols, and synthetic esters (which from the water supply used to dilute the oil
may be synthesized out of natural oils). They con- (Rycroft). Those found include aerobic bacteria
tain germicidal agents, corrosion inhibitors, and such as Pseudomonas aeruginosa, Legionella,
anti-foaming agents. As synthetic fluids tend to be Mycobacteria, and Nocardia and anaerobic bac-
based on soaps, they are potential irritants. teria such as Coliforms and Desulfovibrio.
They are usually supplied neat and used at After a short period of use, most emulsions are
dilutions of 1–5%. They are perfectly transparent at risk of contamination from machine tools, com-
solutions with a clear, watery appearance and may ponents, or operators’ hands. Sumps with little
be referred to by the workforce as “water.” Dye movement of oil may become contaminated if
such as fluorescein may be added, resulting in a other waste materials (food waste, cigarette ends,
clear green or yellow liquid. etc.) find its way in, particularly if there is poor
Although synthetic fluids are excellent cool- hygiene or housekeeping. Within the sump, con-
ants, they lack the oiliness necessary to provide ditions exist for the growth of both aerobic and
the level of lubrication required for many pro- anaerobic organisms (Fig. 1). Swarf may settle on
cesses. Where cooling is a primary function, the bottom of the sump, providing stagnant con-
such as in grinding, they are frequently used ditions, or tramp oil may float on the surface,
together with corrosion inhibitors. allowing anaerobic growth. Tramp oil is lubricat-
Synthetic fluids are specific and sophisticated, ing or hydraulic oil required for the moving parts
but quite fragile as they are not completely heat of a machine; this oil may leak into the sump or
stable and get denatured by contaminating contaminate the cutting fluids.
microorganisms. The presence of bacteria, apart from causing a
nasty smell, leads to a breakdown of the emulsion,
which in turn leads to technically unacceptable oil
5 Preservation and Monitoring of and a poorly machined end product. Germicidal
Metalworking Fluids agents known as biocides are always added to the
oil, and there is a variety of other ways in which
Most machines that use metalworking fluids have bacterial contamination can be minimized.
a reservoir of oil (called the sump), with the fluid Although biocides are usually added to the oil
being continually recycled around the machine during manufacture, they are sometimes added at
until it is replaced. Bacteria, yeast and fungi can the time of use, particularly if there is suspected
all grow in a poorly preserved water-based cutting bacterial contamination. Bacterial contamination
fluid. They mainly grow in the interface of oil and may be suspected if there is a foul odor, if the pH
Fig. 1 Schematic diagram

of a machine sump showing
potential for the
development of anaerobic/
aerobic conditions
becomes more acidic, if there is an accumulation Table 5 Diseases associated with metalworking fluids
of slime or microbiological culture, or if there is a Skin diseases Dermatitis (irritative > allergic)
loss of emulsion with oil droplets appearing. Oil acne
Unfortunately, it is these agents which tend to Folliculitis, furunculosis,
melanosis
cause skin sensitization (see ▶ Chap. 14, “Mech-
Respiratory tract Asthma
anisms of Allergic Contact Dermatitis”). Biocides disorders Rhinitis, pharyngitis, cough,
used in metalworking fluids may be classified into bronchitis
different groups like formaldehyde-releasing bio- Hypersensitivity pneumonitis
cides, isothiazolines, and others. Lipoid pneumonia
Cancers Skin cancer
Lung cancer
Other Infections
6 Metalworking Fluid-Induced Falls
Diseases Explosions
The most common diseases afflicting workers

exposed to cutting fluids are skin diseases, a skin disease is up to three times higher than for
followed by respiratory tract problems and other the total or for the unexposed working population
disorders (Table 5). In a recent investigation in (Suuronen et al. 2007a; Meza et al. 2013).
Switzerland, skin diseases represented more than Primary irritant contact dermatitis seems to be
90% of all occupational diseases induced by met- the most frequently encountered skin problem and
alworking fluids that are recognized by the Swiss makes up between 50% and 80% of all dermatitis
National Accident Insurance Fund (Suva) (Koller (Key et al. 1966; Gellin 1970; Samitz and Katz
et al. 2016). Other conditions such as respiratory 1975; Alomar et al. 1985; de Groot et al. 2010;
tract problems, cancer, wound infections, injuries Koller et al. 2016), followed by allergic contact
due to metal chips, falls, and explosions are much dermatitis. The prevalence of cutting fluid-
less common (Suuronen et al. 2007a; DGUV induced irritative or allergic eczema ranges from
2009). 7% to 27% in metalworkers – depending on the
study and the period of time looked at (Berndt
et al. 2000; Funke et al. 2001; Gruvberger et al.
7 Skin Problems Associated with 2003; Suuronen et al. 2007b; Coenraads et al.
Metalworking Fluids 1985; De Boer et al. 1989; Sprince et al. 1996;
Mirabelli et al. 2009; Meza et al. 2013). An even
Metalworking fluids are among the most common greater number of metalworkers complain about
substances responsible for occupational skin dis- minor skin changes such as dry skin or slight
eases (Jost and Pletscher 2013; Warshaw et al. erythema (31% in a Dutch study) (De Boer et al.
2017). The risk for an exposed worker of getting 1989). One reason for the high frequency of
eczema, dry skin, or slight erythema is the inter- et al. 1996) because water itself may lead to
dict of gloves in most workplaces with metal- maceration and reduced barrier function.
working fluids. The risk of developing dermatitis • Water-based cutting fluids have a high level of
is higher for older workers and those using water- additives, of which especially biocides, emul-
based fluids (especially semisynthetic fluids sifiers, preservatives, amines, and anti-foams
(Sprince et al. 1996)) or those using cutting fluids are potentially irritating to the skin and may
or degreasing agents frequently (i.e., more than degrease the skin, denaturing keratin and low-
4 days a week) (Mirabelli et al. 2009). Superin- ering its hydration (de Boer et al. 1989).
fections of the eczematous skin may occur. • Not only do the ingredients themselves con-
In contrast to water-based oils, neat oils induce tribute toward irritation, but also the concen-
mainly oil acne, folliculitis, furunculosis, or pig- tration of these ingredients and the length of
mentation disorders. However, with the newer exposure to them (Geier et al. 2011). It should
solvent-refined neat oils, these kinds of disorders be noted that the concentration of an ingredient
are now rarely seen. on the skin may increase within minutes due to
Table 6 summarizes the skin problems caused evaporation.
by either neat water-insoluble oils or water-solu- • The high alkaline pH of a fluid (usually
ble cutting fluids. between pH 8.5 and 10.5) is another factor
which facilitates the development of irritant
contact dermatitis.
7.1 Irritant Contact Dermatitis • Secondary components such as solvents and
system cleaners may dry the skin by dissolving
Irritant contact dermatitis is the most frequently lipids. This then results in dryness, flaking,
encountered skin disease caused by metalwork- fissures, and eventually clinical eczema.
ing fluids, varying between 50% and 80% of all • Fine metal particles machined from the work-
reported cases of eczema (Key et al. 1966; piece will add additional abrasion to the skin,
Alomar et al. 1985; Fisher 1979; Koller et al. contributing to the onset of irritant contact
2016). The occurrence of eczema depends on dermatitis.
many factors, such as water content, additives, • Host factors that increase the risk of irritant
alkalinity (especially above pH 9), frequent hand contact dermatitis include increasing age,
cleaning, contact over long periods, solvents, cumulative and repetitive exposure, skin type,
microtrauma caused by metal chips, heat, wet presence of active skin disease, previous his-
work, and host factors (de Boer et al. 1990; tory of atopic eczema (particularly if this
Geraut et al. 2011): affected the hands), wrong hand care and per-
sonal hygiene, additional employment under-
• Water-based cutting fluids are more irritant taken, hobbies pursued, and cigarette smoking
than neat oils (de Boer et al. 1990; Sprince (Sprince et al. 1996).
Table 6 Skin problems associated with cutting fluids

Type of Most irritant contact dermatitis occurs on the
cutting Site of back of the hands, which make up about 50% of
fluid Effects on the skin involvement all sites (Warshaw et al. 2017). This may affect the
Neat Folliculitis / oil-induced Forearms, machine-tool setters who have to change the tool
water- acne, furunculosis thighs, heads, requiring their hands to go right into a
insoluble (boils), allergic contact hands, face
oils dermatitis to additives machine. If the flow of oil is not stopped during
Water- Irritant contact Hands, this procedure, then their exposure is significant.
soluble dermatitis, allergic forearms, A setter responsible for 20–50 machines in a large
fluids contact dermatitis, rarely face factory may be exposed to many different types of
bacterial infection
metalworking fluids. Machine operators may only
operate a few machines in their area, but their irritative and allergic contact dermatitis and the
exposure to oil can vary considerably. If they preferred localizations are mainly the same for
have to place parts into a machine – or remove both kinds of eczema (Geraut et al. 2011; Grattan
them – they may experience constant exposure to et al. 1989) – this stands in contrast to common
oil and be at increased risk of developing irritant knowledge on dermatitis, according to which der-
contact dermatitis. matitis involving the backs of the hands and finger
Most oil flow is over the backs of the hands and web spaces is normally of an irritant nature,
fingers, and the finger web spaces, and it is these whereas dermatitis affecting the palms is allergic
areas that tend to first be clinically involved with (Grattan et al. 1989).
irritant contact dermatitis. If oil comes into contact Allergic contact dermatitis may develop con-
with the wrists and forearms, then these sites are currently with irritant contact dermatitis because
also commonly affected. Protective gloves may potential allergens penetrate easily into the dam-
not be practical because of moving machine parts aged skin of an irritant contact eczema. That is
resulting in gloved hands being drawn into the why allergic contact dermatitis occurs on average
machine. In addition, the task of changing tool about 10 years later than irritative contact eczema
heads is delicate, making glove-wearing imprac- (Geraut et al. 2011), and the prevalence of allergic
tical. If quality control requires frequent micro- contact dermatitis tends to be higher the longer the
scopic measuring (gauging), then frequent study duration is. In many cases, the eczema com-
removal of gloves to enhance manual dexterity bines features of irritant and allergic dermatitis.
may result in contaminated hands going back Factors that may contribute to a high level of
inside the occlusive waterproof glove, contribut- sensitization – apart from the irritancy of oils
ing to skin irritation. Thighs and legs may also be (particularly if inappropriate strengths are used)
involved when clothing is dirty. Eczema may also – include the warmth of the oils, the wetness of the
occur in the face and neck. situation, abrasion from metal fragments, and
The most common pattern in cutting fluid der- occlusion from protective gloves.
matitis is that of a patchy, vesicular, or Neat oils rarely induce allergic contact derma-
rhagadiform eczema. This may be confused with titis (Li et al. 2003) because it is usually not the
constitutional discoid eczema, particularly in mid- base oil itself that causes sensitization, but rather
dle-aged men. Although patchy patterns are most additives (especially formaldehyde-releasing bio-
common, other patterns of eczema may also be cides, colophonium or isothiozolinones (Geier et
seen, including fine follicular eczema, continuous al. 2011; de Groot et al. 2010)) or metal chips
confluent areas, and dry, scaly finger webs. (especially cobalt, nickel, and chrome).
The widespread use of biocides in industrial
and cosmetic products means that sensitization
7.2 Allergic Contact Dermatitis may result from domestic or personal exposure
to cosmetics and toiletries. For example, biocides
Most studies conclude that allergic contact derma- in the Kathon range (chlormethylisothiazolinone)
titis is less frequent than irritant contact dermatitis may be found in cutting oils, but also in sham-
(Geier et al. 2011) – although metalworking fluids poos, cleansing agents, skin care products, and
belong to the most common causes for allergic barrier and after-work creams. By the way, sensi-
contact dermatitis (Warshaw et al. 2017). The tization to a substance does not necessarily imply
frequency of allergic contact dermatitis might, clinical significance.
however, be underestimated because patch tests A special form of sensitization is photosensiti-
are not always performed in clinical everyday life, zation, which may be caused by bisphenolic
and not all patients with eczema are tested for all biocides.
possible allergens (Geier et al. 2000; Henriks- Alomar described four different patterns with
Eckerman et al. 2008). Without patch tests, it is varying incidences of sensitization (Alomar et al.
difficult to clinically differentiate between 1985):
1. Erythematous papules mainly on the forearms formaldehyde may induce tumors in the nasal
and dorsa of the hands accounted for 24% of mucosa of rodents when the animals are exposed
the series, with 47% incidence of positive to it in concentrations above the threshold value, i.
patch tests. e., occupational exposure limit.
2. Papulovesicles on the hands and fingers Those formaldehyde-releasing agents
accounted for 38% of the series, with a 57% described as sensitizers in metalworking fluids
incidence of positive patch tests. include (de Groot et al. 2009, 2010; Geier et al.
3. Lichenified and fissured palmar eczema 2011):
accounted for only 13% of the series, with a Oxazolidines: 7-Ethylbicyclooxazolidine
55% incidence of positive patch tests. (Bioban CS 1246) (Dalquist 1984) and 4,4-
4. Discoid eczema accounted for 25% of the dimethyl-1,3-oxazolidine/2,4,-trimethyl-1,3-oxaz-
series, with a 68% incidence of positive patch olidine (Bioban CS 1135) and N,N0 -methylene-bis-5-
tests. methyloxzaolidine.
Bioban P 1487 is a water-based preservative that
has been in use in the past. It has two active ingre-
7.3 Common Allergens dients: 4-(2-nitrobutyl)-morpholine (M) and 4,40 -
(2-ethyl-2-nitro-1,3-propanediyl)-bis morpholine
The following are some of the specific chemicals (DM). It has been prohibited in Germany since
that may be encountered in cases of allergic con- 1993.
tact sensitization. The most important ones are Others: 2-Hydroxymethyl-amino-ethanol tri-N-
part of recommended patch test series, e.g., the ethylhydroxy-2-aminomethylene (Forcide 78 I).
test series of the Deutsche Kontaktallergen- Hexahydro-1,3,5-tris(2-hydroxyethyl)-5-triazine
Gruppe (DKG) on dkg.ivdk.org (accessed on (in Grotan BK).
28.8.2018).
7.3.2 Isothiazolinones
7.3.1 Formaldehyde-Releasing The most commonly used isothiazolinones are
Biocides methylisothiazolininone (MI), 5-chloro-2-
Formaldehyde solutions are well-known disinfec- methyl-4-isothiazolin-3-one (MCI), benzisothia-
tants and occur in most metalworking fluids zolinone (BIT), and octylisothiazolinone (OIT)
(Henriks-Eckerman et al. 2008). Formaldehyde (Henriks-Eckerman et al. 2008; Geier and
solutions themselves are no longer used as bio- Lessmann 2011). They are non-formaldehyde-
cides in metalworking fluids, but formaldehyde releasing biocides.
originates from formaldehyde-releasing biocides. Isothiazolinones have been widely used since
Formaldehyde-releasing biocides release the 1980s (Thyssen et al. 2007). MCI in combi-
formaldehyde depending upon the pH of the cut- nation with MI at a ratio of 3:1 is frequently found
ting oil, the nature of the releaser, the concentra- in skin care, industrial, and household products
tion, the temperature, etc. (Rossmoore 1981; (Vauhkala et al. 2015). The widespread use of
Engelhardt and Klinkner 1985). Although the MCI/MI lead to an epidemic increase in contact
operating pH of cutting fluids may not favor this, allergies in the 1990s. The EU therefore intro-
it is thought that the pH at cell boundary of poten- duced a maximum permitted concentration for
tial bacteria is more favorable for formaldehyde MCI/MI in skin care products of 15 ppm which
release (Holtzman and Rossmore 1977). Formal- lead to a significant decrease of contact allergies
dehyde releasers are usually water-soluble and (Vauhkala et al. 2015).
oil-insoluble, showing efficacy against bacteria Nowadays, there is again a dramatic increase in
but having less of an effect on molds and fungi MI sensitization since the EU permitted the use of
(Zugerman 1986). stand-alone MI in consumer products up to
Most examples of this class of biocides are 100 ppm (Uter et al. 2013; Schwensen et al.
relatively nontoxic and inexpensive. However, 2014; SCCNEP 2004).
Positive patch tests to MCI/MI, MI, or BIT in Sensitization to alkanolamines is rare (Bhushan
machinists with contact dermatitis make up et al. 1998), although alkanolamines are found in
between 5% and 10%, according to a Danish most metalworking fluids (Henriks-Eckerman et
study (Schwensen et al. 2014). In general, contact al. 2008). Contact allergies occur most often with
allergies occur more often in other occupational monoethanolamine, followed by diethanolamine
groups like hairdressers, cosmetologists, painters, (Lessmann et al. 2009). Triethanolamine has a
pottery, and glass makers (Uter et al. 2007; very low risk of sensitization (Lessmann et al.
Schwensen et al. 2014; Vauhkala et al. 2015). 2009). Diethanolamine can penetrate the skin in
MI and MCI: MI has often been used together physiologically significant amounts; further eval-
with MCI in a 3:1 combination. It is not part of the uation is required to determine whether liver dis-
metalworking concentrate itself, but it is added to ease or cancer can be induced as a result of this
the prepared water-based metalworking fluid penetration (Mirer 2010).
(Geier and Lessmann 2011). The reason of the Alkanolamine borates have become widely
contact allergy is not always the biocide in the used in water-based cutting fluids as corrosion
metalworking fluid, but the personal care product inhibitors and they also have some biostatic
or coating (Warshaw et al. 2017). potential. They induce both irritant and allergic
BIT: BIT does not cross react with MCI/MI reactions.
(Geier and Lessmann 2011). It is only found in A former anti-rust agent was morpholinyl
industrial products. As its use in consumer prod- mercaptobenzothiazole (MOR).
ucts is forbidden, contact allergies due to BIT and Emulsifiers such as diglycolamine (2-(2-
positive patch tests to BIT tend to be less common aminoethoxy)ethanol) or tall oil (liquid colo-
(Schwensen et al. 2014). Positive tests are found phony or rosin) (Matos et al. 1988). Workers
in between 3% and 10% of all tested contact may get sensitized to oxidation products of oxi-
allergies due to cutting fluids (Geraut et al. 2011). dized resin acids of tall oil such as abietic acid
OIT: OIT is the most recent biocide used in (Geier et al. 2011). A former emulsifier was coco-
metalworking fluids. It does not cross react with nut diethanolamide (a surfactant), although expo-
MCI/MI (Geier and Lessmann 2011). Positive sure to this was mainly from barrier creams and
reactions are seen in 3–7% of the cases (Geraut handwashing liquids (Inola et al. 1993).
et al. 2011). Anti-wear additives such as lanolin and
cetearyl alcohol, diethyldithiocarbamate.
7.3.3 Other Non-formaldehyde- Corrosion inhibitors such as ethylenediamine
Releasing Biocides (diaminoethane) in coolants (Crow et al. 1978).
Current biocides: Iodopropynyl butylcarbamate Sensitization to ethylenediamine may lead to
(IPBC), triclosan, sodium 2-pyridinethiol-1-oxide cross-reaction with other amines in cutting fluids.
(sodium omadine) Stabilizers such as propylene glycol
Former biocides: p-Chloro-m-xylenol, a phe- hemiformal and polyethylene glycol. Propylene
nolic germicide also used as a coupling agent glycol hemiformal does not seem to be in use
(Adams 1981), chlorocresol, methyldibromo anymore (de Groot et al. 2010).
glutaronitrile (MDBGN), chloroacetamide, Phenolic compounds such as bisphenols, cre-
2-bromo-2-niropropane-1,3-diol (Bronopol) sols, dichlorophene, hexachlorophene, phenols,
and chlorinated phenols are used as biocides.
7.3.4 Other Sensitizing Substances Bisphenols are photosensitizers.
Other sensitizing oil additives requiring consider- Fragrances or deodorant substances such as
ation and specific investigation include: pine oil, abietic acid, perfumes, or balsam of Peru.
Antioxidants such as p-tert-butylphenol and During working process, tiny metal particles
butylhydroxytoluene (BHT). may be released into metalworking fluids, or
Anti-rust agents such as benztriazole, metal salts may be solubilized in the cutting fluids.
mercaptobenzothiazole, and alkanolamines. It is known that cobalt, dichromate, and nickel
may cause allergic eczema. However, studies do potential contact factors, has to be performed.
not agree on whether sensitizations are more fre- Facilities for control testing are vital in order to
quent in the context of metalworking fluids exclude false-positive irritant reactions. Although
(Alomar et al. 1985; Grattan et al. 1989; Uter many causes of allergies can be identified from the
et al. 2002; Geier et al. 2004). Sensitization to standard series, many other cases will be missed
one of these metals is often due not to contact unless the specific allergen is tested for. Unfortu-
with cutting fluids, however, but to exposure of nately, comprehensive allergen information is not
another kind (Uter et al. 2002). always declared on safety data sheets (Henriks-
Commercial companies produce oil and Eckerman et al. 2008) because their concentration
cooling fluid series for investigation of patients, is below the declaration limit. It is therefore often
which can be useful if access to information on impossible to pinpoint the causative agent.
individual ingredients of the oils is not readily There is often debate as to what represents an
available (e.g., www.chemotechnique.se). appropriate strength at which to can be tested oils.
Some authors suggest using undiluted metalwork-
ing fluid in the first step (Rietschel and Fowler
7.4 Investigation of Metalworking 2007) and then, in case of a positive result or in
Fluid Dermatitis suspected cases, doing “aimed” testing to identify
the exact allergen. The reason why some authors
An investigative approach to a case of cutting recommend using cutting fluids “as is” in the first
fluid dermatitis involves, firstly, the establishment step is because dilution could reduce the additive
of the diagnosis (Rycroft 1981). The main objec- to such an extent that not enough is available to
tive is to determine the roles of irritancy, allergy, elicit a reaction on patch testing in practice.
endogenous factors, or combinations of these in However, patch tests with undiluted fluids may
its etiology. elicit an allergic dermatitis through damaged skin in
Most workers who develop dermatitis have individuals experiencing repeated exposure to low
been exposed to several metalworking fluids; the levels of irritant. Many would argue that the
use of which may have been discontinued since strengths tested will produce a false-positive irritant
the onset of their condition. The names, batch reaction. Although this is more common with syn-
numbers, and manufacturers’ addresses relating thetic fluids due to their high soap content, it rarely
to these fluids must be obtained, and enquiries seems to be the case with other cutting fluids. With
made to determine whether other additives were any new oil tested, however, it is vital to check that
added when the cutting fluid was in use. Other the results are not false-positive irritant, which can
relevant factors to consider include machine- be established by control testing.
cleaning chemicals, protective metal coatings Others therefore advocate patch testing with
(Calnan 1978), solvents for removing oil from unused oil (Geraut et al. 2011) at different dilu-
finished pieces, barrier creams, skin cleansers, tions – e.g., 100%, 50%, and 10% – in order to
protective equipment, and domestic contact fac- eliminate false-positive results. Allergic reactions
tors. Dermal exposure can be analyzed using tend to have a graduated lessening of reaction with
assessment methods such as VITAE and increasing dilution, whereas irritant reactions tend
DREAM (van Wendel de Joode et al. 2005). In to have a sharp cutoff below a certain concentra-
addition, self-administered questionnaires can be tion. Dilution may be done in water with the
used as a screening tool as a routine occupational water-soluble oils diluted in methyl ethyl ketone
medical precaution (van Wendel de Joode et al. with the neat oils.
2007). Testing both the original and the used cutting
Patch testing with a standard metalworking fluid could give additional hints as to whether a
fluid patch test series of allergens, oil batteries positive patch test reaction is due to a substance
(Foulds and Koh 1990), and ingredients of the added later to the circulation system, to a break-
oil at appropriate dilutions, as well as other down product like metal chips, hydraulic oils from
the machine, or cleaning products (Rietschel and are recommended. Barrier creams alone seem to
Fowler 2007). That is why the German working have only a weak protective effect (Bauer et al.
party on “allergy diagnostics in the metal branch” 2018).
(Tiedemann et al. 2002) recommends investigating When developing individualized hand protec-
one fresh and one used sample of metalworking tion plans, three aspects need to be considered: the
fluid. The used sample should not be taken from the machinist, the machine, and the oil itself.
sump so as to avoid inclusion of metal chips –
metals can be tested as single components later if 7.5.1 The Machinist
necessary. In the case of water-mixed cutting fluids, Preemployment screening should try to exclude
the working group recommends diluting the those individuals that have a personal history of
unused cutting fluid concentrate to a 5% aqueous long-standing atopic dermatitis, particularly if this
solution (which corresponds to a commonly used has affected the hands. Individuals with a previous
dilution at the working place) and diluting the used history of hand dermatitis caused by other irritants
cutting fluid to aqueous solutions between 4% and are also at increased risk of recurrence. If they are
8%. In the case of neat oils, the used and unused allowed to work in a cutting fluid environment,
cutting oil should be diluted with the same volume then every effort must be made to enable them to
of olive oil. maintain meticulous hand care.
As diluted solutions may give false-positive Gloves may not be practical because of the risk
results, single components can also be tested of being caught in moving machinery, but some
when patch tests on the metalworking fluid are automatic machines will be compatible with glove
negative, or if the occupational physician has a usage. Gloves need to be impervious to the oil, but
suspicion. Testing single components of metal- contamination of hands with oil may arise due to
working fluids may be troublesome as informa- lacerations to the gloves caused by metal frag-
tion on allergens in the safety data sheets is often ments, oil entry under the cuffs if the gloves are
incomplete and the cutting fluid may have been too short, or contact with oil when the gloves are
contaminated during use. Often it is not possible removed for delicate operations. These factors
to find the single responsible factor (Geraut et al. will lead to occlusion under the glove fabric,
2011). If an allergen is identified, avoidance or which may increase the risk of dermatitis devel-
substitution is required (see below). oping. Armbands can help to keep oil off the
forearms, and with heavy exposure, aprons and
Wellington boots may also be required.
7.5 Prevention of Metalworking If gloves are not practical, then barrier creams
Fluid Dermatitis may offer some limited protection although the
emulsifier content of some oils will tend to dis-
When large numbers of people work with cutting solve them. A water-repellent barrier cream may
fluids, it is impossible to prevent all cases of offer some protection. These creams may also
dermatitis, as skin contact cannot be avoided. allow the use of less harsh cleansers. During
However, severe outbreaks of dermatitis are pre- breaks and at the end of shifts, cleansers which
ventable. Each company should set up a hand are the mildest for the task required should be
protection plan, and all workers (including used, and any drying effects induced should be
apprentices) should be given clear instructions as counteracted with an appropriate emollient after-
to how the plan is to be implemented. Workplace work cream. The regular application of moistur-
information on skin problems and skin care is izing emollient is often difficult to achieve if no
often inadequate (Itschner et al. 1996). In general, problems with dermatitis exist, as their use is often
good skin protection education and the use of considered to be effeminate by a male workforce.
moisturizers (alone or together with barrier If productivity payments are in place, these
creams (Bauer et al. 2018) and sleeves to protect should not be offset by causing workers to take
the forearms – if the machine operation allows it) shortcuts in production-reducing skin care and
protection. Allowing cleanup time at the end of 7.5.3 The Fluid

the shift can encourage good working practice and Fluid formulators should be encouraged to
provide a more psychologically favorable work- develop oils that are potentially less irritating to
ing environment. the skin. This could be achieved by reducing
Adequate training of the employee in correct levels of anionic compounds and increasing
machine use is important, particularly if oil flow those of nonionic compounds, although this
can be stopped when bare hands are placed within would have to balance against the technical
the machine. The worker should be instructed that requirement of the oil. Additives that are known
greatest caution has to be taken when blowing. sensitizers should be excluded or used at low
Education of the workforce to prevent contamina- levels that are less likely to sensitize in the first
tion of the oil is vital. Unfortunately, any system place. If sensitization to an additive has been
that relies on the worker alone for prevention will identified in a dermatitis outbreak, substitution
always fail. of the additive will be required to resolve the
problem. The development of additives to chelate
7.5.2 The Machine metal ions that may be taken up by the oil solution
Machinery should be built in such a way as to from the metal swarf fragments should be
minimize the exposure of workers to cutting encouraged.
fluids. Manual feeding of workpieces, oil con- The working concentration of fluids that
tact when machines are shut off and hands are require dilution is one of the most important fac-
placed into the machines, and the need to hold tors to monitor in order to prevent dermatitis
workpieces under the flow of oil when they are occurring in the first place. All too often, dilution
being machined are machine design problems of oils is left to a poorly informed laborer, or
which increase the risk of workers developing dilutions are guessed at or determined by the feel
dermatitis. Increasing automation with com- of the diluted fluid. Concentration is easy to check
puter-controlled machines that are enclosed to using a refractometer giving an instant readout. If
prevent oil contact will reduce the incidence of oils are prediluted or diluted by using premixing
dermatitis. taps, the concentration should still be checked
Processes should be designed so as to mini- with a refractometer, as errors can occur. Once
mize the need for frequent tool-head changes. the fluid is in the machine, any heat generated
Quality-control measurements should be designed will evaporate the water content of the oil,
so that gloves can still be worn. resulting in increased concentrations within the
Effective filtration methods need to be in place machine. Therefore, if more diluted fluid is
to remove metal fragments from the machine to added without checking the concentration within
prevent anaerobic conditions encouraging bacte- the machine, gradually, there will be a buildup of
rial growth and to lower the potential for metal concentrated oil within the machine, and rather
ions to go into solution. Tramp oil should be than oil being used at 1–2%, concentrations in
prevented from entering the cutting fluid and excess of 20% may occur. Depending on the
removed if it does. Regular cleaning of the tool type of machine, measuring fluid concentration
heads should be encouraged. and taking appropriate action may be required
If machines can be built with smooth internal several times a day. Keeping a record of oil con-
pipework and sumps made of stainless steel, then centrations beside each machine is always a way
cleaning them becomes easier. Machines should of ensuring good housekeeping.
be designed to operate at the lowest possible tem- The pH of the fluid should be regularly moni-
perature, as this reduces evaporation of the water- tored, as a change may be a sign of bacterial
based fluids. Low temperatures as well as low contamination. Addition of caustic soda to
concentrations of cutting fluid will also discour- increase the pH to a more alkaline level should
age bacterial growth and maintain cutting fluid be discouraged, as this is potentially irritating
stability. to the skin. The reason for the bacterial
contamination should be identified. The adding of 8 Other Benign Skin Disorders

additional biocides on-site potentially increases
sensitization risk because of higher biocide work- Petroleum and its derivatives as well as coal tar
ing concentrations. If oil is recycled, then moni- products may cause occlusions of hair follicles,
toring of potential concentrations of sensitizing which may lead to oil acne (Rietschel and Fowler
additives within the recycled oil is required. 2007). Oil acne consists of comedones, papules,
pustules, or even furuncles on the face, arms, and
thighs.
7.6 Prognosis of Metalworking Chronic exposure to straight oils may also lead
Fluid Dermatitis to hyperpigmentation, melanosis, epithelioma, or
keratosis. Hyperpigmented macules mainly occur
The prognosis of cutting fluid dermatitis is unsat- on exposed areas (face, forearms, back of hands)
isfactory in many studies (Johnson and Wilson (Alomar 1994). The underlying mechanism of the
1971; Pryce et al. 1989; Grattan and Foulds development of hyperpigmentation seems to be a
1989; Shah et al. 1996) – however, the results combination of the irritative effect of the oil and
are quite diverse. Whereas in one study only one ultraviolet light (Alomar 1994).
worker in 40 had to quit his job (Grattan and If metalworking fluids contain chlorinated phe-
Foulds 1989), in another study, it was 82% of nols as additives, vitiligo-like depigmentation
employees who changed their job (Johnson and (leukoderma) may develop.
Wilson 1971). In the study of Pryce et al., it was Halogenated aromatic hydrocarbons may
found that 78% of those workers who remained at cause chloracne. Chloracne is not the conse-
work and 70% of those who quit their job contin- quence of follicular occlusion, but it is a toxic
ued to have skin problems, sometimes several effect (Rietschel and Fowler 2007). It is both
years after they changed job (Pryce et al. 1989), clinically and histologically distinct from vulgar
whereas in the study of Grattan and Foulds 75% acne. Typical features are cysts and often come-
improved within 31 months (Grattan and Foulds dones. Pustules and abscesses are less common
1989). The generally poor outcome may be due to than in vulgar acne. After discontinuation of
various factors, including low acceptance of skin exposure, lesions may continue to be present.
protective measures by many workers (Kütting A foreign-body granuloma occurs when cut-
et al. 2009). ting oil is accidentally inoculated in the dermis
If the original clinical problem was predomi- (Alomar 1994).
nantly an irritant one due to inappropriate concen- In the past, all these disorders generally
trations of metalworking fluid being used, the resulted from contact with long-lasting oils and
cumulative damage incurred may be difficult to high exposure to straight oils – they have become
reverse even if the oils are subsequently used at seldom today.
correct working concentrations.
If the problem is allergy-based with minimal
irritation present, then substitution of the aller- 9 Skin Cancer
gen will result in complete clearance with
no ongoing skin disease (Foulds 1998, Follow- Since the 1800s, it was known that mineral oils
up of patients with cutting oil dermatitis follow- cause squamous cell cancer of the skin, especially
ing substitution of an allergen, personal at the scrotum, the back of the hands, forearms,
communication). face, and neck (Cruickshank and Squire 1950;
In practice, many causes of cutting fluid der- Waterhouse 1971; Geraut et al. 2011). It was in
matitis are multifactorial, and the eventual out- the twentieth century that Cook identified benzo
come may be related to how far the individual (a)pyrene, a polycyclic aromatic hydrocarbon
physician is prepared to investigate, advise on, (PAH), to be the responsible carcinogenic agent
and treat each case. in coal tar (products) (Cook et al. 1933). Until the
1970s, neat oils were derived from unrefined or Bauer A, Rönsch H, Elsner P, Dittmar D, Bennett C,
mildly refined petroleum distillates that contained Schuttelaar MLA, Lukás J, John SM, Williams HC
(2018) Interventions for preventing occupational irri-
such carcinogenic PAHs. Since 1975, the use of tant hand dermatitis. Cochrane Database Syst Rev 4:
acid-refined mineral oils containing carcinogenic CD004414
PAHs has been discontinued, and they have been Berndt U, Hinnen U, Iliev D, Elsner P (2000) Hand eczema
replaced with highly solvent-refined petroleum in metalworker trainees – an analysis of risk factors.
distillates that do not contain carcinogenic PAHs Bhushan M, Craven NM, Beck MH (1998) Contact allergy
(Li et al. 2003). Fresh modern mineral oils in use to 2-aminoethanol (monoethanolamine) in a soluble
since 1975 (Thony et al. 1976) are therefore no oil. Contact Dermatitis 39:321
longer carcinogenic (McKee et al. 1990). How- Brinksmeier E, Meyer D, Huesmann-Cordes AG, Herr-
mann C (2015) Metalworking fluids – mechanisms
ever, carcinogenic PAHs may be present in and performance. CIRP Ann Manuf Technol
metalworking fluids in use. Furthermore, nitrosa- 64:605–628
mines and metal chips can also lead to other kinds Calnan CD (1978) Chromate dermatitis from soluble oils.
of cancer. Contact Dermatitis 4:378
Coenraads PJ, Foo SC, Phoon WO, Lun KC (1985) Der-
matitis in small-scale metal industries. Contact Derma-
titis 12:155–160
10 Infections and Injuries of the Cook JW, Hewett CL, Hieger I (1933) J Chem Soc 0:395-
Skin 405
Crow KD, Peachey BDG, Adams JE (1978) Coolant oil
dermatitis due to ethylenediamine. Contact Dermatitis
Water-mixed metalworking fluids are prone to 4:359–361
microbial contamination. This may lead to derma- Cruickshank CND, Squire JR (1950) Skin cancer in the
titis and infection of preexisting dermatitis, but engineering industry from the use of mineral oil. Br J
Ind Med 7:1–11
also to hypersensitivity pneumonitis (Saha and Dalquist I (1984) Contact allergy to cutting oil preserva-
Donofrio 2012). However, infections of the skin tives bioban CS-1246 and P-1487. Contact Dermatitis
do not seem to be more frequent than in non- 10:46
exposed people (Rossmoore 1981). Biocides or De Boer EM, Van Ketel WG, Bruynzeel DP (1989) Der-
matoses in metal workers – (II) allergic contact derma-
UV irradiation have to be used to prevent bacterial titis. Contact Dermatitis 20:280–286
or fungal contamination of cutting fluids. De Boer EM, Scholten RJ, Van Ketel WG, Bruynzeel DP
Injuries of the skin mainly occur due to falls on (1990) The irritancy of metal working fluids: a
slippery ground or contact with metal chips in the laser Doppler flowmetry study. Contact Dermatitis
22:86–94
fluids. De Groot AC, Flyvholm MA, Lensen G, Menné T,
Coenraads PJ (2009) Formaldehyde-releasers: relation-
Acknowledgments I would like to thank Dr. Hanspeter ship to formaldehyde and inventory of formaldehyde-
Rast, dermatologist at Suva, for his helpful comments and releasers. Contact Dermatitis 61:63–85
corrections. De Groot A, Geier J, Flyvholm M-A, Lensen G, Coenraads
P-J (2010) Formaldehyde-releasers: relationship to
formaldehyde contact allergy. Metalworking fluids
and remainder. Part 1. Contact Dermatitis 63:117–128
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Rubber
67
Marie-Noëlle Crepy and Donald V. Belsito
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
3 Rubber-Related Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
3.1 Natural Rubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
3.2 Artificial Rubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
3.3 Vulcanization and Rubber Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992
3.4 Accelerators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
3.5 Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995
4 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
4.1 General Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
4.2 Patch Test Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
4.3 Occupational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
5 Skin Disease in Rubber Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
5.1 Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
5.4 Other Occupational Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001
6 Occupational Skin Disease Outside the Rubber Industry . . . . . . . . . . . . . . . . . . . 1003
6.3 Allergic Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
M.-N. Crepy (*)

Occupational and Environmental Diseases Department
Unit, Hotel-Dieu Hospital, Paris, France
Dermatology Department Unit, Cochin Hospital, Paris,
France
e-mail: marie-noelle.crepy@orange.fr
D. V. Belsito
Department of Dermatology, Columbia University College
of Physicians and Surgeons, New York, NY, USA
e-mail: dvb2108@columbia.edu

https://doi.org/10.1007/978-3-319-68617-2_65
990 M.-N. Crepy and D. V. Belsito
7 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
8 Treatment and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
Keywords condoms, shoes, sporting equipment, etc.)

Rubber · Allergens · Accelerators · and with nonrubber sources of the allergen
Antioxidants · Latex proteins · Allergic contact (s) such as insecticides, fungicides, and
dermatitis · Allergic contact urticaria · medicaments.
Occupational dermatitis · Rubber industry · • For those sensitized to rubber, it is particularly
Gloves · Accelerator-free medical gloves · important to identify specific gloves and shoes
Contraceptive devices · Prevention which are free of their allergens.
New glove manufacturing processes have been

1 Core Messages developed to produce accelerator-free medical
gloves.
• Sensitization to rubber components often
accompanies allergic or nonallergic hand
eczemas; however, without patch testing, the 2 Introduction
diagnosis can be missed.
• Sensitizing rubber products contain multiple Rubber-based products permeate our lives, forming
allergenic constituents; therefore, individuals part of the many materials used for personal, domes-
are often allergic to several rubber allergens. tic, and industrial purposes. Rubber may be natural,
• The allergens in rubber vary greatly depending synthetic, or a mixture of the two. Since the vast
upon the product and the country of origin. The majority of rubberized materials are unlabeled, it is
composition of the same rubber product may difficult to determine whether a product contains
change from lot-to-lot without the consumer natural or synthetic rubber. The overlap between
being aware of any differences in the final “rubber” and “plastic” further complicates the mat-
product. ter, especially since plastics contain many of the
• Rubber additives are the allergens most same catalysts, stabilizers, antioxidants, and pig-
strongly associated with occupational contact ments/dyes that are present in rubber products.
dermatitis. Fregert (1981) listed a number of naphthylamines,
• The rubber accelerators (thiurams, carbamates, substituted paraphenylenediamines, alkylphenols,
thiazoles, and thioureas) cause the greatest and hydroquinone derivatives which are utilized
amount of sensitivity among users of rubber in the manufacturing of both rubber and plastic.
products; in contrast, workers involved in the Although completely cured plastics are rare
manufacture of rubber are more likely allergic sensitizers, fully cured rubber products produce
to the amine antioxidants. allergic reactions since the sensitizers in rubber can
• Vulcanization produces new allergens. leach out or “bloom” over time.
• The amine antioxidants, especially IPPD, are Natural rubber is based on the polymer
highly sensitizing, and positive patch tests are 1,4-polyisoprene, a substance extracted from
typically intense. several plant sources, especially Hevea brasiliensis.
• An individual sensitized to components of Before the 1940s, natural rubber supplied 100% of
rubber must take precautions not only with market demand; now, it supplies about 25%. A
rubberized products used at work (gloves, variety of synthetic rubbers exists, each based on
masks, rubber bands, etc.) but also with different polymers (Table 1), which constitute the
personal products (elasticized garments, remaining 75% of the rubber market. The
67 Rubber 991
increasingly widespread use of rubber has been increase due to the expanding use of rubber
facilitated by the development of new rubber poly- worldwide.
mers with varying properties of industrial value
(Tables 1, 2 and 3). Although as a percentage of
all rubber goods, those made from latex are declin- 3 Rubber-Related Chemicals
ing, the absolute use of natural rubber continues to
3.1 Natural Rubber
The principal source of natural rubber latex is Hevea

Table 1 Commonly encountered synthetic rubbersa
brasiliensis, which belongs to the Euphorbiaceae
Common family. Other commercial sources of natural rubber
name Polymer Usage
include Parthenium argentatum (guayule rubber)
Polyurethane Isocyanates + Elasticized
and plants of the Sapotaceae family (gutta-percha).
(i.e., polyesters clothing, shoes,
Spandex ®) sealants/caulkings, These plants produce a viscous substance which
adhesives, and contains about 30% isoprenes, with the remainder
industrial products consisting of water, proteins, resins, and sugars. The
resistant to abrasion
1,4-polyisoprenes chemically occur in two different
Neoprene Chloroprene Clothing/gloves,
latex foams, and
isomeric forms: the cis form is found in latex and
industrial products guayule rubber; and gutta-percha and balata, which
Nitrile Acrylonitrile + Shoes/gloves,
butadiene waterproof
clothing, adhesives, Table 2 Other specialty synthetic rubbersa
artificial leathers, Acrylic elastomers Polyisobutylene
and industrial
Chlorinated polyethylene Polyisoprene
products designed
elastomers
to resist solvents
and oils Chlorosulfonated Polynorbornene
polyethylenes
Styrene- Styrene + Widely used in
butadiene butadiene industrial rubber Epichlorohydrin elastomers Reclaims and regrinds
products, especially Ethylene/acrylic elastomers Reprocessed synthetic
tires Ethylene-propylene Styrene-isoprene
Butyl Isobutylene + Gas impermeable copolymers rubbers
isoprene or products (inner Fluoroelastomers Thermoplastic
butadiene tubes, hoses, elastomers
electrical Isobutylene- Transoctenamer
insulation, etc.) paramethylstyrene
Polysulfide Polysulfide + Sealants, adhesives, elastomers
(i.e., organic protective clothing, Isoprene-acrylonitrile Vinyl acetate/ethylene
Thiokol ®) dichlorides and other elastomers copolymers
oil-resistant
Polybutadiene elastomers
materials a
Ethylene Ethylene Automobile hoses, Rubber World Magazine’s Blue Book (online; accessed
propylene propylene gaskets, belts, and 15 April 2011)
diene diene monomer industrial rubber
terpolymer (EPDM) resistant to
weathering Table 3 Natural and synthetic rubber blends: emulsions,
Silicon Dimethyl Gaskets, seals, latexes, and dispersionsa
elastomer siloxane hoses, and
insulating tapes Acrylic latexes Polychloroprene latexes
designed to resist Natural latexes Styrene-butadiene latexes
high temperature Nitrile latexes Vinyl pyridine latexes
a a
Rubber World Magazine’s Blue Book (online; accessed Rubber World Magazine’s Blue Book (online; accessed
15 April 2011) 15 April 2011)
have slightly different properties and are much less the proteins responsible for inducing ACU, it has
frequently used, contain the trans form. been reported that the sap from Parthenium
The polyisoprene chains within rubber are dis- argentatum, a member of the Compositae family,
organized to a great extent, but not totally. When contains a cinnamic acid ester of sesquiterpene
rubber is stretched, the polymers assume a parallel which is a potent sensitizer for delayed-type
arrangement which produces frictional heat and hypersensitivity in the guinea pig (Rodriguez
enhanced intermolecular attraction (van der et al. 1981). Perhaps for this reason, guayule
Waals), which add to the resistance of rubber to rubber has not become a significant source of
stretch-induced deformation. The total reversibility rubber worldwide. Although the sap of
of transformations induced by stretching represents Sapotaceae spp. is apparently free of sensitizers,
elasticity, while persistent deformation following it is highly irritating (Mitchell and Rook 1979).
stretching is indicative of plasticity. Natural rubber
is both elastic and plastic; the degree to which
elasticity or plasticity dominates depends primarily 3.2 Artificial Rubber
upon the ambient temperature. Natural rubber is
elastic only between 15 C and 30 C. Below In 1909, Hoffman reported the synthesis of
15 C, rubber gets hard and rigid; above 30 C, it dimethylbutadiene, a molecule similar to the iso-
gets soft and plastic. To alter these characteristics, prene monomer, from acetone. Called Hoffman’s
chemical additives (described below) are needed. rubber, this product was used during World War I,
Delayed-type hypersensitivity reactions to nat- but was of poor quality. Throughout the 1930s, the
ural latex were once considered rare. Sidi and Germans continued production of butadiene-
Hincky (1954) suggested that latex may be a based or Buna rubbers, which were improved by
delayed-type allergen based on their study of copolymerizing methylbutadiene with styrene
patients with allergic reactions to latex gloves, (Buna S) or acrylonitriles (Buna N). In the United
but without evident allergy to the accelerators or States, DuPont synthesized polychloroprene-based
antioxidants likely to be present in the gloves. rubber (Neoprene®) in 1931. However, it was dur-
Substantiated reports of isoprene allergy include ing World War II and the Korean War that, with
those of Wyss et al. (1993) and Wilkinson and little supply of natural latex, the greatest advances in
Beck (1996). In this latter study of 822 patients, synthetic rubbers occurred. Today, one can synthe-
10 (1.2%) exhibited positive patch test reactions size isoprene itself from petroleum derivatives.
to latex. Nonetheless, the majority of delayed- Thus, multiple types of synthetic rubbers with spe-
type hypersensitivity to rubber products is due to cific properties can be manufactured (Tables 1, 2,
reactions to the accelerators and antioxidants and 3). Despite the proliferation of these synthetic
added in the manufacturing process. rubbers, allergic reactions to the synthetic mono-
Despite the increasingly more frequent reports mers/polymers are quite rare. To date, there have
of ACD to natural latex (Sommer et al. 2002), the only been case reports of possible ACD to isocya-
exact chemical nature of the allergen(s) remains nates present in synthetic plastic/rubber wound
unknown. In contrast, proteins (primarily Hev b2, dressings (Helland et al. 1983; Kilpikari and
b5, b6.01, and b13) present in latex obtained from Halme 1983) and to polysulfides in sealants
the Hevea brasiliensis tree are the cause of the (Wilkinson and Beck 1993).
IgE-mediated hypersensitivity/allergic contact urti-
caria (ACU) to natural latex rubber in >60% of
latex allergic patients (Reunala et al. 2004). Since 3.3 Vulcanization and Rubber
Hevea brasiliensis accounts for >99% of natural Additives
rubber used worldwide, ACU to latex was a signif-
icant problem in the 1980s and 1990s. The monomers of both artificial and natural rub-
While the polyisoprene-containing sap from ber must be polymerized into a three-dimensional
Parthenium and Sapotaceae spp. does not contain network to obtain the finished product. Different
67 Rubber 993
processes are used, although they are all quite Table 4 Vulcanization materials and other rubber
similar. The process of polymerization (called additivesa
vulcanization) involves the reaction between rub- Auxiliary and surface Processing materials
ber isomers and sulfur to produce a polymer with materials
enhanced elasticity and reduced plasticity. The Adhesives and bonding/ Homogenizing agents
sealing agents
reaction between the monomers and sulfur is
Blowing agents and blow Peptizers
enhanced by the addition of accelerators and acti- promoters
vators. Other chemicals which can be added to Dusting, dipping, and Plasticizers and softeners
both natural and synthetic rubber include retar- washing materials
dants, antioxidants, curing agents, reinforcers, Finishes Processing aids and
fillers, ultraviolet inhibitors, softeners/extenders, dispersing agents
stabilizers, blowing agents, and colorants. Those Lubricants Tackifiers
Odorants and antistaining Protective materials
additives of principal interest to occupational der-
agents
matologists include certain accelerators (namely, Polymerization materials Antioxidants,
thiurams, thiocarbamates, thiazoles, and guani- antiozonants, and
dines) and antioxidants (namely, derivatives of inhibitors
p-phenylenediamine). In addition, natural rubber Reclaiming materials Chemical and heat
latex is of increasing importance. In contrast, stabilizers
allergic reactions to the other components of rub- Solvents Vulcanization materials
Extenders, fillers, and Accelerators
ber, except for reactions to the phenol formalde-
reinforcers
hyde resins (used as tackifiers/reinforcing agents) Carbon black Activators
and epoxy resins (used as stabilizers), are rare Other black materials Retarders
(Conde-Salazar et al. 1993). Therefore, this chap- Nonblack materials Vulcanizers
ter deals primarily with those problems related to Fiber-reinforced materials
the accelerators and antioxidants (Table 4). a
Rubber World Magazine’s Blue Book (online; accessed
15 April 2011)
3.4 Accelerators
classified as slow (amines and thioureas), medium
Vulcanization of rubber consists of heating the (thiazoles), and fast (thiurams and dithiocarba-
molecules of polyisoprene so that they polymerize mates) accelerators of vulcanization. While some
into a product which maintains its elasticity over a synthetic rubbers (e.g., butyl and nitrile) can be
range of temperatures. The process was discov- polymerized with organic peroxides without the
ered by Goodyear in 1839 and involves heating addition of sulfur, others (e.g., styrene-butadiene)
rubber with sulfur and lead. However, vulcaniza- require much greater amounts of sulfur donors
tion is slow. Temperatures >300 C could be used (viz., 2-MBT, and thiuram) than natural rubber.
to accelerate the process, but these temperature The thiurams used industrially include
extremes destroy the isoprene chains. For this tetramethylthiuram monosulfide (TMTM),
reason, chemical accelerators are added to speed tetramethylthiuram disulfide (TMTD), tetraethy-
vulcanization at lower temperatures. The original lthiuram disulfide (TETD), and dipenta-
accelerators were metallic oxides. In the 1920s, methylenethiuram disulfide (PTD). These
2-mercaptobenzothiazole (2-MBT) was intro- thiurams are frequently used as mixes whose
duced and revolutionized the process. Subse- exact composition varies with the particular rub-
quently, numerous other accelerators have been ber product, as well as with the country of origin.
identified including thiazoles, thiurams, dithiocar- Worldwide, TMTM and TMTD are most used.
bamates, guanidines, thioureas, and amine alde- Thiurams had been among the more frequently
hydes (Table 5). Many of these contain a sulfur used rubber accelerators. However, in the past
moiety and, depending upon their action, are decade, their use, especially in the manufacturing
Table 5 Accelerators in natural and synthetic rubbers Table 6 Thiurams: potential exposures
likely to cause allergic contact dermatitisa
Adhesives Medications (antialcohol, scabicide,
Allergen(s) present in standard fungicides, sunscreens, surgical
Chemical class patch test series wraps)
Thiazoles 2-Mercaptobenzothiazole Animal Pesticides
Mercapto mix repellents
N-cyclohexyl-2-benzothiazyl Crepe soles
sulfenamide (neoprene)
2,20 -Dibenzothiazyl disulfide Disinfectants Polyolefin plastics (antioxidant)
Morpholinylmercaptobenzothiazole Food Preservatives (woods, paints,
Thiurams Thiuram mix wrappings lubricating oils, greases, etc.)
Tetramethylthiuram disulfide Fungicides Putty
Tetramethylthiuram monosulfide Germicides Rubber products, especially gloves
Tetraethylthiuram disulfide Insecticides Veterinary soaps and shampoos
Dipentamethylenethiuram disulfide Antioxidants Pesticides
Dithiocarbamates Carba mix Fungicides Rubber products
Zinc diethyldithiocarmate
Zinc dibutyldithiocarbamate
Guanidines Carba mix numerous other consumer products also contain
1,3-Diphenylguanidine
thiurams (Table 6).
Thioureas No
Thiazoles are derivatives of benzothiazole
Amine aldehydes No
a
compounded with sulfenamides. The benzo-
For a more complete listing of the many available accel-
thiazoles include 2-mercaptobenzothiazole
erators, see Rubber World Magazine’s Blue Book (online;
accessed 15 April, 2011) (MBT), dibenzothiazyl disulfide (MBTS), and the
zinc salt of 2-mercaptobenzothiazole (ZMBT).
The sulfenamides are principally N-tert-butyl-2-
of gloves, has declined. Although the ingredients benzothiazyl sulfenamide (TBBS), N-cyclohexyl-
lists for medical gloves suggest that most interna- 2-benzothiazyl sulfenamide (CBS), and morpholi-
tional rubber glove companies have replaced nylmercaptobenzothiazole (MOR). MBT, MBTS,
thiurams with dithiocarbamates (Hansson et al. and CBS are the more widely used. Historically,
2014; Geier et al. 2012), thiurams still remain thiazoles were considered strong sensitizers and
the rubber allergens that most frequently yield were less frequently used in gloves than thiurams
positive patch test results (Aalto-Korte and or dithiocarbamates; however, over the past
Pesonen 2016; Pontén et al. 2013). This is proba- decade, their use in gloves has increased (Adams
bly because thiuram disulfides and dithiocarba- and Warshaw 2006). Furthermore, they are widely
mates constitute a redox pair, i.e., during used in the rubber, as well as other, industries
oxidation of a dithiocarbamate the corresponding (Table 7). Indeed, MBT remains the most widely
thiuram disulfide is formed, during reduction of used accelerator for industrial rubber. Nonetheless,
thiuram disulfide a dithiocarbamate is formed despite their sensitizing capacity, sensitization to
(Hansson et al. 2014). The higher frequency of thiazoles among consumers is less frequent than it
positive patch test reactions to thiurams than to is to thiurams or carbamates (Uter et al. 2009; Zug
dithiocarbamates is consistent with studies show- et al. 2009), perhaps because they are less likely to
ing that thiurams are better markers for sensitiza- “bloom” from rubber than are other accelerators
tion to the dithiocarbamate/thiuram redox pair (Emmett et al. 1994). In this author’s experience,
(Hansson et al. 2014; Aalto-Korte and Pesonen most consumers sensitized to thiazoles are exposed
2016). However, in some studies, the incidence of to the chemical in shoes. Indeed, in their
positive patch test reactions in clinical populations review, Adams and Warshaw (2006) found
has declined (Bhargava et al. 2009; Uter et al. 2-mercaptobenzothiazole to be the most common
2009; Zug et al. 2009). In addition to gloves, sensitizer in patients with shoe dermatitis.
67 Rubber 995
Table 7 Mercaptobenzothiazole: potential exposures Table 8 Carbamates: potential exposures

Adhesives (neoprene- Germicides Antioxidants Pesticides
based) Fungicides Rubber products
Antifreeze Paints
Caustic cleansers Photographic film emulsion
(automotive cooling
addition to being accelerators, thioureas have
systems)
Cutting oils/greases Refrigerants
other uses including as anticorrosives and anti-
Detergents (granulated Rubber products, especially oxidants (Table 9). Important sources of sensiti-
and tablets) tires or other industrial zation to thioureas have been the foam and
rubber items and boots/ impermeable rubbers used in sporting equip-
shoes ment (sport shoes, diving masks, swimming
Fungicides Veterinarian medicaments goggles, wet suits, etc.). In experimental studies,
Waterproof cements/glues
thiourea compounds are classified as weak sen-
sitizers. Recently, it was found that DPTU
was activated to metabolites including
The dithiocarbamates include zinc dibutyl- phenylisothiocyanate and phenylisocyanate,
dithiocarbamate (ZDBC), zinc diethyldithio- which are strong sensitizers (Samuelsson et al.
carbamate (ZDEC), and zinc dimethyldithio- 2011). Although thioureas have a relatively low,
carbamate (ZDMC). In the rubber industry, the and steady, rate of patch test reactivity over time
carbamates are principally used in gloves, condo (Zug et al. 2009), it should be noted that positive
ms, and elastic bands. Due to their chemical simi patch test reactions are frequently relevant
larity with thiurams, especially following metaboli (Anderson 2009).
sm and haptenation (Chipinda et al. 2008), the pot
ential for cross-reactivity between thiurams and 3.4.2 New Allergens
dithiocarbamates exists (Knudsen and Menné New compounds can be formed during vulcani-
1996). Historically, the greatest use of carbamates zation by reactions between thiurams/dithiocarba-
is not in rubber, but in pesticides and fungicides mates and/or mercaptobenzothiazoles
(Table 8). However, in the past decade, the use of (Bergendorff et al. 2007). For example,
dithiocarbamates in gloves, especially nitrile, has i 2-Dimethylthiocarbamyl benzothiazole sulfide
ncreased. Despite this, an increase in the incidence (DMTBS) (CAS no. 3432-25-5) is a newly
of allergic reactions to carbamates has not been o formed component, with proven patch test posi-
bserved (Zug et al. 2009). tivity in relation to rubber (Hansson et al. 2014).
DMTBS was identified as the responsible allergen
3.4.1 Guanidines in a series of 18 young women who developed
The prevalence of positive patch results to allergic contact dermatitis caused by a specific
1,3-diphenylguanidine has been increasing over brand of canvas boat shoes (Hulstaert et al. 2018).
the past few years (Baeck et al. 2013; Pontén
et al. 2013). The analysis of the European Sur-
veillance System on Contact Allergies (ESSCA) 3.5 Antioxidants
data obtained during 2013 to 2014 on rubber
screening allergens showed high prevalence of Although the various rubber accelerators account
sensitization to 1,3-diphenylguanidine (Uter for the vast majority of allergic reactions to rubber
et al. 2016). among consumers, antioxidants are by no means
Thioureas include dibutylthiourea (DBTU), rare causes of sensitivity, especially occupation-
diethylthiourea (DETU), diphenylthiourea ally acquired sensitization. Also referred to as
(DPTU), and ethylene thiourea (ETU). These antidegradants or antiozonants, antioxidants are
chemicals are frequently used, especially in the of great importance in the manufacture of rubber
manufacture of neoprene and foam rubbers. In products since they retard the deterioration of
Table 9 Thioureas: potential exposures Table 10 Antioxidants in natural and synthetic rubber
likely to cause allergic contact hypersensitivity
Adhesives Neoprene and foam rubbers
Anticorrosives Paint/glue remover Allergen(s) present in standard
Antioxidants Pesticides Chemical class patch test series
Cleaning products Photocopy paper Amines
Detergents (acidic) PVC adhesives/tapes 1. Phenylenediamines Black rubber mix
Fungicides Textile elastic N-phenyl- N0 -cyclohexyl-
p-phenylenediamine
Impermeable rubbers Thermoplastic coatings
N-isopropyl- N0 -phenyl-
p-phenylenediamine
N, N0 -diphenyl- p-
rubber by ozone. Thus, antioxidants prolong the phenylenediamine
usefulness of a rubber product by stabilizing the 2. Quinolines No
polymer, inhibiting tears, and preventing brittle- Phenols
ness. Although there are over 100 existing antiox- 1. Hydroquinones No
idants, the most common are derivatives of amines 2. BHT No
Phosphites No
(alkylamines and quinolines), phenols (hydroqui-
nones), and phosphites (Table 10). The most
important from the aspect of sensitization
are the following phenylenediamine derivatives: Table 11 Amine antioxidants: potential exposures
N0 -isopropyl-N0 -phenyl-phenylenediamine (IPPD), Acrylates Industrial and automotive
N-phenyl-N 0 -cyclohexyl-p-phenylenediamine rubbers
(CPPD), N,N0 -diphenyl-p-phenylenediamine Black rubbers Orthopedic bandages
(DPPD), and N-(1,3-dimethylbutyl) -N0 -phenyl- Cutting oils/fluids Rubber cements
Gasoline (inhibitor/
p-phenylenediamine (DMPPD). Of these, CPPD
antiozonant)
and DPPD are more strongly sensitizing than
IPPD (Hervé-Bazin et al. 1977). These
phenylenediamine derivatives are found princi- a much reduced capacity to sensitize. Although
pally in industrial rubbers (Table 11) and in almost the naphthylamines also appear to have low rates
any rubber of black color. Their capacity to sen- of sensitization, they are rarely used in consumer
sitize is very high, and they easily bloom from the goods because they may contain trace amounts of
surface of rubber with heat or friction; nonethe- the carcinogen β-naphthylamine.
less, the incidence of positive patch test reactions
to the phenylenediamine derivatives has been rel-
atively low and has significantly decreased from 4 Incidence
rates 2% among patients tested by the NACDG
in the 1990s (Table 12), most likely due to increas- 4.1 General Population
ing automation in rubber industries.
Another highly sensitizing antioxidant, mono- The incidence of allergic contact dermatitis
benzyl ether of hydroquinone, also causes contact (ACD) to rubber in the general population is dif-
leukoderma (Oliver et al. 1939) and is now rarely ficult to evaluate. Of 274 nondermatologic
used in the manufacture of rubber. In contrast, patients undergoing hip arthroplasty at a Swedish
other antioxidants such as the hydroquinones general hospital, 1.1% had allergic reactions to
(Norris and Storrs 1990), styrenated phenol thiuram mix and carba mix (both accelerators),
(Kaniwa et al. 1994a), dialkylamines (Kaniwa and 0.4% had reactions to black rubber mix (anti-
et al. 1994b), piperidines (Kaniwa et al. 1994b), oxidant) and mercapto mix (accelerator) upon
dihydroquinolines (Hansson 1994), butylhydrox- routine patch testing (Magnusson and Möller
yanisole (Rich et al. 1991), and 4,40 -thiobis(6-tert- 1979). Since these patients were randomly
butyl- m-cresol) (Rich et al. 1991) seemingly have selected as opposed to those referred for patch
67
Rubber
Table 12 Incidence of positive patch test reactions to rubber allergens in the North American contact dermatitis group over the past two decades
Percentage of positive patch test reactions
Test substance 2005–2006a 2003–2004b 2001–2002c 1998–2000d 1996–1998e 1994–1996f 1992–1994g 1985–1989h
Black rubber mix 0.6%/0.1% IPPD 1.0 1.0 1.0 1.0 1.5 2.3 2.1 2.1
Carba mix 3% 3.9 4.0 4.9 4.8 7.3 5.7 4.8 3.1
Dialkyl thioureas 1% 1.0 1.0 0.8 1.1 1.3 0.7 1.1 0.6
Mercapto mix 1% 0.8 0.9 0.7 1.3 1.8 2.2 2.6 2.5
Mercaptobenzothiazole 1% 0.9 1.3 0.9 2.0 1.8 2.1 1.8 2.5
Thiuram mix 1% 3.9 4.6 4.5 4.7 6.9 6.8 7.7 5.5
a
Zug et al. (2009)
b
Warshaw et al. (2008a)
c
Pratt et al. (2004)
d
Marks et al. (2003)
e
Marks et al. (2000)
f
Marks et al. (1995)
g
Marks et al. (1998)
h
Nethercott et al. (1991)
997
testing, the incidence rates of allergic reactions to Of note is the fact that the percentage of
rubber additives in this study are more represen- patients reacting to the thiurams, thiazoles
tative of those in the Swedish population. In Den- (mercaptobenzothiazole and mercapto mix),
mark, a cross-sectional study of the adult and thiocarbamates has declined since their
population in 2006 found the following incidence peak incidences in the mid-1990s, perhaps due
of positive patch test reactions: thiuram mix, to better quality control in the glove industry. In
0.1%; mercapto mix, 0; mercaptobenzothiazole, addition, the incidence of allergic reactions to
0; and black rubber mix 0.1% (Thyssen et al. phenylenediamine derivatives (black rubber
2009); overall, a decline in the incidence of reac- mix), which is often used as a surrogate for
tions was noted when compared to a similar 1990 industrial exposure, has likewise declined, con-
study (Nielsen and Menné 1992). More recently, sistent with increasing automation within the
the prevalence of contact allergy was assessed for rubber industry. Finally, the percentage of
the allergens of the European baseline series in patients reacting to thioureas, which are little
five different European countries in a cross- used in gloves and most frequently are found in
sectional study of an adult population (Diepgen athletic and foam rubbers, seems to be stable.
et al. 2016). The prevalence of positive patch tests
to thiurams was 0.5%, carba mix 0.5%, black
rubber mix 0.4%, MBT 0.2%, and mercapto mix 4.3 Occupational
0.2%. In the United States, no comparable studies
have been done. Due to genetic variations in a Rubber additives are the allergens most strongly
given population, differing exposure patterns associated with occupational contact dermatitis
within a population, or other demographic factors, (Pesonen et al. 2015). The analysis of the patch
the incidence of allergic reactions to the various test results to the allergens in the European base-
chemicals within rubber will likely vary among line series in 44,277 patients with and without
countries. However, after years of steady increase, occupational contact dermatitis was collected
the reported incidence of sensitization to rubber from the European Surveillance System on Con-
may be declining worldwide (Thyssen et al. 2009; tact Allergy (ESSCA) from 2002 to 2010
Uter et al. 2009; Zug et al. 2009). (Pesonen et al. 2015). The association between
suffering from occupational contact dermatitis
and specific contact sensitization was quantified
4.2 Patch Test Populations with prevalence ratios (PRs). Thiurams were the
allergens with the strongest association with occu-
Most available data on incidence rates are gener- pational contact dermatitis, with a prevalence ratio
ated from patients referred for evaluation of of 4,23 (95% CI).
suspected contact dermatitis; thus, the rates as Among individuals with ACD to rubber addi-
they pertain to the general population are over- tives, a significant proportion has acquired the
stated. The analysis of patch tests results with the dermatitis occupationally, although not from
rubber screening allergens included in the base- working in the basic rubber industry. Because of
line series from the European Surveillance Sys- automation and other preventive measures, cases
tem on Contact Allergies (ESSCA) network of sensitization to rubber among workers
obtained during 2013 to 2014 found the follow- manufacturing it are rare (Toeppen-Sprigg
ing rate of sensitization: thiuram mix 2.03%, 1999). Indeed, irritant contact dermatitis, as
carba mix 2.68%, MBT 0.65%, and mercapto- opposed to allergic, is seen more frequently in
mix 0.62% (Uter et al. 2016). In studies by the the rubber industry (Vermeulen et al. 2001). Indi-
North American Contact Dermatitis Group, a viduals most likely to be sensitized to rubber are
significant percentage of North Americans those in other industries who use rubber since
referred for patch testing had allergic reactions rubberized products can release allergens over
to one or more rubber additives tested (Table 12). time. This release or “blooming” of chemicals is
67 Rubber 999
particularly likely with direct skin contact since have the highest incidence of sensitization; how-
sweat and humidity are liberating factors. ever, the responsible allergen will likely vary with
From 1974 to 1983, allergic reactions to the product and country of origin. Finally, it
rubber-related chemicals accounted for 19.9% of should be noted that many health-care workers
all occupational ACD seen in Finland (Estlander will have an endogenous eczema with or without
1990). Similar results have been reported in the ICD and a superimposed ACD, sometimes to two
United Kingdom (McDonald et al. 2006) and or more rubber-related chemicals.
numerous other European countries. In studies Construction workers represent another occu-
performed outside the rubber/tire industry, the pational group with a high incidence of rubber-
principal source of exposure to rubber-related related dermatoses. In their study of 408 construc-
chemicals is gloves. In a retrospective study tion workers, Conde-Salazar et al. (1995) found
(2002–2010) of patients suffering from occupa- that 104 (25.4%) of the workers were sensitized to
tional dermatitis carried out in Germany, 3448 one or more of the rubber mixes on their standard
(24.4%) were tested for suspected glove allergy screening series. Ninety-seven workers (23.7%)
(Geier et al. 2012). Among these, healthcare were allergic to thiuram mix, which ranked
workers represented the largest group second to chromate as a cause of ACD in these
(n = 1058). The allergens most frequently yield- workers. Additionally, 10% of workers (41/408)
ing positive patch test results were were allergic to carba mix, 2.9% (12/408) to
thiurams (13%), dithiocarbamates (3.5%), mercapto mix, and 2.2% (11/408) to black rub-
1,3-diphenylguanidine (3%), mercaptoben- ber mix. In all workers, the source of sensitiza-
ziothiazole and/or its derivatives (3%), and thio- tion was either gloves and/or boots used for
ureas (0.4%). When comparing their results with personal protection (Conde-Salazar et al.
those from 1995 to 2001, the authors concluded 1995). However, when the results of this study
that the situation has remained unchanged. were contrasted with earlier studies by the same
Workers most likely to develop glove dermatitis authors, the incidence of rubber allergies among
are those engaged in following industries: health/ construction workers was noted to have
laboratory, cosmetology, construction, food, flo- decreased dramatically, which these authors
ral/agricultural, and/or homemaking activities ascribed to better working practices in the con-
(McDonald et al. 2006). However, non- struction industry and to better manufacturing
occupational exposure to items such as condoms, standards in the rubber industry (Conde-Salazar
shoes, boots, elasticized garments, belts, and et al. 1995).
watchbands are also important sources for the Rubber industry workers are another obvious
development of ACD to rubber. high-risk group for rubber-related dermatoses.
Health-care professionals have among the The annual risk of allergic plus irritant dermatitis
highest rates of sensitization to rubber (Warshaw among these workers ranges from 0.31% in Brit-
et al. 2008b). Thus, although irritant contact der- ain (Calnan 1978) to 0.56% in Finland (Kilpikari
matitis is the most likely cause of hand dermatitis 1982). The only available data from the United
in health-care workers, a significant percentage of States state a risk of 0.7% for Californian workers,
these individuals will have allergic contact derma- but this number includes individuals in the plas-
titis to chemicals found in rubber. In recent epide- tics industry as well (Baginsky 1979). The appar-
miological studies, healthcare workers have high ently lower risk of developing ACD among
prevalence of positive patch tests to rubber accel- workers in basic rubber industries relates in part
erators. Delayed-type hypersensitivity to thiuram to the reporting of risk as an annual rate rather
mix is significantly associated with healthcare than as the total percentage of workers with occu-
work (OR of 1.60 (1.10–2.30)) (Schwensen et al. pationally related dermatitis. In addition, increas-
2016) and affects 5–12% of healthcare workers ing automation within the rubber industry
(Molin et al. 2015; Ibler et al. 2016; Kadivar and minimizes direct physical contact with the aller-
Belsito 2015). In general, thiuram derivatives gens and, hence, reduces sensitization rates
(Toeppen-Sprigg 1999; Vermeulen et al. 2000). Table 13 Latex compounding materialsa

Again, an important difference between ACD in Antiblocking agents Gelling agents
rubber workers and that among other workers is Antifoaming agents Preservatives
the high percentage of ACD due to amine antiox- Antiwebbing agents Stabilizers and emulsifiers
idants (e.g., p-phenylenediamine derivatives) in Coagulants Stabilizers and reducers:
the former (Kilpikari 1982). In a 5-year Finnish Thickening/viscosity
study of rubber workers, 15 out of 21 (71.4%) Creaming agents Wetting agents
cases of occupationally related ACD were due to Dispersing agents
a
a component of black rubber mix (Kilpikari Rubber World Magazine’s Blue Book (online; accessed
15 April 2011)
1982). In addition, 2-mercaptobenzothiazole and
carbamates also have relatively high sensitization
rates in this industry (Nethercott 1982; Vestey ICD is also common among rubber factory
et al. 1986). workers (Kilpikari 1982). The most common
irritants are the alkalis, solvents, activators
(e.g., stearic acid and other fatty acids), soaps,
5 Skin Disease in Rubber Workers and the various dusting/dipping/washing mate-
rials (e.g., calcium carbonate, calcium stearate)
5.1 Contact Urticaria encountered in the workplace (Fig. 1). Mechan-
ical friction is another important source of
Dermatitis among rubber plantation workers who irritation.
harvest latex has been little studied. These workers
collect the latex sap from the trees, which is stored
in collection vats containing ammonia, and is then 5.3 Allergic Contact Dermatitis
strained to remove foreign matter. Chaiear et al.
(2001) found that 1.3% of Thai latex tappers were When seen, occupational ACD is more frequent in
latex sensitive by prick testing, compared with those manufacturing finished rubber goods than in
1.7% of latex glove factory workers. Of note, the those harvesting and processing latex since the
factory workers were exposed to higher ambient air
concentrations of latex than were the tappers.
5.2 Irritant Contact Dermatitis
Following its harvest, some of the latex resin is

centrifuged and preserved in a liquid form for pro-
duction of such rubber goods as gloves, condoms,
and medical devices. This liquid latex is treated with
various chemicals which, with the exception of the
preservatives, rarely cause ACD (Table 13). The
majority of latex sap is weighed, concentrated
approximately 70%, and coagulated by the addition
of formic acid, acetic acid, or sodium silicofluoride.
The coagulated mass is then pressed between rollers Fig. 1 The hands of a typical rubber worker are frequently
to form slabs or sheets, which are smoked for contaminated with the various chemicals encountered in the
workplace. The solvents and cleansing agents used to
1–2 weeks. These slabs are bundled into bales remove the accumulated grime are a frequent cause of
which contain approximately 90% rubber hydrocar- irritant contact dermatitis. (Reproduced with the permission
bons. Given their exposure, workers processing of Donald V. Belsito, M.D., Department of Dermatology,
baled rubber are more likely to suffer ICD. Columbia University Medical Center, New York, NY)
67 Rubber 1001
sheets of rubber or to ply rubber to other materials),

the extruders (devices which produce lengths of
rubber with specific cross-sectional characteris-
tics), and the molding machines, are also at some
risk, as are those workers involved in packing and
shipping the final product.
Derivatives of PPD, which are extensively used
in Europe and the United States, are the main sensi-
tizers among rubber workers today (Kilpikari 1982).
Other causes of ACD in the rubber industry
(Brandão 1990; Kanerva et al. 1996) have included
the plasticizers (dialkyl phthalates), the peptizers
(tricresyl phosphate), the blowing agents (e.g., N,
N0 -pentamethylenetetramine and other amines
which release nitrogen gas when heated), and the
retarders (e.g., N-(cyclohexylthio)phthalimide).
Finally, ACD can rarely arise from contaminants,
for example, dinitrochlorobenzene (DNCB) con-
tamination of mercaptobenzothiazole, which caused
an epidemic in an Italian factory where, of
204 exposed workers, 42 had positive reactions to
the DNCB (Zina et al. 1987).
5.4 Other Occupational Diseases

Fig. 2 Despite widespread automation in the rubber
industry, certain workers are at an increased risk of becom- Curious skin reactions can occasionally be seen
ing sensitized to rubber additives. Chief among these are among rubber workers. Plotnick and Birming-
the workers who weigh the various ingredients (a) and
skilled laborers involved in the fabrication of tires (b). ham (1993) reported an epidemic of pronounced
(Photographs courtesy of Dr. Robert Adams, San Mateo, facial flushing, typically appearing after lunch,
CA (a), and Dr. Armando Ancona, Department of Derma- among 10 of 20 Banbury mixers. Patch testing to
tology, National Medical Center, Mexico City, Mexico (b), an expanded rubber tray was completely nega-
and published with their permission)
tive. The cause was tetramethylthiuram disulfide
used as the accelerator together with alcohol
major delayed-type allergens are found among the consumed at lunch. It was surmised that when
chemicals subsequently added to natural and syn- sweat tainted with alcohol contacted the airborne
thetic rubbers. Nonetheless, ACD is rare in the accelerator, a localized disulfiram-like reaction
rubber industry due to automation in most aspects occurred.
of manufacturing. Among rubber workers, those The respiratory tract accounts for the greatest
who weigh the various ingredients which are added amount of occupational disease seen in rubber
to precut chunks of natural or synthetic rubber in workers after the skin (Lewis 1999). In a study of
large mixers (Banbury mixers) and skilled laborers 17 females in a latex manufacturing plant, 5.9%
involved in the fabrication of tires (which require had occupational asthma (CU to latex) and
that layers be gradually built from the inner liner to 58.8% had dyspnea grades 3–4 (Zuskin et al.
the outer tread) are most likely to develop allergic 1998). Other respiratory tract symptoms in
sensitization (Fig. 2). Other workers (Fig. 3), such these workers included nasal dryness (70.6%),
as those operating the Banbury mixers, the calen- burning throat (70.6%), and cough (58.8%). In
ders (two or more steel drums used to produce another study (Tarlo et al. 1990), 7/50 (14%)
Fig. 3 Workers involved in mixing (a), calendering (b), (Photographs courtesy of Dr. Robert Adams, San Mateo,
and extruding (c) rubber are also at risk of acquiring CA, and published with his permission)
allergic and/or irritant occupational contact dermatitis.
workers in a latex glove manufacturing plant Although many studies on the rubber industry
who underwent work shift spirometry had have been published during the last few decades, it
changes consistent with asthma and 2/7 had has seldom been possible to link the identified can-
ACU to latex. Of note, overall, 7/64 (11%) cer risks to any specific chemical substance or task.
workers undergoing prick testing had positive This is likely related to the complex exposures that
responses to latex, although the authors did not workers experience. The rubber industry is associ-
specify whether these workers experienced skin ated with the highest documented occupational
disease (Tarlo et al. 1990). exposure to nitrosamines and a significant associa-
Many types of cancers are found with tion between this agent and cancer of the oral cavity,
increased incidence among rubber workers. In pharynx, and esophagus in rubber workers has been
1982, the International Agency on Research on reported (Straif et al. 2000b). Exposure to benzene
Cancer (IARC) concluded that work in the rubber and other solvents, during the manufacturing of
industry entails a carcinogenic risk (IARC 1987). rubber tires, has been associated with the risk of
The increase in cancers included bladder, hema- leukemia in these workers (Kogevinas et al. 1998;
topoietic, laryngeal, pleural, and lung (Weiland Lewis 1999; Li and Yu 2002). Also, the monomer
et al. 1996; Ward et al. 1997; Kogevinas et al. 1,3-butadiene alone or in combination with styrene
1998). The findings of associations to cancer of has been associated with leukemia risk among syn-
the skin, prostate, pharynx, esophagus, stomach, thetic rubber workers (Delzell et al. 2001; Graff et al.
colon, liver, pancreas, kidney, brain, and the endo- 2005). Significant levels of butadiene (0.06–39 ppm
crine system were less consistent (Bourguet et al. (IARC 1986)) and styrene (2.4 ppm (WHO 1983))
1987; Solionova and Smulevich 1993; Kogevinas can be found in factories where these synthetic
et al. 1998; Stewart et al. 1999; Li and Yu 2000; rubbers are produced; however, due to automation
Straif et al. 2000a; Borak et al. 2005). and safety precautions, workers are not routinely
67 Rubber 1003
exposed to significant levels (Fajen et al. 1990). Table 14 Commercially available rubber additivesa
Korinth et al. (2008) reported that cutaneous absorp- Allergen Conc/vehb
tion of other aromatic amines (aniline and o-tolui- Tetramethylthiuram disulfide (TMTD) 0.25% or
dine) used in the rubber industry was reduced by use 1.0% pet b
of gloves and certain moisturizers; however, the skin Tetramethylthiuram monosulfide 0.25% or
barrier creams used actually increased absorption (TMTM) 1.0% pet
Tetraethylthiuram disulfide (TETD) 0.25% or
(Korinth et al. 2007).
1.0% pet
Other carcinogens in the rubber industry may be Dipentamethylenethiuram disulfide 1.0% pet
present in minimal concentrations as either contam- (PTD)
inants of the raw materials or newly formed com- Dipentamethylenethiuram tetrasulfide 0.25% pet
pounds due to uncontrolled reactions during N-Cyclohexyl- N-phenyl-4- 1.0% pet
manufacturing; for example, n-nitrosamines can be phenylenediamine (CPPD)
found in parts per billion (ppb) quantities in some N, N0 -Diphenyl-4-phenylenediamine 1.0% pet
(DPPD)
accelerators of vulcanization. Disulfiram, a thiuram,
N-Isopropyl- N-phenyl-4- 0.1% pet
is much more controversial since, in experimental phenylenediamine (IPPD)
studies, it has been identified as a potentiator of 2-Mercaptobenzothiazole (MBT) 2.0% pet
carcinogenesis. Rats, exposed simultaneously to N-Cyclohexyl-2- 1.0% pet
ethylene dibromide and to disulfiram in the diet, benzothiazylsulfenamide (CBS)
had a tenfold increase in the incidence of hepatocel- Dibenzothiazyl disulfide (MBTS) 1.0% pet
lular carcinoma as compared to animals exposed 2-(4-Morpholinylmercapto) 0.5% or 1.0%
only to ethylene dibromide (Plotnick 1978). benzothiazole (MOR) pet
Diphenylguanidine (DPG) 1.0% pet
Zinc diethyldithiocarbamate (ZDEC) 1.0% pet
Zinc dibutyldithiocarbamate (ZDBC) 1.0% pet
6 Occupational Skin Disease N, N0 -di-β-naphthyl-4- 1.0% pet
Outside the Rubber Industry phenylenediamine
N-Phenyl-2-naphthylamine (PBN) 1.0% pet
6.1 Allergic Contact Dermatitis Hexamethylenetetramine 1.0% or 2.0%
pet
In some workers outside the rubber industry, the Diaminodiphenylmethane 0.5% pet
sources of sensitization are the same raw ingredi- Diphenylthiourea (DPTU) 1.0% pet
ents to which workers in the rubber industry are Zinc dimethyldithiocarbamate 1.0% pet
(ZDMC)
exposed, for example, the carbamate-based pesti-
Zinc dibenzyldithiocarbamate 1.0% pet
cides among agricultural workers. However, for
Monobenzyl ether of hydroquinone 1.0% pet
most workers, the sources of sensitization are the 2,20 ,4-Trimethyl-1,2-dihydroquinoline 1.0% pet
protective barriers (such as gloves, boots, and Diethylthiourea (DETU) 1.0% pet
masks) used to avoid other sensitizers and irri- Dibutylthiourea (DBTU) 1.0% pet
tants. As a result, sensitization to components of Dodecylmercaptan 0.1% pet
rubber cannot only be the direct cause of acute N-(cyclohexylthio)phthalimide 0.5% or 1%
dermatitis, but can also aggravate an existing pet
allergic or nonallergic eczema. When it coexists 4,40 Dihydroxybiphenyl 0.1% pet
with another dermatitis, ACD to rubber can be 4-Tert-butylcatechol 0.25% pet
difficult to diagnose and may be suspected only 2-Mercaptobenzimidazole 1% pet
after patch testing. The components of rubber Dibutyl phthalate 5% pet
a
commercially available for patch testing are Allergens available from Chemotechnique Diagnostics
AB, Malmö, Sweden; Almirall Hermal GmbH, Reinbek,
detailed in Table 14. It should be noted that use
Germany; and/or Smart Practice Canada, Calgary, AB,
of the dye p-phenylenediamine (PPD), present on Canada
b
most standard screening trays, is not an adequate Conc concentration, veh vehicle, pet petrolatum
screen for allergy to the “black rubber” antioxi- thus, can simulate atopy. Such disease patterns may
dants. In one study, all IPPD-sensitive patients result from indirect manual transfer of the allergen
reacted to CPPD, but only 37% cross-reacted or from multiple different sources of exposure to
with PPD (Hervé-Bazin et al. 1977). the allergen. In addition, the possibility of airborne
The appearance of ACD to rubber depends contact dermatitis (Dooms-Goossens et al. 1986) or
upon the chronicity and the area affected. The systemic contact dermatitis due to ingestion of
most frequently encountered clinical picture is
eczema. The amine antioxidants, especially
IPPD, are strong sensitizers and cause acute,
severe eczemas. In contrast, dermatitis caused by
the accelerators tends to be a more subacute to
chronic-appearing eczema (Fig. 4). In addition to
an eczematous dermatitis, ACD to rubber
can present as hyperkeratosis, purpura, achromia,
urticaria, or other, less frequently observed, clin-
ical manifestations. The primary reason for such
differing forms of cutaneous disease is the multi-
tude of different allergens typically present in
rubber compounds. Fig. 5 Allergic contact dermatitis to a rubber glove. A
ACD to rubber may be sharply demarcated, middle-aged male machinist presented with a many
giving a clear indication of the object or garment months’ history of a pruritic dermatitis of the dorsal
causing the dermatitis (Figs. 5 and 6). Allergic hands that had most recently been complicated by second-
ary bacterial impetigo (right index finger). Note the
reactions to rubber can also appear scattered demarcation at the wrists. Patch testing revealed allergic
over the body including the eyebrows, genitalia, reactions to thiuram mix, mercapto mix, and
face, and/or flexual areas of the arms and legs and, 2-mercaptobenzothiazole. His dermatitis cleared with the
use of nitrile gloves containing carbamate accelerators.
(Reproduced with the permission of Donald V. Belsito,
M.D., Department of Dermatology, Columbia University
Medical Center, New York, NY)
Fig. 4 Subacute ACD of the dorsal foot in an athletic

director allergic to several thioureas and to
2-mercaptobenzothiazole. Although the manufacturer
declined to verify the components of these shoes, patch
tests to rubber portions of the “box” of the shoe were
positive. Thioureas, which are frequently present in rubber Fig. 6 Pulpitis induced by an allergy to
manufactured for use in sporting equipment and clothes, 2-mercaptobenzothiazole present in rubber finger cots uti-
were probably the more relevant allergens. (Reproduced lized by this 52-year-old legal secretary. (Reproduced with
with the permission of Donald V. Belsito, M.D., Depart- the permission of Donald V. Belsito, M.D., Department of
ment of Dermatology, Columbia University Medical Cen- Dermatology, Columbia University Medical Center,
ter, New York, NY) New York, NY)
67 Rubber 1005
rubber accelerators which have migrated into food

substances stored in rubber containers (Stankevich
et al. 1980) should also be considered.
“Bleached rubber syndrome” is an interesting
allergic reaction to rubber accelerators. Although
the eczematous appearance of the eruption
strongly implicates its allergic cause, all standard
patch tests are negative. Patch testing with a piece
of the elasticized rubber from the offending
bleached garment will, however, yield a positive
reaction. The allergen is N, N0 -dibenzylcarbamyl
chloride which is produced by the effect of
chlorine bleach on zinc dibenzyldithiocarbamate
(Jordan and Bourlas 1975).
“Pompholyx” or dyshidrotic-like eczema due to
rubber allergies is found in bank employees and
other workers with frequent exposure to rubber
bands. The dermatitis principally affects the Fig. 7 ACD to black rubber in a work boot. Note the
dorsolateral aspects of the digits of the dominant hyperkeratotic scaling dermatitis most pronounced over
hand. The chief sensitizers are thiurams and thia- the metatarsal area and tips of the toes. This pattern,
together with sparing of the interdigital webs, the toe
zoles (Conde-Salazar 1990). creases, and the arch of the foot should suggest the diag-
Hyperkeratotic lesions due to rubber appear nosis. Patch tests were positive to IPPD and black rubber
mainly over the palmar and plantar surfaces mix. (Reproduced with the permission of Donald
and initially start as dryness with minimal V. Belsito, M.D., Department of Dermatology, Columbia
University Medical Center, New York, NY)
scaling. With continued cutaneous contact to
the allergen, the process intensifies, and hyper-
keratotic fissures, simulating psoriasis and/or Nowadays, such reactions are rare since deriva-
mycotic disease, develop (Fig. 7). At times, it tives of hydroquinone are seldom used as antiox-
can be difficult to differentiate between these idants in rubber, although they are still extensively
diseases, and patch tests can be diagnostic. An used in the photographic industry. Nonetheless,
important characteristic of allergic reactions is one occasionally sees a confetti-like hypo-
the relatively rapid improvement when the pigmentation over the dorsal hands and forearms
patient stops using the offending object. in individuals with glove allergies (Fig. 8).
Although palmoplantar hyperkeratosis could Whether this is due to chemical leukoderma or
be attributable to the effects of any allergen postinflammatory hypopigmentation following
on the thick horny layer of the palms and/or the allergy is often unclear.
soles, it is more frequently seen in people Purpuric reactions to rubber were first
allergic to the amine antioxidants, where it described by Fisher (1974). He called the syn-
has been termed “black rubber hands/feet” drome PPPP since it was characterized by the
(Conde-Salazar 1990). appearance of purpura, petechiae, and pruritus
Leukoderma from rubber products is largely (Fig. 9). Lesions localize to the area in contact
due to hydroquinone and its derivatives. These with the rubber object. The causative factor is the
chemicals were previously used in the rubber amine antioxidant IPPD as demonstrated by a
industry as antioxidants and stabilizers. The first positive patch test which, in some cases, may
cases of occupational leukoderma were caused by also be purpuric. Thiuram derivatives have also
monobenzylether of hydroquinone and were been reported to induce purpuric ACD (Burrows
described by Oliver et al. (1939). Mono- 1972).
benzylether of hydroquinone not only caused Other clinical forms of allergic reactions to
leukoderma but also an intense allergy. rubber have also been described, albeit rarely.
Fig. 8 Hypopigmentation of the dorsal hand believed to Fig. 9 Purpuric ACD in a worker who used an abdominal
be due to an allergic reaction to hydroquinone. Note the waistband lined with black rubber for treatment of an
patchy involvement which, in some areas, is almost abdominal hernia. Note the purpuric maculopapular erup-
confetti-like. The patient was found to be allergic to the tion of the lower back which was extremely pruritic. Patch
offending glove and to only hydroquinone on an expanded testing with black rubber mix induced an eczematous,
rubber tray. The manufacturer would not verify the glove’s nonpurpuric reaction. (Reproduced with the permission
components. (Reproduced with the permission of Donald of Donald Belsito, M.D., Department of Dermatology,
V. Belsito, M.D., Department of Dermatology, Columbia Columbia University Medical Center, New York, NY)
University Medical Center, New York, NY)
6.2 Irritant Contact Dermatitis
Calnan (1971) described lichenoid contact der-
matitis produced by IPPD. Pecegueiro and ICD is common among rubber workers where it is
Brandão (1984) have reported plantar pustulosis usually due to irritant solvents and cleansers
due to MBT and its derivatives. Dooms- unrelated to rubber (Kilpikari 1982). In contrast,
Goossens et al. (1985) described a pustular reac- ACD is the norm among users of rubber products.
tion from hexafluorosilicate, a component used Nonetheless, powder in gloves and the trapping of
in the manufacture of foam rubber. Eun et al. sweat within gloves are not unusual causes of irritant
(1985) described an epidemic of pitted hand dermatitis from gloves (Heese et al. 1991).
keratolysis in building workers using rubber
boots. Cases of erythema multiforme caused by
allergy to IPPD present in a black rubber watch- 6.3 Allergic Contact Urticaria
band (Foussereau et al. 1988) and to natural
rubber latex in gloves (Bourrain et al. 1996) Immunoglobulin (Ig) E–mediated ACU to latex
have been described. Finally, pyoderma previously accounted for significant morbidity
gangrenosum from antioxidants and accelerants among HCWs and non-health-care workers, espe-
in a stomal bag has also been reported (Lenane cially food handlers, construction workers, pain-
et al. 1998). ters, hairdressers, and janitorial workers (Valks
67 Rubber 1007
et al. 2004). However, the incidence of ACU to 4-phenylenediamine, and cyclohexyl thi-
latex has declined dramatically during the past ophthalimide. Testing patient’s own gloves “as
decade due to the use of nonlatex alternatives is” on both sides is also recommended. A “sup-
and to manufacturing practices that significantly plementary rubber series” containing 6 allergens
remove the offending protein allergens, especially of less proven importance, requiring further anal-
hev b 6.02 and hev b5 in latex gloves (Allmers ysis, is also suggested for departments specializ-
et al. 2004; Reunala et al. 2004; Clayton and ing in occupational contact allergy. The following
Wilkinson 2005; Filon and Radman 2006). In allergens are included: N-phenyl-2-naphthyl-
addition to these allergens in latex, hev b2, hev amine, 4,40 -diaminodiphenylmethane, methena-
b6.01, and hev b13 have produced positive reac- mine, cetylpyridinium chloride, ethylenediamine
tions in a significant proportion of latex allergic dihydrochloride, and 4-tert-butylcatechol.
individuals (Reunala et al. 2004). In some countries, carba-mix is included. It
contains three ingredients, 2 carbamates, i.e.,
diethyldithiocarbamate (ZDEC) and zinc
7 Diagnosis dibutyldithiocarbamate (ZDBC), and a guanidine,
i.e., 1,3-Diphenylguanidine. To avoid confusion
The only useful and reliable method for the diag- in the up-to-date “European rubber series,” the
nosis of ACD remains the patch test. In recogni- authors recommend to patch test with DPG and
tion of the significant number of individuals ZDEC separately instead of the carba mix
allergic to rubber-related chemicals, many stan- (Warburton et al. 2017).
dard screening series contain four rubber-related Given the vast number of additives in a given
mixes: carba, thiuram, mercapto, and black rub- rubber product, such as a glove (Rose et al. 2009),
ber, which together contain 14 rubber additives. dermatologists interested in fully evaluating at
The European baseline series contain the follow- least some patients with ACD to rubber must be
ing rubber additives, namely, thiuram mix 1% prepared to perform tests with the patient’s own
pet., 2-mercaptobenzothiazole (MBT) 2% pet., materials. In so doing, pieces of the suspected
mercapto mix (with four constituents, including materials should be cut out to conform to the
MBT) 2% pet., and N-isopropyl-N-phenyl-p- size of the patch; it is frequently helpful to soak
phenylenediamine (IPPD) 0.1% pet. the material in water for 15 min prior to testing.
In all patients with suspected contact allergy Alternatively, one may elect to use ultrasonic bath
to rubber, a specific rubber series is extracts of the suspected rubber product to
recommended (Warburton et al. 2017). An up-to- improve the yield of patch testing (Bruze et al.
date “European rubber series” has been suggested 1992). Patients unreactive to the rubber allergens
including 19 allergens of proven importance on the standard tray who react to their own prod-
with the exclusion of substances of historical uct will often require testing to an expanded rub-
concern (Warburton et al. 2017). The following ber series either obtained commercially (Table 14)
allergens are included: tetramethylthiuram or privately. For physicians compounding their
disulfide, tetramethylthiuram monosulfide, tetra- own allergens, texts detailing appropriate concen-
ethylthiuram disulfide, dipentamethylenethiuram trations and vehicles are available (de Groot
disulfide, zinc dibutyldithiocarbamate, zinc 1994).
diethyldithiocarbamate, 1,3-diphenylguanidine, Finally, as noted by Usmani and Wilkinson
2-mercaptobenzothiazole (as part of the baseline (2007), it is frequently necessary to perform both
series), N-cyclohexyl-2-benzothiazyl sulfenamide, patch and prick testing in rubber-sensitized
dibenzothiazyl disulfide, morpholinylmercapto- patients to fully evaluate their rash. In their
benzothiazole, dibutylthiourea, diphenylthiourea, study, while 9/106 health-care workers referred
diethylthiourea, N-isopropyl-N-phenyl-4-pheny- for prick testing to rule out ACU to latex were
lenediamine (as part of the baseline series), prick test positive, 50 of the 106 had relevant
N-cyclohexyl-N-phenyl-4-phenylenediamine, N,N0 - positive patch tests. These authors recommend
diphenyl-p-phenylenediamine, N,N-di-2-naphthyl- that patients with suspected allergic skin disease
be investigated for both immediate- and delayed- developed accelerator-free polychloroprene

type hypersensitivity when warranted. This is par- gloves such as Ansell (Gammex ® Non-Latex Sen-
ticularly the case for those patients with atopic sitive, GAMMEX ® Non-Latex), Mölnlycke
eczema, suspected rubber allergy, and occupa- Health Care (Biogel ® NeoDerm), and Adventa
tional hand dermatitis. Health (Nuzone ® Advance). In case of nitrile,
the traditional vulcanization rubber is carried out
with sulfur cross-links. It is also possible to use an
8 Treatment and Prevention improved version called Carboxylated Nitrile
Rubber (XNBR). Zinc oxide (ZnO) is again used
The treatment of ACD lies in correctly identifying as vulcanization agent. The cross-link is then
its cause and in properly instructing the patient in made via an ionic bond involving zinc cation
avoidance of the responsible allergen(s). However, it (Zn2+), brought by ZnO. This new process avoids
can be difficult to offer adequate advice for avoiding the use of the sulfur-accelerator complex. Several
a product like rubber, which is widely used in many manufacturers developed accelerator-free nitrile
different substances and which is rarely labeled as to gloves such as Ansell (MICRO-TOUCH ® Nitrile
its chemical composition. The problem is more seri- accelerator-free), Sempermed (SemperSure ®
ous since the chemical composition of a given rub- nitrile), and Adventa Health (Nugard ® Spextra).
ber product can change from lot to lot. Thus, the A new rubber manufacturing process due to photo
same brand of rubber gloves can contain different cross-linking has been developed and patented by
chemical constituents. Furthermore, patients must Semperit ®. This sophisticated production process,
be warned that the term “hypoallergenic” when different from vulcanization, does not require ele-
applied to a rubber article is meaningless unless mentary sulfur and rubber accelerators. Gloves
they know the actual ingredients. based on this technology are marketed under the
In case of thiurams contact allergy, prevention brand name Sempermed ® Syntegra UV surgical
is based on avoidance of contact with the dithio- gloves. Raw materials for this glove are synthetic
carbamate/thiuram redox pair by use of isoprene, photoinitiator, crosslinker, and antioxi-
accelerator-free gloves. It is now possible to man- dant. They are mixed and irradiated with UV light.
ufacture accelerator-free medical gloves (Crepy During the irradiation, the polymer chains (Poly-
2016, 2018). Recently the European Standard on isoprene) are cross-linked. This reaction is very
medical gloves for single use, EN 455–3, was fast. Therefore, no accelerators are needed. Other
updated and the following passage was added to specific synthetic rubbers known as styrenic block
subclause 4.2 “chemicals”: “Manufacturers may copolymers (SBC) can organize themselves in the
only declare the absence of a substance if the form of elastic films with adequate physical and
substance is not used in any part of the mechanical properties without the use of any
manufacturing process.” This implies that “chemical crosslinking,” therefore without the
accelerator-free medical gloves available on the use of any accelerators. For example, Finessis
European market may only be labeled as such if in Corium ® and Finessis Zero® surgical gloves
no part of the manufacturing process accelerators have been developed and patented by Adventa
are used. To manufacture rubber accelerator-free Health. Finessis Aegis ® is also an accelerator-
gloves, particularly medical single-use gloves, free surgical glove developed by Adventa Health,
different base materials can be used such as poly- but it contains in its core a disinfecting liquid.
chloroprene, nitrile, polyisoprene, and styrenic Table 15 is a partial list of accelerator-free
block copolymers (SBC). While the traditional medical gloves.
vulcanization of polychloroprene rubber For many of the patient’s needs, a variety of
(CR rubber) is carried out with sulfur cross-links substitute plastic materials are available. When
and accelerators, it is also possible to use zinc in doubt, the patient can contact the manufacturer
oxide (ZnO) as vulcanization agent. In this pro- who may be able to supply information. Guid-
cess, the presence of the sulfur-accelerator com- ance is generally needed in selecting the
plex is not needed. Several manufacturers following:
67 Rubber 1009
Table 15 A partial listing of available accelerator-free medical gloves

Use Brand Material Manufacturer
Surgical gloves GAMMEX ® Non-Latex Sensitive Polychloroprene Ansell
GAMMEX ® Non-Latex (previously Polychloroprene Ansell
GAMMEX ® PF DermaPrene)
GAMMEX ® Non-Latex Underglove Polychloroprene Ansell
Biogel ® NeoDerm Polychloroprene Mölnlycke
Health Care
Nuzone ® Advance Polychloroprene Adventa Health
Sempermed ® Syntegra UV Polyisoprene Semperit
Finessis ZERO ® Styrenic block Adventa Health
Finessis CORIUM ® copolymers (SBC)
Finessis Aegis ®
Single-use MICRO-TOUCH ® Nitrile accelerator-free Nitrile Ansell
examination gloves SemperSure® Nitrile Nitrile Semperit
Nugard ® Spextra Nitrile Adventa Health
Adapted from Crepy et al. (2018)
Table 16 A partial listing of available gloves and their ingredientsa

Componentsb
Brand name Polymer MBT TH CAR TU Powder
Sterile Surgical
Encorec Latex +
Pristine 2d Latex + +
Safeskin Sterile Criticale Latex +
Derma Prene Ultra PFc Neoprene
Neolon 2Gf Neoprene +
NitriSkin Plus PFg Nitrile +
Nonsterile Exam
Micro-Touch Plusc Latex +
Micro-Touch NitroFreec Nitrile
Safeskin vinyle Polyvinyl chloride
Curad 3G vinylf Polyvinyl chloride
Household
Bluetteh Neoprene +
Allerderm vinyli Polyvinyl chloride
Industrial
Ultimate N-Dexj Nitrile +
Monkey Gripc Polyvinyl chloride
Silver Shield/4H Glovesk Polyethylene
TH tetramethylthiurams and related thiurams, CAR carbamates, TU thioureas
a
The accuracy of components was verified in April 2011. The components of individual brands may have changed since
then
b
MBT: 2-mercaptobenzothiazole and related thiazoles
c
Ansell Healthcare: http://www.ansellhealthcare.com/temps/products/surgical/index.cfm
d
World Medical Supply. Telephone: 1-800-756-9146
e
Kimberly Clark. Telephone: 1-800-524-3577
f
Medline Industries, Inc. Telephone: 1-800-633-5463
g
Medgluv, Inc. Telephone: 1-954-202-7880
h
Spontex, Inc., Telephone: 1-931-388-5632
i
Allerderm. Telephone: 1-800-365-6868
j
Best Co. Telephone: 1-800-241-0323
k
North Safety Products, Inc. Telephone: 1-800-430-4110 [USA] or 31-118-656400 [Netherlands]
Gloves are available for individuals reacting to Table 17 Manufacturers of specialty shoes
the various allergens in latex and nonlatex rubber. Company Shoe types
Table 16 is a partial list which should be sufficient The Cordwainer Shop Men’s and women’s dress
for most patients. A more detailed listing can be P.O. Box 110 shoes and sandals
found elsewhere (American Contact Dermatitis Deerfield, NH 03037
Tel. No.: 603-463-
Society’s Database 2011). Of note, Proksch et al. 7742
(2009) have reported that allergy to household http://www.
gloves is rare, presumably due to short intermit- cordwainershop.com/
tent use, the loose fit, and the incorporation of shoes.php
inner cotton liners. P.W. Minor & Son, Limited men’s and women’s
Inc. dress shoes, men’s work
Shoes present a particular problem since P.O. Box 678 boots, and limited men’s and
tracking the individual ingredients of commer- Batavia, NY 14021- women’s athletic shoes
cially available shoes is rarely successful. Over- 0678
all, rubber ingredients are the most frequent Tel. No.: 1-800-333-
4067
cause of shoe dermatitis (Warshaw et al. 2007). http://www.pwminor.
Fortunately, specialty shoe manufacturers can com/Products/
customize shoes (Table 17). Although expen- Loveless Orthopedic Men’s dress shoes and
sive, custom-made shoes are the easiest way to Appliance women’s dress flats (no heels)
4400 SW 21 St. and men’s and women’s
avoid relevant allergens. Alternatively, one can
Oklahoma City, OK Western-style and hunting
patch test to all components of a patient’s 73108 boots
existing shoes, and if negative, have the patient Tel. No.: 1-405-631-
“use test” only this pair for a period of several 9731
http://www.
weeks. Assuming the “use test” is negative, then
lovelessboots.com/
the shoe is presumptively free of relevant aller- Birkenstock Sandals Sandal-style shoe in leather
gens. Although not guaranteed, by purchasing http://www. with cork inner sole. No
the same make and model of shoe in the future, birkenstock.com rubber products. Bard glues
the patient may be able to avoid recurrent derma- ONGUARD Industries PVC work boot with steel toe
titis. Patients with persistent dermatitis despite 1850 Clark Rd.
Havre de Grace, MD
avoidance of allergen in their shoes should be 21078
advised to purchase new socks since at least one Tel. No.: 1-410-272-
investigator has found that, even when thor- 2000; 1-800-365-2282
oughly washed, socks can harbor the allergens http://www.
onguardindustries.com
(Rietschel 1984).
Medical devices pose a particular problem for
rubber-allergic individuals. Guidance in choosing latex in hospital and home environments and
contraceptive devices is especially needed; also offers acceptable nonlatex alternatives
Table 18 lists some alternatives for these patients. (http://www.spinabifidaassociation.org/atf/cf/%
These individuals must also warn physicians/den- 7bEED435C8-F1A0-4A16-B4D8-A713BBCD9
tists against performing examinations with gloves CE4%7d/LatexList09.pdf).
to which they might react. Finally, there are a vast To lessen sensitization to rubber and its addi-
number of other medical devices containing rub- tives, attempts have been made to substitute or
ber which patients, especially those with ACU to lower the concentration of some of the more
latex, need to avoid. More complete listings of allergenic chemicals used in the production of
these devices can be found elsewhere. The Spina rubber. Furthermore, avoiding the use of the
Bifida Association of America (4590 MacArthur more highly sensitizing chemicals in gloves,
Blvd., N.W., Suite 250, Washington, D.C. 20007- boots, and other items in close contact with the
4226; Tel. No.: 800-621-3141) has a brochure skin would be prudent; however, the higher price
which lists many of the potential exposures to of these “hypoallergenic” products could make it
67 Rubber 1011
Table 18 Contraceptive devices for rubber-sensitive veterinarian products. The carbamates (Table 8)
individualsa are widely used as lawn and garden fungicides, as
Device Comments well as in the plastic industry. The thioureas
Condoms (Table 9) are found in detergents, plastic-based
Natural lamb skin Made from processed sheep adhesives, photocopy paper, and paint/glue
brands intestines; no rubber-related removers. Finally, p-phenylenediamine derivatives
allergens; not completely
effective in blocking may cross-react with PPD in hair dyes and can be
transmission of HIV used in acrylic and other products (Table 11).
Avanti ® condom Thermoplastic elastomer free
(Durex) of latex and rubber additives.
Adequately prevents
transmission of HIV
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Occupational Allergy to Natural
Rubber Latex (NRL) 68
Henning Allmers
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
3 Terminology (TARCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017
3.1 Dry Rubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
3.2 Latex for Liquid Processing (Most Commonly Dipping) . . . . . . . . . . . . . . . . . . . . . . . 1018
4 Glove Use Caused the NRL-Allergy Epidemic in
Health Care Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
5 Time Between Start of Work and First Symptoms of NRL Allergy . . . . . . . . 1019
6 Inhalation Challenge Testing with NRL-Gloves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
7 Glove Use and Relevance of Airborne Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
8 Costs of Occupational Allergies to Natural Rubber . . . . . . . . . . . . . . . . . . . . . . . . . 1023
9 Therapeutic Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025
9.1 Immunotherapy in NRL-Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025
9.2 Avoidance of Allergen Contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Abstract (NRL) examination gloves that contaminated

During the 1980s and 1990s, the need for pro- the room atmosphere with NRL-allergens
tection of health care workers (HCW) from adhering to cornstarch glove powder. Up to
HIV and Hepatitis B and C viruses led to an 17% of health care workers developed a sensi-
increased use of powdered natural rubber latex tization to NRL, up to 5% developed occupa-
tional asthma after first suffering from urticaria
of the hands as symptom of an immediate-type
H. Allmers (*) allergy to NRL when wearing powdered exam-
Department of Dermatology, Environmental Medicine and
ination or surgical gloves. During the late
Health Sciences, University of Osnabrueck, Osnabrueck,
Germany 1990s and early 2000s, several studies showed
that recommendations to use powder-free and
Department of Occupational Medicine, University of
Osnabrueck, Osnabrueck, Germany low-allergen gloves as preventive measures led
e-mail: hallmers@uos.de to successful secondary and primary
https://doi.org/10.1007/978-3-319-68617-2_67
1016 H. Allmers
prevention of NRL-allergy. By the mid-2000s, • Even in NRL-asthma cases confirmed by inha-

there was a steady decline of new cases, and in lation exposure, up to 5% of patients had neg-
most Western countries, there are only few new ative skin-prick-tests and no detectable specific
cases in the health care community. There have IgE-antibodies to NRL-allergens.
also been reported cases in other professions • Patients who have been diagnosed with type-I
using powdered NRL-gloves like food han- NRL-allergy might have a lifelong risk of
dlers and security screeners, but the epidemic developing an anaphylactic shock when being
among health care workers is history. Cave: exposed to NRL-containing devices such as
Patients who have been diagnosed with type-I gloves during diagnostic or therapeutic medi-
NRL-allergy might have a lifelong risk of cal, surgical or dental procedures. Negative
developing an anaphylactic shock when being skin-prick-tests and negative specific IgE-anti-
exposed to NRL-containing devices such as bodies to NRL-allergens do not rule out a rel-
gloves during diagnostic or therapeutic medi- evant sensitization to NRL.
cal, surgical or dental procedures. Negative
skin-prick-tests and negative specific
IgEantibodies to NRL-allergens do not rule 2 Introduction
out a relevant sensitization to NRL.
The chapter concerning the type-I sensitization to
natural rubber latex (NRL) from the rubber tree
Keywords (Hevea brasiliensis) (Fig. 1) is dealing with a phe-
Natural rubber latex (NRL) · Occupational nomenon that can almost called historic in 2018 but
asthma (OA) · Urticaria · Immunotherapy ·
Health care worker (HCW) · Inhalation ·
Examination gloves · Surgical gloves ·
Powdered gloves · Powder-free gloves · Cross-
reactivity
1 Core Messages
• During the 1980s and 1990s, the need for pro-

tection of health care workers from HIV and
Hepatitis B and C viruses led to an increased
use of powdered natural rubber latex (NRL)
examination gloves that contaminated the
room atmosphere with NRL-allergens adher-
ing to cornstarch glove powder.
• The NRL-allergens adhering to cornstarch glove
powder led to sensitization in up to 17% of health
care personnel mainly through inhalation.
• In most cases, the first symptom of NRL-
allergy was urticaria of the hands when wear-
ing powdered NRL-gloves.
• Ninety percent of NRL asthma sufferers could
recall having urticaria of the hands when wear-
ing NRL gloves more than 6 months prior
to developing allergic respiratory tract Fig. 1 Harvesting natural rubber latex from the rubber tree
symptoms. (Hevea brasiliensis)
68 Occupational Allergy to Natural Rubber Latex (NRL) 1017
was a problem of epidemic proportions in the among health care workers is history (Fish 2002;
Western hemisphere’s health care field during the Bousquet et al. 2006; LaMontagne et al. 2006).
1990s and early 2000s. During the 1980s and
1990s, the need for protection of health care
workers (HCW) from HIV and Hepatitis B and C 3 Terminology (TARCC)
viruses led to an increased use of powdered natural
rubber latex (NRL) examination gloves that con- The term “latex” is very imprecise. It can mean:
taminated the room atmosphere with NRL-aller-
gens adhering to cornstarch glove powder (Fig. 2) • The milky liquid coming from a tree (e.g.,
(Turjanmaa 1987; Baur and Jaeger 1990; Baur rubber tree Hevea brasiliensis)
et al. 1998; Allmers et al. 1998). Up to 17% of • The concentrated form of this sold as a raw
health care workers developed a sensitization to material
NRL, up to 5% developed occupational asthma • A formulated version of this used for dipping
after first suffering from urticaria of the hands as • The product in the form of a sheet of rubber
symptom of an immediate-type allergy to NRL • An aqueous suspension of synthetic polymer,
when wearing powdered examination or surgical e.g., some inks and paints
gloves (Charous et al. 2002). During the late 1990s
and early 2000s, several studies showed that rec- When talking about a type-I allergy to latex, we
ommendations to use powder-free and low-aller- are referring to an allergy to latex from the Hevea
gen gloves as preventive measures led to successful brasiliensis (rubber) tree or natural rubber latex
secondary and primary prevention of NRL-allergy. (NRL).
By the mid 2000s, there was a steady decline of Two forms of natural rubber are used in com-
new cases, and in most Western countries, there are mercially available products. “Dry rubber” is dif-
only few new cases in the health care community ferent to natural rubber in the form of “natural
(Sussman et al. 1998; Allmers et al. 2002, 2004). rubber latex.”
There have also been reported cases in other pro- Both originate from the rubber tree as a liquid
fessions using powdered NRL-gloves like food latex. This latex is a colloidal suspension of rub-
handlers and security screeners, but the epidemic ber particles and other materials in a liquid serum.
Fig. 2 ADP cornstarch

powder on the surface of an
NRL examination glove
1018 H. Allmers
These other materials include plant cell organ- unless measures are taken to remove them at some
elles, proteins, sugars, sterols, and fats and oils. stage during product manufacture. Much less heat
It can be processed via two broad routes. is applied at the curing stage. Products may be
formed by dipping, casting, or foaming. NRL is an
excellent material for making dipped products,
3.1 Dry Rubber because it forms smooth, continuous films on
drying that have high strength and elasticity.
The latex is coagulated by treating the white milky A typical, simplified, dipping process is as
liquid with an organic acid which causes the rub- follows.
ber to coalesce and solidify so that it can be A former such a ceramic “hand” is dipped into a
separated from the liquid components. Rigorous tank of formulated latex concentrate, withdrawn with
washing and pounding stages serve to purify the a coating of the latex, and the latex is coagulated,
rubber and separate it from the water soluble then cured. Leaching (or washing) can be performed
components including those proteins which are at the wet gel stage or after drying, by dipping the
the cause of latex protein allergy. Other proteins formers in water. The product is then dried and
will still be present, but they are non-water soluble stripped from the former and prepared for sale.
and become incorporated in the rubber matrix. Examples of dipped NR latex goods:
The rubber is then dried at temperatures above
100 C and compressed to form a bale. Gloves, condoms, bottle teats, dental dam, Foley
To be made into a product, it is heated to soften catheters, toy balloons, cut thread, cold seal
it and cured with sulfur or other chemicals at adhesives, bath mat backings, carpet backings
temperatures exceeding 140 C. It may be (though most are synthetic), bathing caps,
extruded or molded into the final product shape. some mattresses (though many are synthetic).
Examples of dry rubber goods:
Most NR products which are more than a few mm 4 Glove Use Caused the
thick! NRL-Allergy Epidemic in Health
Hoses, bearings, seals, tire components (although Care Workers
most car tires contain no significant NR), most
rubber bands, erasers, hot water bottles, shoe Historically, there were several reasons for the
soles, car mats, windscreen wipers, sink plugs, increased use of powdered NRL-gloves in the
stoppers. health care field. The need for protecting HCWs
against HIV and Hepatitis infection led to an
Rubber bands go through the usual dry rubber increased use of powdered NRL-examination-
treatments (dry rubber is not usually destined for a gloves that reached a peak in the mid-1990s
particular application when it is being baled – the (Heilman et al. 1996; Kelly et al. 1993). A detailed
bales are bought and then turned to a particular analysis of glove use is given below. Before that
purpose. The stretchiness is imparted chemically time, NRL-gloves were mostly used in the oper-
by the way the rubber is cured. ating rooms and for sterile procedures. Increased
demand for these gloves led to increased building
of manufacturing plants close to the rubber tree
3.2 Latex for Liquid Processing plantations instead of shipping the raw product
(Most Commonly Dipping) overseas for production of gloves and condoms.
This change in manufacturing process reduced the
The latex is maintained as a liquid suspension, time between harvesting of the latex milk from
concentrated, and stabilized to produce a material weeks to days. One hypothesis assumes that the
suitable for making dipped goods. Most of the protein denaturing properties of ammonia in
proteins from the tree latex remain in the latex which the latex milk is put after harvesting led to
a decrease of NRL-allergens in the latex milk allergic symptoms. There was also a significant
during the shipping time. Another reason for an reduction in time between start of work and first
increased powder on NRL-gloves was the cost for symptoms of the respiratory tract. No difference in
removing it through repeated washing; therefore latency time could be found when comparing atopy
many cheap gloves had a large powder concentra- (according to SPT or history) and self reported
tion. An increasing environmental pressure to symptoms of hand eczema among the three groups
reduce use of polyvinyl chloride (PVC) gloves or when comparing them separately. There was
because they are hardly biodegradable in landfills also no correlation between the duration of NRL-
and might pose a hazard when burned in inciner- exposure and the concentration of latex-specific
ators also developed during the 1990s. There is IgE-antibodies (Fig. 3) (Allmers et al. 1998).
not just one NRL-allergen. A range of major and
minor latex allergens have been identified among
them Hev b 1, Hev b 3, Hev b 5, Hev b 6.01, Hev b 6 Inhalation Challenge Testing
6.02, Hev b 8, Hev b 9, and Hev b 11. Hev b 6.02 with NRL-Gloves
seems to be the most important allergen for health
care workers. In children with spina bifida and The gold standard for confirmation of suspected
other patients with NRL-allergy, there is a positive occupational allergy cases is an inhalation chal-
and significant correlation between sensitization lenge test with the suspected allergen. In some
to Hev b 5 and the number of surgical interven- countries, these exposure tests are not performed,
tions (Lopes et al. 2004; Sanz et al. 2006). because litigation is a severe risk for the testing
Approximately 30–50% of individuals who are physician (Malo and Chang-Yeung 2001). In
allergic to natural rubber latex (NRL) show an asso- suspected occupational asthma (OA), high levels
ciated hypersensitivity to some plant-derived foods, of sIgE against rHev b 5 combined with rHev b
especially freshly consumed fruits. This association 6.01 or 6.02 are the most efficient predictors of a
of latex allergy and allergy to plant-derived foods is bronchial response to NRL (Vandenplas et al.
called latex-fruit syndrome. An increasing number 2016). In our exposure chamber, we routinely per-
of plant sources, such as avocado, banana, chestnut, form tests. In recent years, we have added the
kiwi, peach, tomato, potato, and bell pepper, have exposure with 10 pair of powder-free NRL-gloves
been associated with this syndrome (Wagner and over a period of 30 min as an additional control.
Breiteneder 2002; Kujala 1999). The verum challenge starts with 1 pair of powdered
NRL-gloves for a maximum of 20 min and if no
significant allergic response of the upper or lower
5 Time Between Start of Work respiratory tract occurs, an additional exposure
and First Symptoms of NRL with 10 pair of powdered NRL-gloves for a max-
Allergy imum of 40 min. So far no subject has had a rhinitic
or asthmatic reaction when challenged with 10 pair
The interval between the start of work and first of powder-free NRL-gloves (Figs. 4–7).
symptoms and onset of OA dropped significantly
in health care workers starting work between 1986
and 1993 (Fig. 4). The age of the subjects at the 7 Glove Use and Relevance of
start of work was comparable. The self-reported Airborne Exposure
first symptoms were urticaria in 39 (56%) subjects,
urticaria combined with other symptoms in Turjanmaa et al. in Finland reported cessation or
8 (11%) subjects, rhinitis or asthmatic symptoms declines in sensitization following changes in
in 16 (23%) subjects, and solitary conjunctivitis in powder and/or allergen levels in gloves in hospi-
1 subject. Of the 70 subjects with a confirmed tals. It was possible to show that by switching to
occupational NRL allergy, only 3 (4%) reported powder-free NRL gloves, detectable NRL
signs of a bronchial obstruction among their first aeroallergens were completely removed in a
1020 H. Allmers
Fig. 3 Interval between 132

start of work and first NRL- First symptoms
allergy symptoms and 120 Occupational asthma
occupational asthma in 70
HCWs who began work 108
Duration to symptoms [months]

between 1986 and 1993
96
(P < 0.0001; Kruskall-
Wallis test). JACI 84
72
60
48
36
24
12
0
86/87 88/89 90/91 92/93
Start of work between:
Fig. 4 Face, flow-volume-

loop and spirometric data of
dental assistant before and
after challenge test with
ADP. Baseline: pre
exposure. FEV1:
2.9 L = 100% (baseline)

cornstarch. Negative
control: cornstarch ADP 30-
min exposure. FEV1:
2.9 L = 100%

powder-free NRL-gloves.
Negative control ten pair
powder-free NRL-gloves
30-min exposure. FEV1:
2.9 L = 100%

powdered NRL-gloves.
Verum exposure: one pair
of powdered NRL-gloves
20-min exposure. Note
urticaria between the eyes
and on the glabella.
Coughing artefacts clearly
visible. FEV1:
2.3 L = 79% of baseline
health care facility. Sensitized health care workers The number of purchased nonsterile examina-
were able to remain at work by supplying them tion NRL gloves increased by 24.26% between
with NRL free gloves, thus showing that these 1986 and 2007 reaching almost 1.7 billion per
simple and practical measures led to a successful year. In contrast, the number of purchased surgical
secondary prevention of NRL allergy in HCWs. NRL-gloves only rose by 56% in the same period
The increased adherence to rules and technical (Fig. 8).
regulations prohibiting the use of powdered In 1986, 48.5% of all surgical and examination
NRL gloves has led to a decrease of new cases gloves purchased were made from NRL. Of the
of type-I allergic diseases (asthma and urticaria) in 217 million gloves, 19.5% were surgical and
health care personnel. 80.5% examination gloves. The number of pur-
In the Department of Dermatology and Allergy chased examination gloves increased by 957%
Centre, Odense University Hospital in Denmark, between 1986 and 2007. The acquisition of surgi-
the prevalence of NRL sensitization declined from cal gloves only increased 58% during the same
6.1% in 2002–2005 to 1.9% in 2006–2009, and time period. Overall, the total number of gloves
then to 1.2% in 2010–2013 (p < 0.0001). The used reached 1.9 billion in 2007, an increase of
prevalence of clinical NRL allergy declined from 737% from 1986. Only 4% of surgical gloves
1.3% in 2002–2005 to 0.5–0.6% in 2006–2013 were made from non-NRL materials (Fig. 9).
(p < 0.004) (Blaabjerg et al. 2015). The main non-NRL materials for nonsterile
1022 H. Allmers
Fig. 8 Purchase of surgical and examination NRL-gloves in all German acute care hospitals from 1986 until 2007
Fig. 9 Increase of glove use and decrease of non-NRL glove material from 1986 to 2007
examination gloves (1.8 billion) were vinyl (6%), German hospitals were made from NRL, an
neoprene/nitrile (5.2%), and polyethylene (0.4%). increase of >80% from 1986. Approximately,
Only in the section of sterile examination gloves 1% of NRL gloves being used were powdered in
(26.6 million) more non-NRL material, mostly 2007.
copolymer (72.3%) than NRL-gloves (27.5%) The incidence of suspected occupational
was used. In 2007, 87.9% of all gloves used in allergy cases caused by NRL rose until 1997
(OA) and 1998 (skin allergies). By 2012, there The following points suggest that inhalation of
was a 97% decrease of new skin allergy cases and NRL-allergens is the major cause of sensitization:
a 99.15% reduction of reported new cases of OA
(Figs. 10 and 11). There was a positive linear 1. The amount of gloves used in the health care
correlation between the declining purchase of field and the total powder they release.
powdered-NRL examination gloves and the 2. The continuous inhalative contact to NRL-
reduction in new suspected occupational allergy allergens during a work shift.
cases (Fig. 12). 3. The decrease of new cases of NRL-sensitiza-
Substitution of powdered NRL gloves with tion when only powder-free gloves were used.
powder-free NRL gloves or gloves not 4. The major causes of environmental sensitiza-
containing NRL is a useful device in reducing tions against, e.g., house dust mite, cat, dog,
NRL aeroallergen loads below the assay detec- and pollen are all caused via inhalation. There
tion limit within 24 h. Stopping exposure to is no scientific explanation why NRL-sensiti-
NRL aeroallergen led to a decrease of specific zation should be an exception.
IgE-antibody levels in sensitized individuals
(Fig. 13).
NRL allergen load adhering to clothing does not 8 Costs of Occupational Allergies
seem to cause a significant atmospheric contami- to Natural Rubber
nation. To prevent detectable atmospheric contam-
ination with NRL aeroallergens, the use of powder- The Berufsgenossenschaft für Gesundheitsdienst
free NRL gloves is a sufficient measure. und Wohlfahrtspflege (BGW) is the statutory acci-
The glove use data indicate that there is a dose- dent insurer for nonstate institutions in the health
response curve between the amount of airborne and welfare services in Germany. All private phy-
allergen in the workplace and the number of peo- sicians’ and dentists’ offices as well as all private
ple developing allergic symptoms as well as the and church-run hospitals (nearly 60% of all Ger-
time between exposure and development of first man hospitals with almost half of all hospital staff)
symptoms. are insured by the BGW. Financial data for the
Fig. 10 Decline of NRL-induced occupational asthma in all German acute care hospitals insured by BGW between 1997
and 2012
1024 H. Allmers
Fig. 11 Decline of NRL-induced contact urticaria cases in all German acute care hospitals insured by BGW between
1997 and 2012
Fig. 12 Purchase of nonsterile NRL examination gloves and contact urticaria per 1000 insured healthcare workers
in all German acute care hospitals plus incidence of in private and church-run acute care hospitals from 1996 to
suspected cases of NRL-induced occupational asthma 2005
evaluation of suspected cases of NRL-caused OA 1996–2005. Total evaluation, treatment, and com-
and skin diseases as well as compensation and pensation cost data for all cases of OA and skin
treatment costs for HCWs confirmed to be NRL- diseases were also available. From 1996–2005, a
allergic were available for the 10-year period from total number of 1806 suspected cases of NRL-
Fig. 13 Concentration of NRL-specific IgE antibodies in during 12 months without exposure is highly significant
seven subjects exposed to aerogen NRL allergens before as determined by using the two-sided Page test (P < 0.003)
and 12 months after the end of exposure. IgE decrease
caused OA were reported with a peak of 378 cases amounted to 5.6% of complete costs for all
cases newly reported in 1998. By 2005, only skin disease cases within the BGW, and in 2005,
38 new cases were reported, a decrease of this figure was down to 4.3%. The costs for
90%. The cumulative costs during that period evaluating, treating, and compensating HCWs
amounted to 8.1 million € with a peak of 1.14 with NRL-allergy has also decreased since 2000
million € in 2000. The cost per reported by a cumulative amount of 1.87 million € for
suspected OA case was 4531 € for the 10-year skin disease cases and 1.5 million € for OA
period. In 2005, the BGW spent 0.58 million € cases.
for all NRL-allergy OA cases (including Recommendations to use powder-free, low-
suspected cases), a decrease of 50%. In 2001, protein NRL gloves or non-NRL gloves have
costs for NRL-allergy cases amounted to 15.4% been available, e.g., by the Occupational Safety
of complete costs for all OA cases caused by & Health Administration (OSHA) in the USA and
allergens within the BGW, and in 2005, this other organizations in the UK, Australia, and
figure was down to 7.6% (Fig. 14). Scandinavia (Witt 1999).
From 1996 to 2005, a total number of 4293
suspected cases of NRL-caused skin diseases
were reported with a peak of 884 cases newly 9 Therapeutic Options
reported in 1998. By 2005, only 115 new cases
were reported, a decrease of 87%. The cumula- 9.1 Immunotherapy in NRL-Allergy
tive costs during that period amounted to 12.3
million € with a peak of 1.8 million € in 2000. In There have been some trials using immunother-
2005, the BGW spent 1.34 million € for all apy to treat NRL-allergy, due to the effectiveness
NRL-allergy skin cases (including suspected of allergen avoidance and some severe side
cases), a decrease of 27%. The cost per reported effects immunotherapy is not widely used or
suspected skin disease case was 2859 € for the advocated for treatment of NRL-allergic
10-year period. In 2001, costs for NRL-allergy individuals.
1026 H. Allmers
Fig. 14 Cost of evaluation, compensation and treatment in BGW insured HCWs for the 10-year period from 1996
of all NRL-caused allergic diseases as well as suspected to 2005
and confirmed cases of NRL-caused OA and skin disease
9.2 Avoidance of Allergen Contact NRL-gloves had a positive rhinitic or bronchial

reaction although no antibodies were detectable.
The most effective way to manage NRL-allergy is The latex-specific IgE-concentrations decreased
avoidance. The following prevention methods after work was terminated or use of powdered
have proved effective since 1994 (Tarlo et al. NRL-gloves at work was stopped. This confirms
1994, 2001; Sussman et al. 1998; Allmers et al. our earlier findings that stop of exposure will lead
1998, 2002, 2004; Vandenplas et al. 2009): to a significant decrease of NRL-specific IgE-
Primary prevention: In order to prevent devel- antibodies. Preventive measures like using pow-
opment of NRL sensitization, use only powder- der-free NRL gloves in the health care environ-
free NRL gloves and powder-free other materials. ment are increasingly carried out. A growing
It is not necessary to change from natural rubber number of NRL allergic subjects will not have
latex to natural rubber latex free material to imple- detectable IgE antibodies but remain at risk of
ment primary prevention. having a severe allergic reaction that may even
Secondary prevention: High-risk approach for be fatal, when reexposed to NRL containing mate-
those individuals who are already sensitized or rial. In screening for NRL allergic patients before
allergic. Give individuals with NRL-sensitization routine procedures or elective surgery, it is not
or NRL-allergy latex free materials and use only sufficient to look for IgE antibodies. A positive
powder-free materials in their work environment, history of NRL allergy in a patient together with a
the co-workers should not use powdered natural work history suggestive of NRL exposure must
rubber latex devices, especially gloves. have as consequence that therapeutic and diagnos-
Finally, one major clinical issue needs to be tic medical, surgical, and dental procedures must
underscored. Eight out of 111 subjects who be carried out without the use of NRL-containing
underwent an inhalation challenge with powdered materials.
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(2006) Primary prevention of latex related sensitisation
Allmers H, Brehler R, Chen Z, Raulf-Heimsoth M, Fels H, and occupational asthma: a systematic review. Occup
Baur X (1998) Reduction of latex aeroallergens and Environ Med 63(5):359–364
latex-specific IgE antibodies in sensitized workers Lopes RA, Benatti MC, Zollner Rde L (2004) A review of
after removal of powdered natural rubber latex gloves latex sensitivity related to the use of latex gloves in
in a hospital. J Allergy Clin Immunol 102:841–846 hospitals. AORN J 80(1):64–71
Allmers H, Schmengler J, John SM (2004) Declining inci- Malo JL, Chan-Yeung M (2001) Occupational asthma.
dence of occupational contact urticaria caused by nat- J Allergy Clin Immunol 108(3):317–328
ural rubber latex allergy in German healthcare workers. Sanz ML, García-Avilés MC, Tabar AI, Anda M, García
J Allergy Clin Immunol 114:347–351 BE, Barber D, Salcedo G, Rihs HP, Raulf-Heimsoth M
Allmers H, Schmengler J, Skudlik C (2002) Primary pre- (2006) Basophil activation test and specific IgE mea-
vention of natural rubber latex allergy in the German surements using a panel of recombinant natural rubber
health care system through education and intervention. latex allergens to determine the latex allergen sensiti-
J Allergy Clin Immunol 110:318–323 zation profile in children. Pediatr Allergy Immunol
Baur X, Chen Z, Allmers H (1998) Can a threshold limit 17(2):148–156
value for natural rubber latex be defined? J Allergy Clin Sussman GL, Liss GM, Wasserman S (1998) Update on the
Immunol 101:24–27 Hamilton, Ontario latex sensitization study. J Allergy
Baur X, Jäger D (1990) Airborne antigens from latex Clin Immunol 102:333
gloves. Lancet 335:912 Tarlo SM, Easty A, Eubanks K, Parsons CR, Min F, Juvet
Blaabjerg MS, Andersen KE, Bindslev-Jensen C, Mortz S, Liss GM (2001) Outcomes of a natural rubber latex
CG (2015) Decrease in the rate of sensitization and control program in an Ontario teaching hospital.
clinical allergy to natural rubber latex. Contact Derma- J Allergy Clin Immunol 108:628–633
titis 73(1):21–28. https://doi.org/10.1111/cod.12386 Tarlo MS, Sussman G, Contala A, Swanson MC (1994)
Bousquet J, Flahault A, Vandenplas O, Ameille J, Duron Control of airborne latex by use of powder free gloves.
JJ, Pecquet C, Chevrie K, Annesi-Maesano I (2006) J Allergy Clin Immunol 93:985–989
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Charous BL, Tarlo SM, Charous MA, Kelly K (2002) Vandenplas O, Larbanois A, Vanassche F, Franois S,
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98:325–330 Wagner S, Breiteneder H (2002) The latex-fruit syndrome.
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(1993) Skin and serologic testing in the diagnosis of Witt SF (1999) Technical Information Bulletin – Potential for
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Kujala V (1999) A review of current literature on epidemi- rubber products. Occupational Safety & Health Adminis-
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Occup Med (Lond) 49(1):3–9 www.osha-slc.gov/html/hotfoias/tib/TIB19990412.html
Pesticide-Related Dermatoses
69
Michael O’Malley, Mai A. Ngo, and Howard I. Maibach
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1030
2.1 Pesticide Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031
2.2 Pesticide Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
2.3 Pesticide-Dermatitis Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
3 Pesticide-Related Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1036
3.1 Irritant Versus Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037
3.2 Tests of Irritation and Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1037
3.3 Predictive Tests for Delayed Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
3.4 Dermal Manifestation of Systemic Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
4 Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
4.1 Isothiazoline Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
5 Fumigants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
6 Fungicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
6.1 Inorganic Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
6.2 Phthalimide Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
M. O’Malley
Center for Health and Environment, UC Davis, Davis, CA,
USA
Department of Pesticide Regulation, California
Environmental Protection Agency, Sacramento, CA, USA
e-mail: maomalley@ucdavis.edu; momalley@cdpr.ca.gov
M. A. Ngo (*)
Department of Pesticide Regulation, California
Environmental Protection Agency, Sacramento, CA, USA
e-mail: mai.ngo@cdpr.ca.gov
H. I. Maibach
e-mail: howard.maibach@ucsf.edu

https://doi.org/10.1007/978-3-319-68617-2_68
1030 M. O’Malley et al.
6.3 Thiocarbamate Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047

6.4 Ergosterol Synthesis Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
6.5 Miscellaneous Fungicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
7 Herbicides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
7.1 Bipyridyl Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
7.2 Plant Growth Promoters and Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
8 Insecticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1050
8.1 Inorganic and Organometallic Insecticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1052
8.2 Kerosene, Petroleum Distillates, and Other Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
8.3 Organophosphates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
8.4 Carbamates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054
8.5 Insect Repellants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054
Abstract literature and in California use and surveillance

Pesticides include chemicals, as well as biolog- data between 1982 and 2014.
ical and physical agents used to control a
diverse array of pests. Although a number of Keywords
occupational and nonoccupational situations Pesticide · Agrochemical · Agriculture ·
affect the extent and route of exposure to Exposure · Dermatitis · Sensitization · Allergy/
pesticides, most skin effects are associated Allergic · Irritant · Contact · ACD · ICD ·
with a relatively small number of compounds. Antimicrobial · Insecticide · Fumigant ·
The highest exposures and risk of dermatitis Fungicide · Herbicide · Patch test
involve individuals employed in agricultural
pest control operations. The degree of pesticide
contact may be lessened by use of protective 1 Core Messages
clothing and engineering controls such as
closed mixing and loading systems. • Pesticide-related dermatoses are a significant
For evaluating the effects of pesticides on problem in the agricultural industry.
the skin, the most relevant tests include dermal • Agricultural workers contact pesticides, other
absorption tests, the 72 hr Draize dermal irrita- chemical irritants, and potential allergens
tion study, and sensitization studies. For the doing any number of farm-related activities.
Draize irritancy test, a general protocol utiliz- • The two major types of contact dermatitis,
ing albino rabbits is provided. Suggested con- irritant contact dermatitis (ICD) and allergic
centrations are also given for sensitization contact dermatitis (ACD), may be differenti-
studies using the patch test methodology. ated by diagnostic patch testing.
Registries for monitoring pesticide-related ill- • A list of suggested patch-test concentrations
ness exist in numerous U.S. and worldwide juris- and vehicles for common pesticides suspected
dictions. The most complete historical data to be allergens is provided.
derive from the California Pesticide Illness Sur-
veillance Program. The following chapter briefly
presents data on illnesses associated with indi- 2 Introduction
vidual classes of pesticides and pesticide mix-
tures, discussed separately as 5 categories Pesticides include chemicals, as well as biological
(antimicrobials, fumigants, fungicides, herbi- and physical agents used to control a diverse array
cides, and insecticides), focusing on the principal of pests. In the State of California, currently reg-
causes of pesticide dermatitis reported in medical istered pesticides include 1042 active ingredients
69 Pesticide-Related Dermatoses 1031
(AIs) formulated into 13,622 separate products Table 1 Amount of pesticide active ingredient used by
including adjuvants and antimicrobial com- pesticide type
pounds. Adjuvants must be registered as pesti- World
cides in California but are exempt from federal Year and Market US Market US %
pesticide (billion (billion World
registration requirements. Both State and Federal type pounds) pounds) Market
regulatory agencies classify antimicrobial com- 2006
pounds as pesticides, although many clinicians Herbicidesa 2.018 0.498 25
do not naturally regard them as such. Insecticides 0.955 0.099 10
The most recent U.S. Environmental Protection Fungicides 0.519 0.073 14
Agency (EPA) report on pesticide sales and usage Otherb 1.705 0.457 27
(U.S. EPA 2017), based upon data sources for 2008 Totalc 5.197 1.127 22
and 2012, estimated annual world pesticide usage 2009
totaling nearly 6 billion pounds in 2012, with herbi- Herbicidesa 2.189 0.498 25
cides accounting for almost half of global usage, Insecticides 1.016 0.099 10
followed by fumigants, insecticides, and fungicides. Fungicides 0.784 0.073 14
Pesticide use in the U.S. totaled over 1 billion Fumigants 1.019 0.457 27
pounds 2012 (Table 1). The survey did not include Totalc 5.008 1.127 22
antimicrobial agents, which account half of the pes- 2012
Herbicidesa 2.847 0.678 24
ticides sold and taxed in California (980,637,605
Insecticides 1.065 0.064 6
pounds, based upon 2015 sales data) (DPR
Fungicides 0.799 0.105 13
2015b). If antimicrobials account for a similar pro-
Fumigants 1.110 0.435 39
portion of U.S. pesticide use, the national total
Totalc 5.821 1.182 20
would be more than two billion pounds annually.
Source: U.S. EPA estimates based on Cropnosis Limited
The long list of pesticide agents can best be (www.cropnosis.com), USDA/NASS (www.nass.usda.
understood by grouping them into target pest or gov), and US EPA proprietary data (U.S. EPA 2011, 2017)
use categories and then by chemical structure
a
“Herbicides” include herbicides and plant growth
(Table 2). Most skin effects of pesticides are associ- regulators
b
“Other” includes nematicides, fumigants, and other mis-
ated with a relatively small number of compounds. cellaneous conventional pesticides
These include the fumigant compounds (metam- c
Totals may not add due to rounding. Does not include
sodium and methyl bromide), selected fungicides wood preservatives, specialty biocides, and chlorine/
(conazoles, phthalimide, thiocarbamate, copper hypochlorites
salts, elemental sulfur, organotins, naphthenate
salts, and halogenated nitrile benzene compounds), ornamental crops in 1997, but now has agricul-
halogenated organophosphates (dichlorvos and tural uses. Also, the chitin synthesis inhibitor
naled), pyrethroids, and bipyridyl herbicides. novaluron, initially registered in 2008, has a low
Nevertheless, in field investigations of current overall mammalian toxicity and negative tests for
pesticide illness episodes, compounds with novel dermal irritation and sensitivity.
chemical structures and different modes of action
are sometimes implicated. These novel pesticide
groups may be unfamiliar to many clinicians. 2.1 Pesticide Regulation
Many of these compounds have selective or rela-
tively selective modes of action and a very limited Pesticides are regulated differently from other
number of illness reports and no indication that chemicals in the U.S. Prior to enactment of the
they cause dermatitis (Table 3). For example, the Federal Insecticide, Fungicide, and Rodenticide
compound spinosad (Kirst 2010) fits this safety Act (FIFRA) in 1970, there was little regulation
profile. As a selective nicotine receptor inhibitor, and testing of pesticides in the U.S. Since
spinosad was initially registered for turf and the enactment of FIFRA, the U.S. EPA has
Table 2 Active ingredients of pesticides registered in California, July 2017

# of
Use category AIs Structural categories
Antimicrobial 213 Alcohol, isothiazilone (Kathon) compounds, thiocarbamate salts, phenols, quaternary
Bactericide 215 ammonium, aldehydes, carboxylic acid, chlorine, chlorine releasers, biological
Disinfectant 172 preparations, calcium salts, epoxides, copper compounds, iodines, hydantoin
Virucide 73 compounds, peroxides, silver compounds, bromide salts, silicates, morpholine
derivatives, organotin compounds, chelating agents, bacteriophages
Avicide 3 Pyrimidinol, chloro-toluidine, aminopyridine
Fumigant 12 Halonitromethane, low molecular weight halogenated hydrocarbons, phosphine,
phosphine releasers, MITC releasers
Fungicide 316 Carbamate, phthalimido compounds, thiocarbamate, biological agents
Herbicide 186 Triazines, thiocarbamates, bipiridyls, Pyridinecarboxylic acid, acetanilide, amide,
ammonium salt, urea compounds, thiourea compounds, arsenic compounds,
sulfonamide, biological, boron, phenoxy compounds, cyclohexanedione,
dimethoxypyrimidine, dintiroanilines, imidazolinone
Insecticide 258 Organophosphate, carbamates, pyrethrins/pyrethroids, biological, pyrethroids
Insect growth 44 Methoprene analogues
regulator
Molluscicide 33 Aldehydes
Nematicide 25 Biological, phosphonothionate, biological
Plant growth 55 Triazol, acetamide, alkyl ammonium, vinylglycine, fatty acid, fluorene derivative, furan
regulator derivative, hexadione, hydrazide, indole derivative, inorganic cyanamide, phenylamine,
phenylurea, phosphonic acid, piperidinium, pyrimidine, low molecular weight
unsaturated organic compound, naphthalene derivative
Repellent 77 Plant oil extracts, isothiocyanates, mercaptans, ammonium derivatives, coyote and fox
urine granules, ketones, piperidine, egg proteins, toluamide derivatives, biological oils
Vertebrate 37 Warfarin derivative, phosphide salt, biological alkaloid, cyanide salt, vitamin D
control derivative, inorganic nitrate salt, rotenone, anthranilate
applied an increasingly strict testing scheme to route of exposure to pesticides. The vapor pres-
registration for sale and use of pesticides. The sure and other physico-chemical properties of
data required by the U.S. EPA for registration of individual compounds also affect the degree of
a pesticide include product chemistry, environ- inhalation or skin contact. For compounds that
mental fate, acute and chronic toxicology, and may cause systemic allergy or other generalized
studies of hazards to nontarget organisms. skin eruptions, the degree of dermal absorption is
Pesticide materials tested in animal studies may also important. A high percentage of pesticides
include pure AI, technical grade AI, or individual are absorbed across intact human skin because of
product formulations. Solvents, surfactants, and a combination of relatively low molecular weight
preservatives in product formulations may affect and high lipid solubility. This correlates with the
the results of both irritation and sensitization tests requirement for many of these compounds to be
in animals. This observation parallels clinical expe- absorbed through the protective coverings of
rience with patch testing showing paraben and insects or plants.
other preservatives as the underlying cause of sen- The highest exposures and risk of dermatitis
sitization for many different commercial products. involve individuals employed in agricultural pest
control operations: mixing, loading, applying, and
flagging. These workers are often grouped under
2.2 Pesticide Exposures the category of “pesticide handlers”. Mixers and
loaders may handle concentrated pesticides in
Table 4 lists a variety of occupational and non- large volumes. The degree of contact may be
occupational situations that affect the extent and lessened by use of protective clothing and
Table 3 New/selective pesticide chemistry Table 3 (continued)

Dermal irritation/ Dermal irritation/
Chemical category – sensitization; illness data Chemical category – sensitization; illness data
Mechanism of action for typical compound(s) Mechanism of action for typical compound(s)
Insecticides Triazine insecticides Pymetrozine – mode of
Pheromones, biological (S)-verbenone – bark action not definitively
insecticides beetle antiaggregation known; 50% wettable
pheromone; 94.8% granule minimal irritant
concentration, nonirritant Fungicides
in the Draize assay, Benzamidoximes (inhibit Cyflufenamid – 10%
sensitizer in the Buehler fungal colony formation) suspension minimal
guinea pig test; registered irritant, negative in
in 2012, no reported GPMT; no reported
illnesses illnesses since initial
Insect growth regulators Methoprene – animal registration in 2012
(mimicking natural irritation studies show Biologicals Pseudomonas syringae –
juvenile hormone) reversal (moderate- Minimal irritant in Draize
minimal) irritation; no test; no sensitization
cases associated with studies
isolated exposure to Carboxamide (selectively Iprodione – 75% granules
methoprene were reported concentrates in fungal moderate irritant; 3
since initial registration in cells; inhibits succinic liquids, (23%AI, 41.6%
the 1980s dehydrogenase) AI, 19% iprodione-20.4%
Neonicotinoids Imidacloprid – minimal thiophanate-methyl), 50%
(differential effect on irritation in animal studies; granular product caused
insect vs. mammalian nonsensitizer in Buehler minimal irritation;
nicotine receptors) test, GPMT; 5 illnesses dermatitis cases with
reported since initial direct accidental exposure
registration 1998, Strobilurin (inhibits fungal Azoxystrobin – category
including 2 cases mitochondrial respiration) IV (minimal) irritant in
following direct accidental Draize test; nonsensitizer
contact in Buehler test; limited
Chitin synthesis inhibitors Novaluron – a category IV illness reports
(minimal) irritant in Herbicides
Draize test; nonsensitizer
Carotenoid synthesis Norflurazon – 5%
in Buehler test; no
inhibitors granules, 99.6% solid
illnesses reported
minimal
since initial registration
Irritants; nonsensitizer in
2006
LLNA; 1 possible case of
Tetronic acid inhibitors Spirotetramat – 1 possible dermatitis; sensitization
(inhibits lipid synthesis) case, with only indirect reported since registration
contact, reported since in the 1980s
initial registration in
2008
Ryanodine receptor Chlorantraniliprole –
equipment, closed mixing and loading systems, or
modulators (differential 96.5% technical material
effect on insect muscle nonirritant in Draize test; use of water soluble bags. Exposure to applicators
receptor) nonsensitizer in the varies with the type of application, from backpack
GPMT; no reported illness sprayers to enclosed-cab vehicles with filtered
since initial registration in
cooled air. Leaking or poorly maintained equip-
2008
Spinosyns (selective Spinosad – Negative
ment may fail, resulting in overexposures with
nicotine receptor binders, irritation and sensitization any type of application device.
extracted from studies; limited illness Exposures in most manufacturing facilities are
Saccaropolyspora spinosa reported in 19 years of use low owing to the use of automated closed sys-
and semi-synthetic
derivatives)
tems. Extensive contact with contaminated equip-
(continued)
ment may be involved during unscheduled
Table 4 Points in pesticide-processing or use resulting in Table 4 (continued)

potential exposure
Activity/process Potential exposure situation
Activity/process Potential exposure situation Structural use: residents and
Research and Accidental release of materials occupants of buildings
development during synthesis or during bystanders, early reentry into
analytical measurements or failure to clear fumigated
Manufacturing and Technical grade material buildings
formulation produced in enclosed and Contamination: food, water,
semi-enclosed operations; air
exposures during leaks/spill Agriculture-urban interface
and process repairs – (e.g., pesticide drift)
packaging operations vary in
degree of enclosure; technical
grade material mixed with
“inert” ingredients such as maintenance such as with breakdowns or leaks. In
solvents, and adjuvants production facilities, exposures may be much
Transportation Small to moderate volume
higher if dusts, powders, or granules are processed
spills associated with highway
transport, potentially large in open systems.
volume spills associated with Issues arise in the agricultural work environ-
bulk rail transport; fumigation ments which do not occur in the industrial setting
in transit (rail or shipping)
because of the widely scattered seasonal labor
Pesticide handling Mixing: commercial material
diluted with water or other
force. Hazards are transient and may be difficult
material to evaluate after-the-fact. For the workers, super-
Loading: into tanks in planes, visors, and ranch operators living on farm proper-
ground rigs, backpacks, or ties, there is also a very limited division between
hand-held sprayers. Closed
versus open mix/loading
work and living space. Unexpected hazards
systems. include intermittent presence of pesticide residues
Flagging: standing at the end or pesticide application equipment in children’s
of fields to mark the rows to be play areas or exposures due to pesticide drift
sprayed by crop-dusting
aircraft. Flagging is currently
(where airborne pesticide applications to one
being replaced by Global field may inadvertently disperse to adjacent fields
Positioning System (GPS) or residential areas), and accidental intrusion of
flagging in some operations soil-applied nematicides and fumigants into well
Agriculture-related Field workers, pickers, sorters, water. Pesticide levels in house dust have also
work packers, and others who come
into contact with pesticide been associated with the “take home” exposure
residues on leaves and fruit. scenario where pesticide residues are transferred
High contact work tasks from the workplace to home via work clothing,
include hand labor in grapes; shoes, vehicles, and tools.
picking row crops, such as
lettuce or strawberries, results
in markedly less contact – as
described in results of residue 2.3 Pesticide-Dermatitis
transfer studies Surveillance
Emergency response Exposure to contaminated
and medical workers persons and equipment in the
process of responding to spills, Registries for monitoring pesticide-related illness
accidents, and poisonings exist in numerous U.S. (NIOSH 2017) and world-
Environmental and Spills and accidents, especially wide jurisdictions. The most complete historical
consumer exposures ingestion by children (floor data derive from the California Pesticide Illness
level materials – ant traps,
Surveillance Program (PISP). The registry began
etc.), suicide and homicide
Home use: house and garden as collections of newspaper clippings in the 1930.
(continued) It was operated by the California Department of
Food and Agriculture beginning in the 1970s and unknown whether factors affecting reporting have
has been operated by the California Environmen- significantly changed over time, accounting for
tal Protection Agency since 1991. The electronic apparent variations in population incidence.
database in its current form dates to 1992. Data Figure 1 shows trends in cases of pesticide-
collected between 1982 and 1991 are still avail- related dermatitis reported in California between
able electronically but have not been completely 1982 and 2014. There were a total of 9763 cases
recoded according to the current system. Data for reported in that interval. During the mid-1980s,
this time period serve as a valuable reference point episodes of dermatitis in agricultural workers
for evaluating dermatitis trends. Several large- accounted for 300–400 cases annually but have
scale episodes have also proved important in accounted for 100 or fewer cases in the years since
understanding the role of slow environmental dis- 2000. Possible explanations for the decreasing
sipation for key irritant materials causing derma- number of cases since 2000 include changes in
titis in field workers (Smith 1991; Saunders et al. pesticide regulations, pesticide use, work prac-
1987; O’Malley et al. 1990). tices, and illness reporting.
Other U.S. states registering pesticide illnesses Clusters identified by assigned reference case
currently include Washington, Florida, Illinois, numbers accounted for 25% of the total cases.
Iowa, Louisiana, Michigan, Nebraska, New Years with unusually high percentage cluster cases
Mexico, New York, North Carolina, Oregon, included 1986 (122 cases in orange harvesters asso-
Texas, and Washington (NIOSH 2017). The larg- ciated with propargite residue), 1988 (47 cases in
est volume of cases, approximately 100 annually, nectarine harvesters also associated with pro-
come from Texas and Washington. Specific data pargite), and 1991 (100 cases in workers cleaning
on skin effects are not presented in the summary up a metam-sodium spill in the Sacramento River).
data available. A 1980s requirement for formulation of pro-
The completeness of illness reporting has been pargite in water-soluble bags had a definite impact
controversial. Under-reporting may be especially on the number of cases of eye-irritation and der-
frequent for skin reactions that do not result in time matitis in mixing and loading operations. The
lost from work. Grouping of cases in clusters, on the long re-entry interval for propargite set in the
other hand, demonstrably increases illness reporting early 1990s provides an example of a regulation,
in the affected group. Interviewing co-workers of an possibly accounting for the subsequent decline in
index case in a group with similar exposures typi- large-scale field residue dermatitis episodes (refer
cally reveal cases who never sought treatment. It is to examples above). An episode did subsequently
Fig. 1 Pesticide dermatitis

cases in California
1982–2014
Fig. 2 Propargite and sulfur use in California 1990–2015
Fig. 3 Farm labor

contractor (FLC)
employment as percentage
of total California
agricultural Employment
1991–2016
occur in 1995, but may have been caused by retaliation against employees making workers’
an over-application of the AI. Overall use of compensation claims make this seem plausible,
propargite has declined since the 1990s but did but it is difficult to ascertain how frequently this
not decline significantly until many years after may occur. The overall low percentage of farm-
the long re-entry interval took effect. The long workers with employer-provided health insurance
re-entry time may have impacted the timing of means many seek care at overburdened safety-net
work practices, so that exposure was limited to clinics. The lack of routine access to care may also
performing hand-labor tasks prior to applica- decrease the likelihood of seeking treatment for
tion rather than afterwards. Over the same workplace injuries and illnesses.
period, use of sulfur changed only slightly
(Fig. 2).
A gradual increase in the percentage of agri- 3 Pesticide-Related Dermatitis
cultural workers employed by farm labor contrac-
tors (as opposed to being directly employed by The following sections briefly present data on
growing operations) has been noted in California illnesses associated with individual classes of
since the 1980s (Fig. 3). It is conjectured that pesticides and pesticide mixtures, discussed sep-
this arrangement may discourage reporting of arately as 5 categories: antimicrobials, fumigants,
work-related illnesses and injuries. Episodes of fungicides, herbicides, and insecticides.
3.1 Irritant Versus Allergic Contact patch test series or specific pesticide or plant aller-
Dermatitis gens. Exceptions included occasional published
case reports (Dannaker et al. 1993) or patch test
Surveillance data do not inherently distinguish studies of reported cases (O’Malley et al. 1995)
between allergic contact dermatitis (ACD) and and a patch test performed by a rural dermatologist.
irritant contact dermatitis (ICD) or other skin One of the key problems that became apparent
effects of pesticides. However, since allergic der- as patch testing proliferated was that different
matitis is characteristically idiosyncratic, clusters investigators were using different concentrations,
usually involve irritant dermatitis affecting a vehicles, and, in some cases, chemicals to detect a
group of field workers performing a common given allergy. In recognition of the need to stan-
work task. Most dermatitis cases in pesticide han- dardize patch testing, the Scandinavian Commit-
dlers are probably also due to irritation, but occur tee for Standardization of Routine Patch Testing
singly and may require diagnostic patch testing to was created in 1962. The International Contact
rule out ACD in some circumstances. Dermatitis Research Group (ICDRG) was later
ICD is a nonimmunologic reaction caused by formed in 1967, followed by the North American
direct damage to the skin following exposure to Contact Dermatitis Group (NACDG), which was
an agrochemical or other harmful agent. Immune modeled after the ICDRG. By patch testing using
response and resulting inflammation is secondary standardized procedures with the same screening
to the cutaneous damage. Some agents do cause allergens, long-term trends in patch test reactions
subjective skin symptoms while producing mini- may be analyzed. Lachapelle (1997) produced an
mal inflammation by stimulating the cutaneous original coding system (0 = no relevance/not
nerves. Corrosive substances, such as strong traced, 1 = doubtful relevance, 2 = possible rel-
acids and alkalis, are examples of immediate irri- evance, 3 = likely relevance) for recording clini-
tants that produce skin damage within minutes or cal results of patch tests, grading relevance to
hours of exposure. Cumulative irritation is more the current and past clinical condition of tested
subtle, resulting from exposure to an inherently patients. The Lachapelle coding system may
less irritating material or a dilute concentration of a prove helpful in reviewing results of patch testing
severely irritating or corrosive substance. Because series involving exposed workers with no current
of the delay between initial contact and the subse- skin condition but a history of prior occupational
quent response, the specific cause of cumulative exposure (O’Malley et al. 1995; Verma et al.
irritation may prove difficult to recognize. 2007; Sharma and Kaur 1990). Positive test
With ACD, an immunologic reaction is trig- results in these cases would be graded as having
gered by dermal contact to a skin allergen. After no current relevance, but possible past relevance.
sensitization, subsequent exposures may elicit In typical case reports, positive reactions have
an immunologic reaction. This response may obvious current relevance (Dannaker et al. 1993).
occur at the site of contact but may also occur
systemically. Once individuals are sensitized to a
pesticide, exposure to even minute amounts of the 3.2 Tests of Irritation and
chemical may cause a reaction. Sensitization
Clinical history and examination can provide
some help in differentiating ICD and ACD. For evaluating the effects of pesticides on the skin,
However, patch testing often proves useful when the most relevant tests include dermal absorption
the clinical symptoms overlap and may also identify tests, the 72 hr Draize dermal irritation study, and
confounding allergies to plants. Penagos et al. sensitization studies. For the Draize irritancy test,
(2004) have emphasized the need to test agricultural a general protocol utilizing albino rabbits is as
workers with specific pesticide patch test series. follows (O’Malley 2010). A single dose of the
California illness registry records seldom contain technical material with detailed characterization
information about testing with either the standard of contaminants, or an end-use product, is applied
to the skin of one or several experimental animals epicutaneous application of test material (Buehler
(depending on the possibility of a corrosive reac- closed patch test, open epicutaneous test) and
tion) for 4 hrs. Solid materials are moistened with two that employ intradermal induction (the guinea
distilled water, saline, or other vehicle at the time pig maximization test and Freund’s complete
of application. The irritation is scored at intervals adjuvant test). All four tests use visual scoring
until the irritation has resolved or is considered of relative degrees of erythema over the course
permanent. Materials are categorized based on of the test. The local lymph node assay uses
scores at 72 hr and persistence of irritation for epicutaneous induction but is scored based upon
more than 14 days (Table 5). For sensitization activation of regional lymph nodes (measured by
using the patch test methodology, suggested con- radioactive thymidine uptake).
centrations are shown in Table 6.
The U.S. EPA requires the signal word
“Danger” for formulations scored as corrosive in 3.4 Dermal Manifestation of
the Draize test, “Warning” for those scored as Systemic Absorption
severe irritants, and “Caution” for those scored as
moderate or minimally irritant. The U.S. EPA does Typified by the cholinesterase inhibitors, many
not require changes in the label signal word for dermally absorbed pesticides have systemic
formulations that cause sensitization in predictive effects. In relatively few cases, the systemic
test but does require use of appropriate cautionary effects manifest themselves with skin eruptions.
statements (e.g., “Prolonged or frequently repeated Examples include urticaria or drug-like eruptions
skin contact may cause allergic reactions in some resulting from absorbed AIs or their metabolites.
individuals” (U.S. EPA 2014). Interpretation of pre- Notable examples are organophosphates that
dictive irritation tests proves simplest for directly cause both contact irritation and cholinesterase
corrosive or strongly irritant materials. Materials irritation (Mathias 1983).
scored as minimally irritant may seem relatively
innocuous, but can still produce significant short-
term reactions with accidental direct exposure. 4 Antimicrobials
The compounds discussed below account for a

3.3 Predictive Tests for Delayed substantial portion of all reported cases of derma-
Allergy titis associated with antimicrobials. Frequently
reported classes of antimicrobials included qua-
Approved predictive tests for delayed allergy ternary ammonium compounds, isothiazoline
include methods that induce sensitization with (kathon) compounds, chlorine and hypochlorites,
the chlorine releaser cyanuric acid, glutaralde-
hyde, phenolic disinfectants, pine oil, and
Table 5 Draize irritation test categories creosote (Table 7). All of the agents have the
Dermal irritation capacity to cause significant irritation or corro-
Description Category scorea sion. Glutaraldehyde, the isothiazioline com-
Corrosive I >1 pounds, and quaternary ammonium compounds,
Severe irritant II 5–7 as discussed below, can also cause sensitization.
Moderately III 2–5 Dairy workers typify the risk antimicrobials
irritant
may pose to agricultural workers. ICD or
Minimally IV 0–2
irritantb ACD may result from disinfectants used to clean
a
Measured at 72 hr
equipment or directly on udders prior to milking.
b
May be divided into compounds that produce no irritation Equipment disinfectants include sodium hydrox-
(nonirritants) and those that produce transient, mild ide and nitric acid. Dairy farmers are also exposed
irritation to hypochlorite iodine, phenolic compounds, and
Table 6 Suggested patch test concentrationsa

Concentration
AI/use or structural category CAS # (%) Vehicle
Antimicrobials an antibiotics
Methylchloroisothiazolinone- 2682-20-4 0.005–0.01 Aqueous
methylisothiazolinone (Kathon CG)
Benzisothiazoline 2634-33-5 1 Petrolatum
Formaldehyde (formalin – 40% solution) 50-00-0 2 Aqueous
Glutaraldehyde 111-30-8 1 Aqueous
Benzalkonium chloride 8001-54-5 0.1 Aqueous
Sodium hypochlorite 10022-70-5 1 Petrolatum
1 Aqueous
Hexahydro 1,3,5,tris (2-hydroxyethyl) triazine 4719-04-4 0.2 Aqueous
(Grotan)
Fumigants
Chloropicrin 76-06-2 0.25 Petrolatum
Dazomet 533-74-4 0.1 Petrolatum
0.025–0.0025 Vaseline
Metam-sodium 137-42-8 0.3 Aqueous
1,2-Dichloropropane 78-87-5 1, 2, 5, 10 Petrolatum
D-D mixture (dichloropropene and 26952-23-8 0.05 Petrolatum
dichloropropane); dichloropropenes
Fungicides
Phthalimide compounds
Captafol (Difolatan) 2939-80-2 0.05–0.1, 1 Petrolatum
1,5,10 Aqueous
Captan 133-06-2 0.25 Petrolatum
Thiocarbamates
Maneb 12427-38-2 1 Petrolatum
Zineb 12122-67-7 1 Petrolatum
Ziram 137-30-4 1 Petrolatum
Other fungicides
Benomyl 17804-35-2 0.1 Petrolatum
1.0 or water
Undiluted and Petrolatum
diluted 1:5 Olive oil
PCNB (pentachloronitrobenzene) 82-68-8 1 Petrolatum,
10 butanol
Aqueous
Dichloronitroaniline 6641-64-1 1 Butanol
Chlorothalonil 1897-45-6 0.001 Butanol
0.01 Acetone
0.005–0.0001 Aqueous
Imazalil 35554-44-0 1 Vaseline
Sulfur 7704-34-9 1 Butanol
5–20 Alcohol
Herbicides
2,4-D 94-75-7 1 Petrolatum
Alachlor (Lasso) 15972-60-8 0.1 Petrolatum
Atrazine 1912-24-9 0.1 Petrolatum
Thiobencarb 28249-77-6 1 Aqueous
Diquat 85-00-7 0.1 Petrolatum
(continued)
Table 6 (continued)
Concentration
AI/use or structural category CAS # (%) Vehicle
Paraquat 1910-42-5 (dichloride) 0.1 Petrolatum
2074-50-2 (dimethylsulfate)
Glyphosate 1071-83-6 10 Aqueous
1, 5 (end use Aqueous
formulation)
Insecticides
Organophosphates
Acephate 30560-19-1 1 Butanol
Chlorpyrifos 2921-88-2 1 Butanol
Diazinon 333-41-5 1 Butanol
1 Petrolatum
Dichlorvos (DDVP) 62-73-7 0.02 Aqueous
1 Petrolatum
Dimethoate 60-51-5 1 Petrolatum
1 Alcohol
1 Oil
1–2 Aqueous
Malathion 121-75-5 1 Butanol
Naled 300-76-5 0.01 Petrolatum
0.5 (technical) Aqueous
N-Methyl-carbamates
Methomyl 16752-77-5 0.5 Petrolatum
0.2% (a.i) Aqueous
1% (formulated Aqueous
product)
Carbaryl 63-25-2 1 Aqueous
Carbaryl 50% 0.25 Vaseline
Methiocarb 2032-65-7 0.5, 1 Petrolatum
Pyrethroids/pyrethrins
Allethrin 584-79-2 1 Petrolatum
Cypermcthrin 52315-07-8 1 Petrolatum
Deltamethrin 52918-63-5 1 Petrolatum
Fenvalerate 51630-58-1 1 Petrolatum
Permethrin 52645-53-1 1 Petrolatum
1 Butanol
Resmethrin 10453-86-8 1 Petrolatum
Pyrethrum 8003-34-7 (powder) 2 Petrolatum
121-21-1 (pyrethrins,
pyrethrum oleoresin)
Miscellaneous insecticides, insecticide repellants
Fenbutatin Oxide 13356-08-6 0.1 Butanol
Nicotine 54-11-5 1, 5 Aqueous
Propargite 2312-35-8 0.5–1.0 Aqueous
2.5 Not
specified
DEET (diethyl toluamide) 134-62-3 5 Ethanol/
Petrolatum
a
Taken from Penagos et al. (2000)
Table 7 Cases of pesticide-related dermatitis 1982–2014 – selected antimicrobials, fumigants, fungicides, herbicides,
and insecticides
Field Emergency Packaging/
Active ingredient Total Handler worker responders processing Other
Antimicrobials
Quaternary ammonium 499 429 1 69
Isothiazoline disinfectants 35 27 8
Glutaraldehyde 85 72 13
Creosote 89 40 1 15 33
Pine Oil 19 12 7
Phenolic disinfectants 87 71 5 11
Hypochlorite 836 512 4 3 51 266
Cyanuric acid 84 68 2 14
Chlorine 100 15 2 46 37
Fumigants
1,3-Dichloropropene 22 16 6
Dazomet 7 2 1 4
Ethylene dibromide 7 5 2
Methyl bromide 83 69 1 13
Chloropicrin 13 2 11
Metam-sodium, potassium 277 72 22 4 179
Ethylene oxide 8 4 1 3
Methyl iodide 1 1
Fungicides
Anilazine 6 4 2
Azoyxstrobin 1 1
Benomyl 21 11 7 2 1
Copper compounds 52 22 8 5 17
Captafol 5 1 4
Captan 41 9 16 3 13
Imazalil 6 1 5
Chlorothalonil 53 21 22 1 9
Dicloran 6 2 3 1
PCNB 2 1 1
(pentachloronitrobenzene)
Lime-sulfur 9 4 2 3
Sulfur 564 95 281 5 1 182
Mancozeb 27 4 23
Maneb 6 1 4 1
Thiram 8 6 2 0
Zineb 1 1
Ziram 13 8 1 4
Herbicides
2,4-D 10 7 3
Dinoseb 25 18 7
Diquat 34 25 9
Paraquat 38 33 2 3
EPTC 11 5 6
Ethephon 7 3 3 1
Fluazifop-butyl 13 12 1
(continued)
Table 7 (continued)
Field Emergency Packaging/
Active ingredient Total Handler worker responders processing Other
Glyphosate 292 255 2 35
Hydrogen cyanamide 5 4 1
Pentachlorophenol 13 6 1 6
Trifluralin 25 16 4 5
Insecticides
Abamectin 10 6 3 1
Potassium salts of fatty acids 2 1 1
Bacillus thuringiensis 2 1 1
Bendiocarb 15 2 1 12
Spinosad 2 1 1
Carbaryl 32 9 8 1 14
Methomyl 20 3 9 8
Propoxur 12 5 7
Acephate 13 7 2 4
Chlorpyrifos 125 31 27 67
Diazinon 56 18 9 4 1 25
Dichlorvos, DDVP 16 2 8 6
Dimethoate 13 4 1 8
Malathion 41 17 1 23
Naled 18
Pyrethrins 4 2 2
Bifenthrin 12 5 1 6
Lambda cyhalothrin 38 16 1 21
Cyfluthrin 59 20 11 1 27
Cypermethrin 39 16 1 22
Deltamethrin 13 3 10
Esfenvalerate 8 5 1 2
Fenvalerate 5 3 2
Permethrin 37 16 3 18
Resmethrin 11 4 7
Propargite 338 94 203 41
Fenbutatin-oxide 5 1 2 1 1
Dienochlor 5 3 1 1
Dicofol 11 4 3 4
Endosulfan 15 1 6 8
Cyhexatin 10 10
Cryolite 10 2 6 2
DEET 3 3
Capsaicin 16 16
quaternary ammonium compounds. Preservative currently registered in California and the U.S. as
solutions for milk sample analysis in the U.K. an antimicrobial, fungicide, and algaecide/
have contained 8% bronopol and 20% methyl- slimicide. Primarily used as a preservative and a
chloroisothiazoline and methylisothiazoline or microbiocide in the processing of industrial water,
methyisothiazolinone (KathonR CG), with anti- it has also been used in seed treatment and foliar
bacterial and fungicidal properties. Bronopol is spray in some countries. ACD have been
identified in workers exposed to bronopol and Glutaraldehyde is principally used as a medi-

KathonR CG as milk preservatives. cal disinfectant. Public literature on glutaralde-
Quaternary Ammonium Compounds (quater- hyde contains numerous reports of irritant and
nary ammonium salts) or “Quats” contain a cen- allergic dermatitis, as well as cases of related
tral nitrogen with 2 short chain (usually methyl or irritant or allergic occupational asthma, chiefly in
ethyl) and long chain alkyl groups of varying medical personnel.
length substituted for the hydrogens in the Hypochlorites and Other Chlorine-Based
ammonium atom. Commercial products contain Antimicrobials account for a large percentage
mixtures of multiple compounds. The variation of overall pesticide use on account of reported
in chain length affects the activity against industrial sales. Hypochlorite products have
specific bacterial or viral pathogens (Anderson been reported to cause severe irritation in the
et al. 2016). Draize assay. Triazine derivatives, used to prevent
The 1982–2014 registry data showed 499 photodegredation of chlorine in pools and water
reported cases of dermatitis associated with qua- treatment systems, also have extensive use and
ternary ammonium compounds (grouping marked irritant properties. One such triazine
all registered products) and an additional 148 derivative is cyanuric acid.
involving mixtures of quaternary ammonium Sensitization to hypochlorite has been reported
compounds with other products. The large major- in the form of contact urticarial (Hostynek et al.
ity affected those directly handling the products. 1989). Nevertheless, most sodium hypochlorite-
A total of 408 of the quats cases involved only containing antimicrobials are not labeled as sen-
dermatitis; 52 involved skin and eye symptoms; sitizers. Although testing with the Buehler and
and the remaining 39 cases involved dermatitis guinea pig maximization protocols did not show
and respiratory or systemic symptoms. evidence of sensitization. No sensitization study
Numerous animal and human studies have on cyanuric acid was available for review. Irritant
shown skin irritation and sensitization to quats. dermatitis associated with hypochlorite is a fre-
Animal studies on quaternary ammonium quent occurrence. In cases with breakdown of the
compounds show that concentrations greater epidermis, sensitization may occur (Hostynek
than 5% can cause irritation in the Draize assay. et al. 1989).
Occupational allergic contact dermatitis from 2,3- Phenolic disinfectants include 173 different
epoxypropyl trimethyl ammonium chloride chemical codes, many with numerous inactive
(EPTMAC) and Kathon LX have been reported. and no active registrations. These include note-
Positive patch test reactions to various quats have worthy agents such as tert-butyl-phenol, a sensi-
been reported. Asthma and other respiratory con- tizer and a classic cause of occupational leukoderma,
ditions associated with quaternary ammonium and the chloracnegens 2,4,5-trichlorophenol and
cleaning products are also reported in the public pentachlorophenol. Hexachlorophene is no longer
domain literature. registered but has been reported to cause sensiti-
Creosote has had a long history of use as a zation (Praditsuwan et al. 1995), occupational
wood preservative, but has been replaced by asthma (Nagy and Orosz 1984), and neurotoxicity
alternative products containing copper, chro- (Shuman et al. 1974; Rose et al. 1975; McCarl
mium, or synthetic organic compounds. In addi- 1975; Ramu et al. 2016). Formerly registered
tion to ICD, literature reports on creosote dinitrophenol compounds, used as herbicides,
include cases of ICD, ACD, and squamous uncouple oxidative phosphorylation; during the
cell cancer. The International Agency for 1940s, they were prescribed as weight loss agents,
Research on Cancer (IARC) classified creosote but were associated with the occurrence of
as a probable human carcinogen based upon cataracts.
a very large number of case reports as well Pine oil is a mixture of terpenes produced by
as clear evidence of carcinogenicity in animals the high temperature distillation of oil of turpen-
(IARC 2017). tine residues or by the catalytic hydration of
pinenes. It contains tertiary and secondary cyclic structural pest control, or to disinfect materials
terpene alcohols, varying with the source of tur- that can be enclosed to contain the fumigant.
pentine and the production method. Pine oil has In California, a primary use of fumigants is on
potential systemic toxicity on ingestion due to its strawberry, carrot, and tomato fields.
content of isopropanol. Sensitization may be due Soil fumigants typically pose potential risks to
to the multiple terpene alcohols in the distillate. those involved in the application or perform work
following the application of these chemicals.
There may also be potential risk of eye and respi-
4.1 Isothiazoline Compounds ratory irritation for those who reside near fumi-
gant treated fields (O’Malley et al. 2005). Cases of
Isothiazoline compounds are used as biocides for dermatitis associated with select fumigants are
disinfection. The illness registry categorizes iso- shown in Table 7.
thiazolones as Kathon or “isothiazoline disinfec- Ethylene oxide (also known as epoxy eth-
tants.” The 1982–2014 data identified 35 cases of ane) is used as a fumigant and a sterilant.
dermatitis associated with Kathon or as iso- Ethylene oxide, first used as an agricultural
thiazoline, cases principally occurring in handlers fumigant in 1928, is effective against all
(Table 7). Numerous reports in public domain microorganisms. In California, ethylene oxide
literature document the capacity of isothiazolines is registered for commercial and institutional
to sensitize. Cases of occupational ACD to uses. In these settings (hospitals, nursing
octhilinone used as a fungicide for surface paint homes, and veterinary clinics), ethylene oxide
of roof sheets, for workers in paint manufacturing, is used to sterilize medical equipment sensitive
and farm workers have been reported. Recent to heat sterilization.
articles have noted multiple cases of sensitization Public domain literature includes reports of
related to isothiazoline preservatives (Kathon CG) severe irritant dermatitis and chemical burns
used in makeup and other skin care products, from direct skin contact with ethylene oxide con-
with clusters of cases from the Czech Republic, sistent with cases reported to the California regis-
Belgium, France, Spain, and Brazil. Isothiazoline try. Animal studies strongly suggest that ethylene
compounds used as preservatives in formulations oxide is carcinogenic. Multiple studies have pro-
can also cause sensitization, sometimes mistak- duced limited evidence of elevated human cancer
enly attributed to the formulation AI (refer to rates. Some studies showed a mildly increased
glyphosate discussion). risk of breast cancer and evidence of a dose-
Octhilinone, an isothiazoline compound, has response effect (Steenland et al. 2004; Mikoczy
registered uses as a microbiocide, algicide, or et al. 2011).
fungicide. As a biocide, it is used in industrial Methyl bromide (bromomethane) is a broad-
processes and water systems. Octhilinone is also spectrum fumigant used as an acaricide, anti-
used as a preservative in paint, adhesives, and microbial, fungicide, herbicide, insecticide,
plastics, to control sapstain and mold on wood, nematicide, and vertebrate control agent. It has
as a treatment for textiles, and even in shampoos been used for insect control in grain elevators,
and cosmetics. This does not include cutting oils mills, ships, and greenhouses. It has also been
and other industrial fluids. used as a postharvest treatment of commodities.
The most prevalent use for methyl bromide is as a
preplant fumigant, injected into the soil at various
5 Fumigants depths. Use for structural fumigation is now pro-
hibited. Under the Clean Air Act and the Montreal
Fumigants produce gas, vapor fume, or smoke Protocol on Substances that Deplete the Ozone
intended to destroy insects, bacteria, or rodents. Layer, U.S. production and import of methyl
They may be volatile liquids and solids as well as bromide has been banned as of January 1, 2005,
substances already gaseous. They may be used for except for critical use exemptions.
Methyl bromide causes corrosion in the Draize jurisdictions around the world. Current problems
assay. The public domain literature on methyl with metam-sodium involve environmental expo-
bromide contains many reports on burns from sures from off-site movement. Typical events
methyl bromide. In many instances, the topical involve multiple cases, with predominantly eye,
exposure was associated with systemic absorption respiratory and systemic symptoms, rather than
and neurological symptoms. contact dermatitis (O’Malley et al. 2004, 2005).
Dichloropropene and ethylene dibromide Dazomet, like metam-sodium, breaks down
(EDB), like methyl bromide, are volatile, low to release MITC, but is typically formulated in
molecular weight alkylhalogen compounds with a granular form that allows low volume preplant
high systemic toxicity. EDB was cancelled during treatment of ornamental beds. When dazomet is
the 1980s because of concern about its carci- applied to soil, it quickly breaks down to its major
nogenicity in rodent bioassays and widespread degradant, MITC, but formaldehyde, mono-
contamination of groundwater. Prior to the can- methylamine, hydrogen sulfide, and (in acid
cellation, it was used as a broad-spectrum fumi- soils) carbon disulfide are also formed. Contact
gant in a manner similar to current use of dermatitis, both irritant and allergic, has been
dichloropropene. Dichloropropene mixtures with reported to dazomet in the public domain
chloropicrin caused corrosion in the Draize assay. literature.
No animal sensitization studies were available for Chloropicrin used in concentrations greater
review, but the products registered in California than 2% is considered an active biocidal ingredi-
are labeled as sensitizers. ent rather than a warning agent. Similar to other
Methyl iodide (iodomethane) has been used as fumigants, it interferes with target cell chemistry
an intermediate in the manufacture of some phar- at multiple sites. The 99.5% technical liquid
maceuticals and pesticides. Although approved in caused corrosion in the Draize assay. There were
2010, methyl iodide is no longer registered as a no dermal sensitization studies available for
pesticidal AI with the State of California. Preplant review. Corrosion associated with liquid chloro-
fumigant uses of methyl iodide are proposed to picrin was reported during World War I, when it
replace those of methyl bromide. It had limited was used as a chemical weapon (Underhill 1919).
use in 2012, before registration was cancelled by 1,3-Dichloropropene (1,3-D, or trade
the registrant in March 2012. name Telone) is a mixture of 1,3-dichloropropene
Metam sodium and metam potassium are cis- and trans- isomers. A contaminant, 1,2-
broad-spectrum soil fumigants with fungicidal, dichloropropane may also be present in small
insecticidal, nematocidal, herbicidal, and antimi- quantities (<0.1%). It is used as a nematicide,
crobial properties. Metam fumigants are regis- fungicide, insecticide, and herbicide on food,
tered as agricultural soil fumigants for use on all feed, fiber, and on nursery crops. As a restricted
food, feed, and fiber crops. They are also regis- use pesticide, 1,3-D can only be applied by certi-
tered as antimicrobial agents, used to treat wooden fied applicators. In 2009, 1,3-D ranked fifth for
poles, timbers, sewage sludge, and animal waste. pesticide use in California, based on use by
Restricted uses of metam sodium include uses as a weight. 1,3-D is a cutaneous irritant and may
root control agent in sewers and drains. As either occasionally provoke ACD.
the potassium or sodium salt, metam rapidly
degrades to methylisothiocyanate (MITC) in
the environment, particularly in the presence of 6 Fungicides
moisture. MITC is highly volatile compound
responsible for the biocidal properties of metam There are various pesticides used to kill or inhibit
fumigants. MITC itself is registered as an antimi- the growth of fungi and their spores. Categories
crobial agent for wood poles and pilings. of fungicides include inorganic compounds
Cases of contact dermatitis associated with such as sulfur and copper, phthalimide com-
metam sodium have been reported in several pounds, thiocarbamates, and ergosterol synthesis
inhibitors. Cases of fungicide-related dermatitis or benzene) ring joined to a heterocyclic 5 sided

are shown in Table 7. (indole) ring, the phthalimido compounds can
act as reactive electrophiles. This chemical
property correlates with contact sensitization
6.1 Inorganic Compounds and carcinogenity in animal studies. According
to studies of captan given orally to animals,
Sulfur probably is the oldest known fungicide, phthalimide breaks down to the irritant
used to control powdery mildews, certain rusts, thiophosgene and to metabolites with partially
leaf blights, and fruit rots. Ticks and mites are also intact dicarboximide compounds such as tetra-
susceptible to sulfur. Elemental sulfur exists in hydrophthalimide (THPI), thiazolidine-2-thione-
various crystalline forms, with rings containing 4-carboxylic acid (TTCA), or phthalic acid.
6, 8, 10, or 12 sulfur atoms, or repeating Measurement of metabolites can be used to
concatenated chains (Cotton and Wilkinson estimate exposure when the relationship
1972). Insoluble in water but soluble in organic of absorbed dose and individual metabolites has
solvents, wettable sulfur is prepared by adding been established (Galea et al. 2011, 2015; Berthet
wetting and dispersing agents to finely ground et al. 2012). For purposes of predicting the skin
sulfur. Micronized wettable sulfur is made by effects of captan and the other phthalimido
means of a special manufacturing process to compounds, the potential formation of irritant
ensure an extremely fine particle size. thiophosgene by dermal metabolism appears the
In 2015, sulfur ranked number one for pounds most significant. Captan is still used in the U.S.
applied in the State of California (DPR 2015a) Based upon the published literature, plandrel,
with over 50 million pounds applied according captafol, and folpet have chiefly been used in
to reported pesticide use. Many of the sulfur prod- Europe.
ucts registered are for fruits and vegetables. Captan is a widely used fungicide on a variety
Grapes and peanuts are examples of crops com- of food and feed crops and ornamental plants. It is
monly treated with sulfur. Sulfur also has uses for also used as a seed protectant and in adhesives and
vertebrate control and for treatment of conditions paints as an antimicrobial. Agricultural workers
in domesticated animals such as dogs and horses. may be exposed during and after spraying opera-
Cases of dermatitis in applicators demonstrate its tions. Studies on pesticide ACD in India and
capacity for causing skin irritation, especially in Taiwan identified captan as a common sensitizer
hot weather when transformation to irritant oxides in farmers. Marzulli and Maibach (1974) demon-
of sulfur may occur more readily. Cases of ACD strated that a captan concentration of 1% is a
have also been reported. significant contact allergic sensitizer. Captan was
Copper products are extensively used in vari- reported to be a frequent sensitizer in Danish
ous agricultural and industrial settings as fungi- greenhouse and garden workers (Paulsen 1998).
cide, algaecide, and wood preservatives. Copper The ICDRG and NACDG later found captan in a
compounds formulated as dusts and as powders 1% concentration to be an irritant on patch testing;
are irritating to the skin, respiratory tract, and the 0.25% in petrolatum is now preferred for patch
eyes. Particularly, copper hydroxide, basic copper testing. Positive photo-patch-test reaction to 0.1%
sulfate, and copper sulfate pentahydrate have been captan in petrolatum has also been reported (Mark
reported to have severe skin and eye irritation et al. 1999).
potential (Hostynek and Maibach 2004). Captafol (Difolatan) is a broad-spectrum pro-
tective contact fungicide that is no longer sold in
the USA. It is effective for the control of almost all
6.2 Phthalimide Compounds fungal diseases of plants except powdery mildews
and is still used outside the U.S. It is reported as a
With a common structure of a 6 sided moderate irritant and sensitizer on an Extoxnet
(cyclohexene, partially unsaturated cyclohexane, toxicology summary (EXTOXNET 1998). Public
domain literature includes multiple reports field crops, turf, and ornamentals. Positive patch
regarding captafol-associated ACD. testing to PCNB, 1% in petrolatum, has been
described for a worker packing pesticide powders
who developed dermatitis (Cronin 1980). Positive
6.3 Thiocarbamate Compounds PCNB patch test reactions occurred in nursery
workers with exposure from routine handling
The thiocarbamate class includes reactive disul- and residue contact (O’Malley et al. 1995). Most
fide and tetrasulfide compounds and related sul- workers did not recall individual materials han-
fur-metal complex compounds with manganese or dled and work records were not available. It was
zinc. Related potassium and sodium not possible to determine if the PCNB reactions
thiocarbamate salts are used as fumigants. The arose from prior exposure or from de novo
compounds interact broadly with fungal enzyme sensitization.
systems. Potential systemic adverse reactions
include antithyroid activity produced by the
thiocarbamate metabolite ethylenethiourea (ETU), 6.4 Ergosterol Synthesis Inhibitors
antithyroid activity similar to propylthiouracil
(PTU), and inhibition of alcohol metabolism sim- The ergosterol synthesis inhibitors have a com-
ilar to disulfiram (Antabuse). ETU produces thy- mon mechanism, that of blocking synthesis of
roid adenomas in rodent cancer studies and the fungal desmethyl sterols or ergosterols which are
International Agency for Research on Cancer important to the integrity of the fungal cell mem-
(IARC) terms the evidence as sufficient to classify brane. The inhibitors include conazoles (triazoles)
it as an animal carcinogen, although the evidence and miscellaneous complex ring compounds
from human cancer studies is inconclusive (clas- such as myclobutanil, metalaxly, and triforine.
sified as inadequate by IARC). Pharmaceutical products with similar mecha-
Thiocarbamates and ETU have wide use in nisms include miconazole, clotrimazole, and keto-
the production of rubber products. Bruze and conazole. Triforine (Saprol) inhibits ergosterol
Fregert (1983) initially identified ETU as a con- synthesis in fungi, similar to conazole com-
tact sensitizer in a 53-year-old woman with der- pounds. Ergosterol inhibitors have broad agricul-
matitis of the fingers, who had worked for tural use on nuts, stone fruit, berries, vineyards,
15 years handling natural and synthetic rubber. ornamental crops, and landscape. Cases of ACD
20 controls did not react to 1% aqueous ETU. to pharmaceutical ergosterol-inhibitors have been
She reacted to a sample of black rubber and to reported in the public domain literature. Imazalil,
ETU in aqueous concentrations between 0.01% used to prevent postharvest spoilage of fruit,
and 1%, but not to 0.001% ETU. Many of the has caused ACD in banana packing/processing
thiocarbamate fungicides also cause sensitiza- workers (Penagos et al. 2004; Penagos 2002).
tion, possibly because of metabolism that gener- California illness surveillance data include similar
ates ETU in the skin. cases in workers packing/processing citrus treated
Thiophanate-methyl (TM) is a systemic fungi- with an imazalil.
cide with a broad spectrum of activity for plant
disease. TM is used on a variety of trees, vine, and
other crops, as well as lawns and ornamentals. 6.5 Miscellaneous Fungicides
There are no registered food uses in the U.S.
There have been many cases of apparent ICD, Fluazinam (Shirlan) is a broad-spectrum fungi-
but few cases of ACD to thiophanate-methyl cide of the phenyl-pyridinamine chemical class;
have been reported. it functions by interfering with fungal mitochon-
Pentachloronitrobenzene (PCNB) is a haloge- drial function. It is registered with the U.S. EPA
nated nitrobenzene fungicide used as a seed treat- for agricultural use on a variety of crops, including
ment and to control diseases on vegetable and peanuts, potatoes, and beans.
Chlorothalonil is an electrophile that inhibits formulations are inherently low risk (e.g., oral
thiol enzymes important for fungal spore germi- LD50 >5000 mg/kg in the rat, per acute toxicity
nation (Leroux et al. 2002) and sulfuhydryl reported to (DPR 2001)). A commonly marketed
groups important in glycolysis and fungal respi- formulation mixing glyphosate and the bipyridyl
ration. Depending upon species and route of diquat presents additional risk. Mixtures with the
administration, various glutathione conjugates herbicide metolachlor may present an unexpected
can be measured as urinary metabolites (Parsons risk of dermal sensitization. During the 1980s,
2001). It has a soil half-life of about 2 months and a case of sensitization initially attributed to glyph-
is stable on exposure to ultraviolet light. The U.S. osate subsequently proved related to an iso-
EPA (1999) noted in its registration-eligibility- thiazoline compound used in the formulation
document (RED) that manufactured chlorothalonil (Hindson and Diffey 1984a, b). Penagos (2002)
contains up to 0.05% contamination with hexa- reported 2 cases of apparent sensitization to
chlorobenzene. In a path test study, Liden (1990) glyphosate in patch test series from Panama. It is
reported that a chemical analysis of a sample not clear whether an isothiazoline preservative
40.4% chlorothalonil obtained from the manufac- might have been present in either of the reported
turer contained pentachlorobenzonitrile in con- cases.
centrations of 1–6 g/L. Public domain literature
includes reports of irritant dermatitis, ACD, and
contact urticaria. 7.1 Bipyridyl Compounds
Paraquat and diquat are bipyridyl compounds that

7 Herbicides have reactive ammonium ions in their core struc-
tures. Superoxides generated by the bipyridyl
Herbicides are used to control undesirable vege- compounds damage plant cell membranes and
tation and are now frequently used in place of cytoplasm and are especially active during photo-
hand labor or machine cultivation. Modes of synthesis. The compounds are absorbed by
action include by interfering with electron trans- foliage and translocated into the plant vascular
port in photosynthesis, disruption of microtubule system. Both paraquat and diquat are contact
function, inhibition of lipid synthesis and amino herbicides and desiccants, used on cotton, pota-
acid synthesis, and mimicry of plant hormone toes, and soybeans, alfalfa, clover, and soybeans.
(auxin) function. Most have low systemic toxicity, They have no biological activity once absorbed
but the very reactive bipyridyl compounds inter- onto clay soils or organic matter (Penagos et al.
fere with many mammalian cell functions and 2000). However, some degradation on leaf
may prove fatal with sufficient exposure. The surfaces results from photodecomposition
most numerous agricultural application of herbi- (Tomlin 1997). The acute toxicity of paraquat
cides occurs in row-crop farming, but non- (rat oral LD50 = 126 mg/kg) far exceeds that of
agricultural applications of lawns, parks, golf glyphosate.
courses, and other areas are also common. Herbi- Paraquat-related ICD have been reported.
cides are also used to control aquatic weeds in Because of limited dermal absorption, skin con-
irrigation and industrial water systems. Cases of tact with paraquat does not usually result in sys-
dermatitis associated with select herbicides are temic poisoning, with exceptions as reported
shown in Table 7. in public domain literature (Zhou et al. 2013;
Glyphosate [N-(phosphonomethyl) glycine] Wesseling et al. 1997; Garnier et al. 1994; Smith
is a nonselective, postemergence herbicide used 1988; Newhouse et al. 1978). Prolonged skin
on many food and nonfood field crops as well contact and prior damage to skin appear as pre-
as lawns and turf, residential areas, greenhouses, disposing factors in many fatal cases.
forest plantings, and industrial rights-of-way. Workers in factories where paraquat is
Based upon its mode of action, most manufactured have an increased risk of
occupationally induced keratoses, Bowen’s dis- Phenmedipham (Betanal) belongs to the

ease, and squamous cell carcinoma of the skin phenylcarbamate family and functions by inhibiting
(Bowra et al. 1982; Wang et al. 1987). The electron transport during plant photosynthesis. It
manufacturing process stream, potentially con- controls early stage broadleaf weeds for beets and
taminated with tarry polynuclear aromatics, may spinach. Severe allergic dermatitis associated with
have caused these premalignant and malignant phenmedipham (Betanal) was confirmed by patch
skin lesions, rather than the paraquat itself. testing in two farmers (Nater and Grosfeld 1979).
Diquat (or diquat dibromide), like paraquat, Cases of dermatitis accompanied by systemic
owes its herbicidal action to its effect on cell hypersensitivity have also been reported.
membranes and enzyme systems. This non- Dichlobenil (2,6-dichlorobenzonitrile) inhibits
selective mechanism accounts for its mammalian shoot formation from roots, acting principally as a
toxicity. Clark and Hurst (1970) reported a rat oral pre-emergent herbicide. Draize tests on multiple
LD50 for diquat equal to 231 mg/kg. Doses higher formulations showed only minimal irritation. The
than the LD50 produced CNS symptoms; chronic technical formulation did not produce sensitiza-
low dose administration in both dogs and rats tion in a guinea pig study, but a 15% aqueous
produced both produced cataracts. concentrate was positive in an assay using an
Amitrole (Aminotriazole) is a systemic herbi- intradermal induction phase. Development of
cide used to control nonselective grasses, broad- facial comedones in men engaged in mixing or
leaf weeds, cattails, poison ivy, and certain aquatic bagging dichlobenil was also reported. The lag
weeds. It is registered for nonfood uses, primarily times varied from 1 week to 5 months after begin-
industrial and nonagricultural uses, soils, and ning work and none of the men had prior history
ornamental crops. One case of ACD to of facial acne.
aminotriazole has been reported in a contract Triazines (Atrazine, Propazine, and Simazine)
weed control operator (English et al. 1986). are chlorinated triazine herbicides, systemic her-
Pyrazon [5-amino-4-chloro-2-phenyl-3(2H)- bicides usually applied to the soil. Once absorbed
pyridazinone], also known as chloridazon, is an through leaves and roots, these herbicides act by
herbicide belonging to the pyridazinone class of inhibiting photosynthesis within the targeted
pesticides. It inhibits photosynthesis by blocking plant. They are widely used as selective to control
electron transport. Pyrazon is registered for use on most annual grasses and broadleaf weeds before
sugar beets and red table beets to control certain the weeds emerge or after removal of weed
weeds. This compound is also registered for com- growth. The triazine herbicides have common
mercial use on ornamentals, including bulb crops chlorinated breakdown products and common
and roses. Pyrazon can persist in the soil for mechanisms of toxicity.
several months. The triazines cause minimal irritation in the
Pyrazon causes minimal irritation in the Draize Draize test and do not cause sensitization in pre-
assay and is negative in predictive animal sensiti- dictive allergy testing. California surveillance
zation studies. A formulation registered in Canada data does include occasional cases of irritation in
carries a sensitization warning, possibly related pesticide handlers associated with direct acciden-
to an isothiazolin compound that was included tal exposures. The public domain literature does
as a preservative. ACD to pyrazon spray has not clearly document cases of ACD associated
been reported in a farmer who developed derma- with triazines.
titis every spring when spraying pyrazon Acetanilides (chloroacetamide) herbicides
(chloridazon) or thinning treated plants (Bruze include Alachlor, Butachlor, Metolachlor, and
and Fregert 1982). Patch testing with a 1% con- Propachlor. These herbicides inhibit cell elonga-
centration of the AI and the formulated product tion and cell division, limiting emergence of
(43% AI) caused a vesicular, bullous reaction. developing leaves and roots. They act by electro-
Additional testing showed positive response to philic inhibition of elongase, the enzyme initiating
0.01% but not to 0.001% AI. the elongation of very long chain fatty acids.
Draize tests show moderate irritation for in the metabolism of alcohol, permitting the accu-
concentrated formulations of allidochlor and mulation of acetaldehyde.
butachlor. Predictive sensitization assays are Cases of work-related illness involving
positive for acetochlor, alachlor, and butachlor. hydrogen cyanamide have been reported. These
ACD confirmed by patch testing has been involved a mix of irritant skin reactions and
reported in public domain literature. A case of systemic symptoms. A case involving accidental
IgE-mediated allergic hepatitis associated with ingestion required intensive medical attention for
dermal exposure to butachlor in a worker from shock, coma, miosis, and hepatic necrosis.
India was reported (Daryani et al. 2007). Another case involving deliberate ingestion of
Butachlor is a rice herbicide, not currently regis- 50% hydrogen cyanamide proved to be fatal.
tered in the U.S. or the EU, but widely used in Because of the potential embarrassment of
Asia. claiming compensation for Antabuse-like reac-
2,4-Dichlorophenoxyacetic acid (2,4-D) is an tions, the actual number of cases is unknown.
herbicide in the phenoxy or phenoxyacetic acid
family. Like 2,4,5-Trichlorophenoxyacetic acid
(2,4,5-T) and sterically similar products, it func- 8 Insecticides
tions as a synthetic plant hormone or auxin that
disrupts normal growth of broadleaf weeds. Cases The new structural categories of insecticides
of ACD in farmers have been reported. Severe shown in Table 3 were associated with few
contact dermatitis associated with a mixture of reported cases of dermatitis. The section below
2,4-D and 2,4,5-T have been noted. concentrates on plant-derived compounds (pyre-
thrum, pyrethrin, and their synthetic derivatives;
nicotine and rotenone), the cholinesterase
7.2 Plant Growth Promoters and inhibitors, currently registered organochlorines,
Inhibitors organotin compounds, and biologicals.
Pyrethrum from the dried flowers of Chrysan-
Choline chloride (also known as chlormequat themum cinerariaefolium is the most widely used
chloride) belongs to the quaternary ammonium botanical insecticide in the U.S. Refined pyre-
class of chemicals. As a growth inhibitor, choline thrum or pyrethrin esters are the AIs extracted
chloride interferes with the synthesis of various from pyrethrum. The flowers and extracts for
plant hormones related to plant growth and pyrethrum are imported from Kenya and Ecuador
development. It is used on a variety of ornamen- into the U.S. Although pyrethrins are powerful,
tals grown in greenhouses and nurseries, and as a fast-acting contact-insecticides that are effective
turf treatment. There are currently no registered at very low concentrations, they have a low order
residential or food uses. A case of contact der- of systemic toxicity to most mammals.
matitis to choline chloride has been reported The active principals are pyrethrins I and II,
(Fischer 1984). California surveillance data do cinerins I and II, and jasmolin I and II, collectively
not show illnesses associated with choline chlo- known as pyrethrins. Pyrethrins are used exten-
ride, but do show occasional reports of dermatitis sively in stock sprays, pet sprays, household
associated with the related compound mepiquat sprays, aerosols, and food protection in ware-
chloride. houses. Considered nonsynthetic, pyrethrins
Hydrogen cyanamide stimulates plant growth have been allowed in organic crop production.
in a fashion similar to mechanical pruning by Pyrethrins are stable for long periods in water-
breaking dormancy in grapevine floral buds. based aerosols, in which modern emulsifiers are
This appears to result from intracellular accumu- used. To increase effectiveness, pyrethrins may be
lation of reactive oxygen and nitrogen species. mixed with a synergist such as piperonyl butoxide
In mammals, the biochemical effects include (PBO). PBO is a synthetic compound which
blocking the action of aldehyde dehydrogenase inhibits metabolic degradation of the AI.
Dermatitis from natural pyrethrins is usually The primary route of occupational exposure for
reported to occur on exposed body parts. Mitchell pyrethroids is skin contact. Systemic toxicity from
et al. (1972) identified the sesquiterpene lactone occupational contact with these agents is minimal.
pyrethrosin, as the chief allergen in unrefined The most prominent health symptom that accom-
pyrethrin. Asthma and urticaria have also been panies topical contact with these agents appears to
reported as reactions to natural pyrethrin be paresthesia caused by pyrethroid stimulation of
(Franzosa et al. 2007). However, the authors con- cutaneous nerve endings. The symptom resem-
tend that refined pyrethrum currently used lacks bles paresthesias produced by stimulant drugs,
the presence of proteins and other allergens likely but occurs at the site of contact. Inhalation may
to cause type I hypersensitivity. The report also produce stimulation of superficial nerves in the
provides an interesting summary of possible cases upper respiratory passages, increased nasal secre-
of type I reaction to unrefined or minimally tions, and other rhinitis symptoms, sometimes
refined pyrethrins dating back to 1897. accompanied by transient systemic symptoms
Caution should be used when interpreting (Spencer and O’Malley 2006).
results of allergy tests performed with current Temporary paresthesias manifested by numb-
pyrethrum allergen extracts; Osimitz et al. ness, itching, burning, tingling, and warmth have
(2009) found no detectable pyrethrins and been reported following cutaneous exposure to
pyrethrosin in six commercially available pyre- the synthetic pyrethroid fenvalerate. Fenvalerate,
thrum allergen extracts analyzed. Aside from produced in the U.S., produces more paresthesias
the absence of pyrethrins and pyrethrosins, following topical exposure than pyrethrin and
unknown components, such as high-molecular- other pyrethroids. Topical vitamin E acetate
weight proteins or other impurities that may appears to be highly effective in treating paresthe-
cause dermal reactions, could be present in sig- sias induced by pyrethroids (Tucker et al. 1984)
nificant amounts. Moreover, recent reports of if applied in a timely way after exposure.
pyrethrum producing ACD in humans and spec- Nicotine is extracted from tobacco plants
ulations of cross reactions occurring in rag- (Nicotiana species) and is one of the oldest botan-
weed-sensitized people should also be ical insecticides in use today. Having largely been
interpreted critically. replaced by organophosphate insecticides, only
Pyrethroids are synthetic compounds produced one product is currently registered for use with
to duplicate the biologic activity of the active the U.S. EPA. Nicotine may be readily absorbed
principals of pyrethrum. Pyrethroids have a longer through the skin and is toxic to mammals
duration of activity against insects than pyrethrum (Saleeon et al. 2015; Gehlbach et al. 1974;
and have greater biologic potency. In acute oral McBride et al. 1998).
toxicity studies, they typically have much lower Transdermally absorbed nicotine-induced
LD50 than pyrethrin. They are not teratogenic, predominantly sudorific and rubiform reactions,
mutagenic, or carcinogenic in animal studies. which may be accompanied by subtle piloerection,
There are two main classes of these synthetic hyperalgesia, and pruritus. Exposed workers may
insecticides. Type I pyrethroids do not have an develop nausea, vomiting, dizziness, prostration,
alpha-cyano group (allethrin, alphamethrin, and weakness. Abrasions on the skin during
barthrin, biopermethrin, bioresmethrin, cis- the harvesting of tobacco leaves increase the per-
methrin, cyclethrin, indothrin, permethrin, cutaneous absorption of nicotine. No positive
phthalthrin, and resmethrin), while type II pyre- patch-test reactions have been reported, even
throids have an alpha-cyano group attached to among cigar makers with dermatitis (Bonamonte
the 3-phenoxybenzyl alcohol of the molecule et al. 2016).
(deltamethrin, cypermethrin, fenvalerate, and Rotenone is a selective contact insecticide and
fenpropathrin). Like with pyrethrins, the activity repellent. Current registered products primarily
of pyrethroids may be enhanced by the addition of target vertebrate animals, specifically fish. The
a synergist such as PBO. cube plant is now the only commercial source in
the U.S. of rotenone for insecticide production, arsenicals have been superseded because of their
although derris, timbo, and other related rotenone- hazard to humans and animals.
containing plants have been utilized. The plant A handful of products remain registered as a
root may be ground as a dust or extracted to fungicide and insecticide for use as wood protec-
provide concentrate. tion treatments (arsenic acid and arsenic pentox-
Rotenone has, in the past, been used as dust for ide). Arsenic trioxide is also currently available as
garden insects, lice, and ticks on vertebrate ani- an ant bait and insecticide. Organic arsenicals
mals. Rotenone has also been used in combination such as monosodium methanearsonate (MSMA),
with pyrethrin and PBO (a synergist) to control a disodium methanearsonate (DSMA), calcium acid
wide variety of insects on food crops. methanearsonate (CAMA), and dimethylarsinic
Rotenone results in relatively low acute toxic- acid (cacodylic acid) were herbicides used primar-
ity with dermal exposure and has not been ily on cotton and turf and lawns. However, uses of
reported to be a sensitizer. Skin irritation from organic arsenic herbicides were discontinued due
rotenone has been reported among workers in to concerns that applied organic arsenicals could
rotenone processing plants in South America. potentially transform to more toxic inorganic
Skin inflammation was most notable in forms, which may contaminate drinking water.
intertriginous areas or where the powder had Inorganic arsenic is both a cutaneous irritant
been trapped by perspiration on the skin. A similar and sensitizer. Hyperkeratosis, hyperhidrosis,
outbreak was reported among workers in France, and hypermelanosis are considered evidence
but improved ventilation and dust masks dimin- of chronic systemic exposure. The hyper-
ished the occurrence of dermatitis in these pigmentation is most marked on surfaces exposed
workers (Hayes 1982). to light and does not extend to mucous mem-
Odor from an application of rotenone to a branes. There may be a speckled depigmentation
Northern California lake was associated with of pigmented areas giving a “raindrop” appear-
symptoms in residents of a nearby community. ance. Arsenic compounds similar to or identical
The odor was probably related to a naphthalene- with those used as pesticides have been shown to
range aromatic solvent present in the formulation be carcinogenic in man (Hayes 1982). Agricul-
rather than the AI (Verder-Carlos and O’Malley tural workers are also exposed to chronic ultravi-
2002). olet (UV) light. It had been believed that UV light
Spinosad is an organic insecticide made up exposure was a more significant factor for these
of spinosyn A and spinosyn D, derived from workers than their exposure to inorganic arsenic.
soil microbes (actinomycete organism Saccharo- Fenbutatin-oxide provides an alternative to
polyspora spinosa). Spinosad compounds selec- propargite for the control of mites. Other
tively inhibit nicotine receptors in insects organotin compounds are used primarily as anti-
(Kirst 2010). microbials in industrial settings. No public
domain reports on skin effects of fenbutatin-
oxide were found. The 31 studies retrieved
8.1 Inorganic and Organometallic focused on analytical and product chemistry,
Insecticides and pest resistance.
Propargite is an organosulfite which controls
Arsenic compounds were the earliest insecticides mites by inhibition of a mitochondrial enzyme,
against chewing insects, chiefly as copper ATP synthase. It causes direct skin irritation,
acetoarsenite (Paris green), lead arsenate, and cal- both in pesticide handlers (mixer, loaders, appli-
cium arsenate. Sodium arsenite has been used as a cators, field flaggers for aerial applications, and
sterilant herbicide and a potato vine killer. Sodium workers who repair contaminated spray equip-
arsenate was formerly the toxicant in many ant ment) and field workers in contact with residue.
syrups for household use, but this application has The long environmental half-life has necessitated
been discontinued. For the most part, inorganic long postapplication re-entry intervals.
A noteworthy 30% extended release prepara- general, petroleum distillates and other solvents
tion has not been registered since the 1990s; it was have poor dermal permeability in the vapor phase.
associated with an outbreak of dermatitis among Some compounds can be dermally absorbed with
orange harvesters published in 1986. The envi- prolonged skin contact (e.g., toluene, carbon tet-
ronmental dissipation rate for this formulation did rachloride). For some aliphatic solvents, mild skin
not differ substantially from the rate for the 32% irritation has been reported for short-term expo-
wettable powder (WP), studied during a subse- sure, while dermatitis has been reported with
quent outbreak in 1988. However, the initial res- repeat or prolonged skin contact.
idue deposition was markedly elevated compared
to the WP formulation.
8.3 Organophosphates
8.2 Kerosene, Petroleum Distillates, As a group, organophosphate compounds have a

and Other Solvents low capacity for causing skin irritation, based
upon their chemical structure. Individual com-
Aliphatic solvents include mineral oils and ali- pounds have reactive subgroups (termed “leaving
phatic petroleum hydrocarbons, which are prod- groups,” separated by hydrolysis of the parent
ucts of various types of petroleum distillation compound) that may produce irritation or sensiti-
processes. These chemicals have had insecticide zation. Noteworthy examples include naled and
and/or larvicide uses as spray oils on agricultural dichlorvos.
crops and by residential homeowners, as well as Many of the most toxic organophosphate com-
occupational and residential uses as acaricides, pounds are no longer registered and the number of
fungicides, and herbicides, in addition to aquatic reported systemic poisonings drastically reduced
uses as mosquito larvicides/pupacides. These (DPR 2004, 2010, 2015c). Nevertheless evalua-
chemicals are also commonly used as inert ingre- tion for systemic toxicity is usually indicated
dient in formulations of pesticides with other AIs. when dermatitis from one of these agents occurs.
Petroleum oil, mineral oil, petroleum distillates, Dimethoate is a systemic organophosphorus (OP)
and kerosene each ranked in the top 100 pesticides insecticide/acaricide used on a variety of field grown
used in California in 2015, based on pounds agricultural crops, tree crops, and ornamentals. All
applied statewide (DPR 2015a). nonagricultural uses in the U.S., including residential
Kerosene, first used in 1877, may have been uses, were cancelled in 2000. The major toxic
the first petroleum oil to be used for insect control. degradate of dimethoate is omethoate [O,O-dimethyl
Presently, it is widely used as a solvent or carrier S-(Nmethylcarbamoylmethyl) phosphorothioate].
for household and industrial pesticide sprays. Omethoate is registered as an AI internationally, but
Registered in the State of California as an adju- not in the U.S. Use of OPs in California has contin-
vant (broadly defined as any nonpesticide material uously declined since 1995 (DPR 2004, 2010,
added to a pesticide product or pesticide spray 2015c).
mixture to enhance the pesticide’s performance), Malathion is a broad-spectrum organophos-
kerosene is considered to be an “inert” ingredient phate (OP) insecticide, with moderate to low sys-
by the U.S. EPA. Kerosene may be sulfonated to temic toxicity. Its uses include control of a wide
provide an odorless oil, or deodorants may also be variety of insects: in various food and feed crops,
added. pastures and rangeland, outdoor garden insects
Kerosene and other petroleum distillates are around the home, and for pest eradication pro-
known cutaneous irritants. An eruption similar to grams. The small number of current registrations,
that of toxic epidermal necrolysis “irritant pseudo- in contrast to the larger number of inactive regis-
toxic epidermal necrolysis” was described in a trations, reflects changing patterns of use.
boy whose clothing became contaminated with Naled is an insecticide and acaricide used on
kerosene (Barnes and Wilkinson 1973). In food and feed crops and on nonfood crops (such
as ornamentals, and alfalfa grown for seed and propoxur. Patch test series with positive tests for
cotton). Public health and residential uses for carbaryl include Penagos (2004) and Sharma and
naled are primarily for the control of mosquitos. Kaur (1990).
It is also used to control black flies and leaf-eating Methiocarb (Mesurol) is a carbamate insecti-
insects. Intermediate in toxicity between mala- cide, acaricide, molluscicide, and avian repellant.
thion and parathion, naled is broken down ACD due to methiocarb has been reported.
by hydrolysis within a few hours. In its native
form, the reactive element in naled is the
dibromodichloropropanol moiety, hypothetically 8.5 Insect Repellants
formed as an intact molecule on breakdown.
Dichlorvos (DDVP) forms as an environmental Diethyltoluamide (DEET) is an insect replant
transformation product of naled. Surface residues first developed by the U.S. Army for use by
after naled application on grapes, for example, military personnel and later registered for use as
contain about 30% dichlorvos 6 hr after applica- an insect repellent in 1957. DEET, considered the
tion (Penagos et al. 2000). best all-purpose insect and acaricide, is espe-
Dichlorvos (2, 2-dichlorovinyl dimethyl phos- cially effective against mosquitoes. Poorly solu-
phate), also known as DDVP, has been formulated ble in water, it is soluble in ethanol and propylene
as sprays, wettable powder, aerosols, resin strips, glycol and remains effective for several hours
flea collars, and as a veterinary anthelmintic. It is post-application. DEET has repeatedly been
closely related to two other OP insecticides, naled associated with contact urticaria. At application
and trichlorfon. Both compounds metabolize or rates greater than 30%, it can cause skin
degrade to DDVP in food, water, or the environ- irritation.
ment. Accidental contact can cause irritation to
the skin, possibly complicated by systemic cho-
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70
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1060
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1060
3 Irritancy (Lovell 1993a; Modi et al. 2009) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
3.1 Mechanical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
3.2 Chemical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
4 Phytophotodermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
5 Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
5.1 Chemical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
5.2 Immunological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
6 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
6.2 Chemistry of Plant Allergens (Benezra and Ducombs 1987) . . . . . . . . . . . . . . . . . . . 1067
6.3 Investigation of the Patient with Suspected Plant Contact Dermatitis . . . . . . . . . . 1067
6.4 Specific Plant Families . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
7 Occupations at Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1072
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073
Abstract a standard series can often provide clues to

Many occupations entail exposure to plants plant allergy; this can be supported by adding
and plant products. Plants can induce photo- a plant series. Unfortunately, reliable screening
toxic, irritant and allergic reactions. A careful materials are not commercially available for
clinical history should distinguish phototoxic investigating many plant allergens and it may
from allergic reactions, and patch testing is not be necessary to test with the plant itself, ensur-
appropriate in the former case. In suspected ing that it is not a known irritant or toxic on
allergic contact dermatitis, patch testing with contact. If a “new” allergenic plant is identi-
fied, it is important to test control subjects to
the material to exclude irritancy.
C. R. Lovell (*)
Department of Dermatology Unit, Royal United Hospital,
Bath, UK
e-mail: christopher.lovell@nhs.net

https://doi.org/10.1007/978-3-319-68617-2_69
1060 C. R. Lovell
Keywords Table 1 Some occupations exposed to plants and plant

Skin · Plants · Dermatitis · Irritant · products
Phototoxic · Urticaria · Occupation · Gardeners, horticulturalists, nursery workers, fruit
Allergens · Irritants · Hypersensitivity · Patch pickers
testing · Anacardiaceae · Compositae · Farmers, agricultural workers (e.g., compositae, notably
Parthenium hysterophorus)
Apiaceae · Herbal medicines · Alstroemeria
Florists, flower arrangers, flower pickers, packers
Botanists, naturalists, laboratory workers
Herbalists, aromatherapists (> Fig. 1), masseurs,
1 Core Messages homeopaths
Pharmacists, pharmacologists, organic chemists, plant
1. Occupational skin reactions to plants are com- biochemists
mon and under-reported. Dentists (e.g., oil of cloves), veterinary surgeons (plant
contaminants in animal fur)
2. Reactions may be irritant, phototoxic, urticar-
Perfumers (e.g., essential oils, lichen acids), beauticians,
ial, or allergic. cosmetologists
3. Correct identification of the plant is essential. Food handlers, chefs, sandwich makers, food/grain
Do not patch test “blind” with an unknown processing workers
plant as it may cause chemical burns or sensi- Bartenders (e.g., mint in cocktails)
tize the patient. Sports (e.g., golf, fishing, climbing)
4. Urticaria may be chemically or immunologi- Military (plant exposure on exercise, dhobi marking)
cally induced. Delivery drivers, packers
5. Phototoxic reactions are confined to areas Tobacco workers
exposed to plant material plus UV light. They Musicians (e.g., cane reeds used for saxophones/
clarinets, tropical hardwood recorders)
can be prevented by adequate photoprotection.
Office workers (e.g., foliage plants such as Philodendron,
6. Most allergic reactions are caused by Schefflera)
a small number of plant families, inclu- Textile/flax workers
ding Anacardiaceae (e.g., poison ivy) and Beekeepers (propolis)
Compositae or Asteraceae (e.g., Toddy tappers (Sri Lanka – frictional dermatitis)
chrysanthemum).
7. Patch testing should be performed in depart-
ments with expertise in the technique, using occupations, notably floristry, forestry, agricul-
commercially available plant allergens where ture, and horticulture. Allergic contact dermatitis
possible and testing controls to suspected to plants was attributable to occupation in 30.4%
“new” plant allergens. of patients in a series from Northern Spain
(Cabanillas et al. 2006). Plant products are
increasingly used in cosmetics and toiletries, and
2 Introduction the prevalent desire for “natural” remedies puts
aromatherapists (Fig. 1), masseuses and herbalists
Plants are essential to our existence; we eat them, at risk of plant dermatitis.
grow them for ornament, wear clothes derived Skin reactions to plants include irritancy,
from them, and use plant products in cosmetics, phototoxicity, urticaria (due to toxic substances
toiletries, and medicines. It is therefore not sur- in the plant), or allergic contact dermatitis.
prising that adverse reactions to plants can affect These mechanisms are discussed below, foll-
many different occupations (Table 1). The propor- owed by a summary of the principal plant fami-
tion of occupational dermatitis due to plants is lies causing allergic contact dermatitis and the
difficult to determine; reports range from 1% in major occupations at risk of plant toxicity and
Denmark (Halkier-Sorensen 1996) to 14.3% in allergy. The subject was reviewed elegantly by
South Carolina (Shmunes and Keil 1983). Plants JD Guin in the first edition of this textbook (Guin
are a more frequent cause of dermatitis in some 2000).
70 Plants 1061
Fig. 1 A selection of
aromatherapy oils
Accurate Latin identification of the suspected

plant is highly desirable, but sometimes difficult. It 3 Irritancy (Lovell 1993a; Modi
is useful to have illustrated copies of the local wild et al. 2009)
and garden flora in the clinic. Remember that the
same common name is often applied to several 3.1 Mechanical
different plant species. If the patient is asked to
bring in plant material for testing, stress that each Several plants are armed with spines or hooks as a
plant sample should be packaged separately to avoid defense against predation. Hairs (trichomes) on
cross-contamination of potential allergens. If you the plant surface may also discourage predators
wish to send plant material for botanical identifica- and also facilitate trapping water, notably in desert
tion, it is best to dry it, e.g., lightly compressed regions. Penetration of the skin by thorns may
between paper towels; a botanist will not be pleased facilitate entry of microorganisms, e.g., sporotri-
to receive a soggy mass of decayed plant soup in a chosis and Mycobacterium ulcerans in the tropics.
sealed polythene bag! Good photographs showing Farmers and agricultural workers walking bare-
the plant habit, details of leaves and flowers, foot are especially at risk.
together with details of the habitat, are invaluable. Many gardeners handling tomato seedlings will
A careful clinical history and examination notice tingling of the fingers, but repeated handling
should help to elucidate the type of clinical reac- of hair-bearing herbs such as borage (Borago
tion. Patch testing is only helpful when allergic officinalis) may induce irritant contact dermatitis.
dermatitis is suspected. Never patch test with an Cacti such as Opuntia ficus indica possess tufts of
unknown plant; there is a risk of inducing chem- small spines (glochids) which can induce pruritus
ical burns or sensitizing the patient. Initially in operatives harvesting the fruit (e.g., Sabra der-
screen the patient with commercially available matitis in prickly pear pickers). Mechanical and
plant allergens as well as a baseline series which chemical irritation of the skin can enhance the
may often give clues to plant allergens. Before penetration of potential allergens.
reporting “new” plant allergens, it is important to
test the suspected plant for irritancy in control
individuals. 3.2 Chemical
Several textbooks (sadly mostly out of print)
have been written on plant dermatoses. The major Many plants contain chemical irritants in the sap
ones are listed below. A useful historical database (latex), which may drip from uninjured leaves
of dermatitic species, based on Mitchell and (guttation fluid), or housed in specific organelles
Rook, is available on the Internet (Schmidt 2001). which release chemical irritants on trauma. Mass
1062 C. R. Lovell
production may enhance the irritant effect of plant family (Araceae) can induce severe chemical irri-
sap, as in chicory production (Rycroft et al. 1987, tation, even leading to cutaneous necrosis. An
Figs. 2 and 3). The Euphorbiaceae (spurge family) example is the dumb cane, Dieffenbachia, com-
contain many species which induce severe monly sold by florists and used as an ornamental
irritancy on skin contact, resembling burns house or office plant. In addition to calcium
(Bucak et al. 2016) and conjunctival irritation or oxalate crystals, the irritants include matrix meta-
even blindness; these include the manchineel tree lloproteinases (Mirastschijski et al. 2010). Some
(Hippomane mancinella) and many ornamental genera possess urticant hairs (see Sect. 5 below).
garden plants and weeds; the unsuspecting gar- Because of the potential irritancy of many plant
dener is particularly at risk. Several bulb species species, an unknown plant should never be
contain calcium oxalate crystals in the bulb and applied to the patient’s skin under patch test con-
flower stem, inducing irritant contact dermatitis in ditions. In addition to the risk of chemical burns,
pickers and bulb handlers, e.g., “daffodil itch” there is a risk of active sensitization to the plant.
(Julian and Bowers 1997). Members of the arum
4 Phytophotodermatitis
This term refers to a toxic eruption induced by

contact with furocoumarins in plant sap and expo-
sure to ultraviolet light. Furocoumarins are het-
erocyclic compounds formed by fusion of a furan
ring with coumarin (benz-α- pyrone). They appear
to act as natural fungicides in the plant, and their
concentration may be increased if the plant is
injured. They are found in several members of
the umbellifer family (Apiaceae), which include
parsley, celery, and parsnip, Rutaceae, including
rue, citrus fruit and burning bush (Dictamnus),
and Moraceae (Ficus carica – fig tree). Phototoxic
reactions are typically linear (caused by brushing
against the plant with bare skin and subsequent
exposure to UVA), dusky red, and bullous, later
Fig. 2 Processing of chicory becoming hyperpigmented. The distinguishing
Fig. 3 Sap exuding from

broken chicon
70 Plants 1063
Table 2 Distinctions between phototoxicity and allergic contact dermatitis

Phototoxicity Allergic contact dermatitis
All lesions develop simultaneously Lesions may gradually evolve
Sharply demarcated to light-exposed areas Not restricted to light-exposed areas
Typically streaky, vesicular, or bullous May be streaky, erythematous, but can be vesicular or bullous
Often painful Pruritic
Hyperpigmentation may persist for months Minimal, if any hyperpigmentation
Common in children Typically resolves with scaling
Commoner in adults
Recurrent episodes typical
features from allergic contact dermatitis are

outlined in Table 2. The hyperpigmentation has
been used in folk medicine in many cultures to
treat vitiligo and is the basis of PUVA therapy in
dermatology and some tanning remedies.
Children at play are particularly at risk of pho-
totoxicity and may be wrongly diagnosed as vic-
tims of child abuse. Horticultural and agricultural
workers frequently present with phototoxic reac-
tions, when working scantily clad in sunny
weather (Figs. 4 and 5). Atypical patterns include
a more widespread maculopapular eruption
caused by release of plant sap by string trimmers
(“strimmer rash”) (Oakley et al. 1986; Reynolds
et al. 1991). Mechanical processing of parsley
and other herbs, e.g., for Balti cuisine (Fig. 6),
may also induce an airborne pattern of phototox-
icity. Phototoxic reactions to citrus fruit
include “berlock” or “breloque” dermatitis from
application of oil of bergamot from Citrus
bergamia and exposure to limes in catering
and bar work. Fig harvesters may develop photo-
toxicity and even photoallergic dermatitis to
furocoumarins (Bonamonte et al. 2010). The con-
dition can be prevented by adequate photo-
protection with clothing and sunscreens effective Fig. 4 Bullous phototoxic reaction after harvesting pars-
in the UVA range (Vale 1993). nips in summer
5 Urticaria defense against predation. The hairs themselves

elicit a mechanical irritant reaction (Cummings
5.1 Chemical and Olsen 2011). The toxic chemicals
include histamine (which induces urticarial
The term urticaria (hives) is derived from weals), acetylcholine, and 5-hydroxytryptamine
the stinging nettle (Urtica spp.) which injects and also a neurotoxin which can cause
toxins into the skin from sharp hairs (emergences) delayed dysaesthesiae (Oliver et al. 1991; Ander-
on the surface of the plant (Fig. 7). This acts as a son et al. 2003).
1064 C. R. Lovell
Other stinging plants include Laportea spp. at risk. The reactions are often trivial but may be
and members of the Loasaceae, mostly found in severe with some tropical and subtropical species,
South America (Thurston and Lersten 1969). notably Dendrocnide in Australasia.
Agricultural and horticultural workers are chiefly
5.2 Immunological
Immediate type 1 reactions occur in individuals

who have been previously sensitized to the plant
or plant product. Irritant hairs on the plant surface
enhance the penetration of the antigen. Food han-
dlers are especially at risk, perhaps aggravated by
wet working conditions leading to maceration of
the skin; however, gardeners and agriculturalists
are also at risk. Even office workers may be sen-
sitized to house plants such as Ficus benjamina
(Pradalier et al. 2004). Health care workers in
particular are at risk of sensitization to hevein in
rubber latex, derived from the sap of Hevea
brasiliensis, although operatives tapping the trees
to extract the sap are also at risk. Cross-reaction
may occur with fruit, including banana and
avocado.
Allergenic proteins in several fruit, vegeta-
bles, and nuts are implicated (Amaro and
Goossens 2008). Type 1 reactions may present
as an exacerbation of chronic dermatitis
(protein contact dermatitis); patch tests are
typically negative, but prick tests positive
(Levin and Warshaw 2008). Some plants
reported to cause immunological contact urti-
Fig. 5 Phototoxic reaction to rue. This decorator was
painting a window, wearing shorts and calf-length boots,
caria are listed in Table 3. Oral allergy
whilst leaning against a rue bush syndrome may be induced by profilins.
Fig. 6 Parsley
processing mill
70 Plants 1065
These are found in many plants, especially in the

pollen. Different profilins share IgE epitopes,
explaining the frequent cross-reaction between
widely diverse plant species (Sirvent et al. 2011).
Detecting IgE antibodies to a single represe-
ntative profilin is often sufficient to diagnose or
exclude profilin sensitivity (Villalta and
Asero 2010).
Reactions range from urticaria to life-
threatening anaphylaxis, e.g., from ingesting pea-
nuts, and the severity of the reaction may be
enhanced by exercise. Plant food additives may
put food handlers at risk of urticaria, asthma, or
anaphylaxis, including the increasing use of ses-
ame seeds and flour derived from lupin (Lupinus)
in bakery (Hieta et al. 2009; Campbell and
Yates 2010). Prick testing with the suspected
plant material is usually diagnostic. Although
generally a safe procedure, it should always be
performed where resuscitation facilities are avail-
able, in view of the rare risk of anaphylaxis, e.g.,
to henna or some nuts (Van de Scheur and
Fig. 7 Urtica dioica Bruynzeel 2004).
Table 3 Plants or plant products reported to cause immunological contact urticaria or anaphylaxis (Lovell 1993a)
Vegetables/herbs Beans (alfalfa, chick peas, runner beans, winged bean (Psophocarpus), cabbage, carrot,
cauliflower, celery, chives, coriander, caraway, cumin, cucumber, dill, endive, garlic, bell pepper,
leek, lettuce, mustard, onion, parsley, parsnip, potato, rapeseed, shallot, spinach, thyme, tomato,
watercress
Fruits Apple, apricot, banana, grapefruit, kiwi fruit, lemon, mango, melon, orange, pineapple,
strawberry
Spices Cinnamon
Nuts Tree nuts, almond, hazel, Brazil, peanuts
Other economic Coffee, Cannabis, cotton, rubber tree (Hevea), hop, henna, flax, castor oil plant, Semecarpus
plants anacardium (source of dhobi mark)
Essential oils Sesame oil
Cosmetic Balsam of Peru, lime extract in shampoos
ingredients
Grasses/cereals Wheat, maize, barley, rye
Herbaceous plants Ivy, iris, Blumea gariepina (South Africa), Tanacetum cinerariifolium, Monstera deliciosa (edible
fruit in tropics), Salsola kali (tumbleweed), Trifolium pratense (red clover), tulips,
chrysanthemums, Bougainvillea
Shrubs Agave, Cornus sanguineus (bloodtwig dogwood), Cotoneaster, Crataegus (hawthorn), Grevillea
juniperifolia, Hakea suaveolens (Australia)
Algae Lyngbya majuscula
Lichens
Horsetails Equisetum
Trees and woods Birch, Indian rosewood (Dalbergia latifolia), Eucalyptus, larch, Philippine red mahogany
(Shorea), teak (Tectona grandis), Limba tree (Terminalia superba), Thuja plicata (arborvitae,
western red cedar), obeche/abachi (Triplochiton scleroxylon)
1066 C. R. Lovell
6 Allergic Contact Dermatitis there is repeated handling of plants on a massive

scale (Fig. 8). Typically a pruritic eruption
6.1 Introduction develops in a streaky pattern within 24–48 h of
re-exposure, and it may be bullous and may
Relatively few plant families are major causes of evolve gradually over a few days, perhaps due to
allergic contact dermatitis, although several spe- persistence of the allergen. Several clinical fea-
cies have been implicated in case reports tures distinguish it from phototoxicity (Table 2).
(Table 4). Worldwide, the Anacardiaceae, includ- Tulip bulb handlers develop hyperkeratotic fis-
ing Rhus (Toxicodendron) (poison ivy, poison sured areas on the finger tips and cooks develop
oak) and Compositae or Asteraceae, daisy family, a similar eruption affecting the thumb, index, and
predominate. Other significant genera include middle finger tips of the nondominant hand,
Primula, Hedera helix (ivy), bulbous genera caused by garlic (Fig. 9).
such as Tulipa, and the related Alstroemeria. Some plant allergens are volatile, inducing an
Tropical hardwoods and ingredients of plant- airborne pattern of dermatitis; in others, e.g.,
derived fragrance materials and colophony from Compositae, the allergens are transferred through
pine trees are also important allergens. airborne particles on the plant surface (Paulsen
Sensitization can follow repeated exposure et al. 2007) or by finger contact with the face or
to the plant, and florists (see ▶ Chap. 153, “Flo- penis. Contact allergy to quinones such as primin
rists”) and gardeners (see ▶ Chap. 158, “Gar- and allergens in some tropical hardwoods may
deners”) are especially at risk, particularly if present as an erythema multiforme-like eruption.
Table 4 Some plant families implicated in allergic contact dermatitis

Important families: Anacardiaceae (including poison ivy/oak)
Compositae (Asteraceae)
Primulaceae (Primula obconica)
Araliaceae (ivy)
Lamiaceae/Labiatae (mint, thyme, lavender, sage)
Alstroemeriaceae (Alstroemeria)
Liliaceae (tulip, lily)
Alliaceae (garlic, onion)
Jubulaceae (liverworts, e.g., Frullania)
Lichens (Evernia, Parmelia, etc.)
Cupressaceae and Pinaceae (conifers)
Tropical hardwood families, including Dipterocarpaceae, Sterculiaceae, Burseraceae, Meliaceae, Leguminosae,
Sapotaceae, Ebenaceae, Bignoniaceae, Verbenaceae, Lauraceae, Hernandiaceae, Proteaceae (Grevillea), Thymelaceae,
Moraceae
Other families reported to cause allergic reactions: Magnoliaceae, Illiciaceae (star anise), Annonaceae (ylang ylang),
Papaveraceae (Meconopsis cambrica), Brassicaceae/Cruciferae (black mustard, radish), Capparidaceae (caper),
Cistaceae (Cistus), Cactaceae (Schlumbergia), Caryophyllaceae (carnation), Malvaceae (okra), Linaceae (flax),
Zygophyllaceae (creosote bush), Geraniaceae (Pelargonium), Rutaceae (citrus fruit), Burseraceae (olibanum), Vitaceae
(grape), Hippocastanaceae (horse chestnut), Aceraceae (maple), Saxifragaceae (Tolmeia), Hydrangaceae (hydrangea),
Hamamelidaceae (storax), Myrtaceae (tea tree, Eucalyptus), Lecythidaceae (Brazil nut), Lythraceae (henna), Apiaceae/
Umbelliferae (carrot, Centella asiatica), Rubiaceae (coffee, madder), Styraceae (styrax), Oleaceae (olive, jasmine),
Apocyanaceae (periwinkle), Hydrophyllaceae (Phacelia, Wigandia), Solanaceae (Capsicum, tobacco), Gesneriaceae
(Streptocarpus), Pedaliaceae (sesame), Myristicaceae (nutmeg, mace), Lauraceae (sweet bay, cinnamon), Santalaceae
(sandalwood), Euphorbiaceae (poinsettia), Buxaceae (Simmondsia), Cannabinaceae (hop, cannabis), Juglandaceae
(walnut), Fagaceae (oak), Salicaceae (poplar), Orchidaceae (vanilla), Zingiberaceae (ginger, myoga), Dioscoraceae
(yam), Aloeaceae (aloe), Asparagaceae (asparagus), Agavaceae (agave, century plant), Hyacinthaceae (hyacinth),
Amaryllidaceae (Narcissus), Iridaceae (iris), Commelinaceae (Tradescantia), Palmaceae (palms), Araceae
(Philodendron, Epipremnum), Graminaceae (grasses, cereals), Ginkgoaceae (Ginkgo), Dryopteridaceae, Oleandraceae
(ferns)
70 Plants 1067
Reactions may be severe, requiring potent top-

ical steroids, even on the face for short periods and
often systemic prednisolone (30–60 mg od).
6.2 Chemistry of Plant Allergens

(Benezra and Ducombs 1987)
The chemistry of the major plant allergens can be

classified according to their chemical structures.
Lipophilic phenol derivatives include urushiol in
poison ivy and related phenols in Gingko and
Grevillea. They are prohaptens, being converted
to allergenic electrophilic haptens after they pen-
etrate the skin. Lactones include over several hun-
dred Sesquiterpene lactones, found especially in
Compositae (daisy. Quinones include primin
(in Primula obconica) and related quinones in
Phacelia and several tropical woods. Terpenes
are found in conifers (e.g., allergens in colophony)
and many essential oils (e.g., limonene in
lemon rind). Terpenes such as linalool are impor-
tant causes of fragrance allergy; oxidization ren-
ders them allergenic (Karlberg et al. 2008;
Fig. 8 Mass production of bedding plants Christensson et al. 2010).).
6.3 Investigation of the Patient

with Suspected Plant Contact
Dermatitis
A careful clinical and occupational history

should be taken. A site visit may be necessary.
Patch testing in a specialized dermatology
department is the most definitive investigation,
but it is fraught with problems. The patient may
bring a vast array of poorly identified plants.
Patch testing “blind” with plant material carries
Fig. 9 Fingertip dermatitis in non-dominant hand due to a significant risk of chemical burns due to
garlic (patient is left-handed) irritancy, or active sensitization of a previously
unsensitized patient, notably to Alstroemeria,
Although airborne contact dermatitis may result in Primula obconica, or Anacardiaceae. Where
photosensitivity (chronic actinic dermatitis), true possible, it is desirable to test using purified
photoallergy to plants is very rare; exceptions allergens, e.g., primin (a screen for Primula
include photosensitization to psoralens in obconica), α-methylene γ-butyrolactone
fig (Ficus carica) (Bonamonte et al. 2010) and (in tulips and Alstroemeria), diallyldisulphide
possibly Parthenium hysterophorus in India (garlic), and the sesquiterpene lactone mix
(Lakshmi and Srinivas 2007; Kar et al. 2009). (a screen for Compositae). Testing with a
1068 C. R. Lovell
standard series may also give clues to possible allergenic, and it is important to wash the contam-
plant allergy, e.g., fragrance allergens, propolis, inated area, ideally with soap and water or an
and colophony. organic solvent, as soon as possible after contact
If testing with the plant is unavoidable, lightly (Boelman 2010; Paniaqua and Bean 2011). The
crush leaves or petals and cut stalks into thin black spot test can be used in the field to distin-
slices. Always identify the plant before testing guish toxic Rhus species from similar-looking
and check that it is not a known irritant. Try not innocuous plants (Guin et al. 1981). The allergens
to test with several different plants at one time; are not transmitted by pollen. Systemic contact
multiple positive reactions may create an “angry dermatitis can be induced by ingestion, notably
back” or “excited skin” syndrome. If a positive Rhus added to chicken as a health food in Korea
patch test reaction is elicited to a plant, test 10–20 (Yoo et al. 2010) in individuals previously sensi-
controls for irritancy. tized to lacquer.
Where possible, it is desirable to confirm a The allergens are alk(en)yl catechols (uru-
positive patch test to plant material by testing to shiols); allergenicity depends in part on the num-
extracts and ideally identifying the allergen. This ber of double bonds in the side chains (Johnson
can prove time-consuming, frustrating, and et al. 1972). Similar catechols are found in Ginkgo
expensive. Inflammable organic solvents such and the Australian genus Grevillea (Fig. 13).
as ethyl ether or methanol are often used to Recent preliminary studies have determined the
make extracts, and further purification requires DNA sequence of Toxicodendron radicans
chromatographic techniques including thin layer (Weisberg et al. 2017).
chromatography and high pressure liquid chroma- Prevention ideally involves avoidance of plant
tography. The precise chemical structure is iden- contact, a counsel of perfection in rural parts of the
tified using mass spectrometry and nuclear USA. Barrier creams such as quaternium benton-
magnetic resonance. (Lepoittevin 2000). ite or antigen binding agents such as Stokogard
may be helpful (Orchard et al. 1986). Hyposensi-
tization was previously attempted but is no longer
6.4 Specific Plant Families current practice. However, some individuals
working with Anacardiaceae woods appear to
6.4.1 Anacardiaceae become tolerant to the allergen.
This family is probably the most important
cause of allergic contact dermatitis worldwide. 6.4.2 Compositae/Asteraceae
It includes Rhus, formerly Toxicodendron, The daisy family is one of the largest, with over
radicans, and toxicarium (poison ivy and poison 22,750 known species, and a worldwide distribu-
oak respectively), major allergens in the USA, tion. Many species are weeds. Accidental intro-
Rhus succedaneum and vernicifluum (sources of duction of Parthenium hysterophorus, a Texan
Japanese lacquer) (Figs. 10 and 11), Anacardium native, in grain to India has created major out-
occidentale, the cashew nut tree, and Mangifera breaks of dermatitis in rural areas; the species has
indica (mango), both cultivated in the tropics, and also spread to Queensland and several African
Smodingium in Southern Africa. countries, where it can decimate sorghum crops.
Dermatitis can be severe, often starting on the Similarly, the introduction of South African gen-
face and later extending to the arms following era such as Arctotheca to Australia has led to
delayed absorption of the allergen (Fig. 12). Usu- airborne “bush” dermatitis in farmers, and the
ally the affected individual will have worked or Mediterranean Dittrichia graveolens is natural-
taken recreation in woodland or the garden. The ized in California.
eruption may be elicited by contact with contam- The major allergens are sesquiterpene lactones,
inated animal fur or fomites such as clothing worn of which there are more than 1600, which some-
by others. The sap hardens and turns black on the times, but not always, cross-react on patch testing.
skin, where it persists; even the hardened resin is Sesquiterpene lactones are found in botanically
70 Plants 1069
unrelated plants such as the liverwort genus and woodworkers (Fernandez de Corres 1984),
Frullania (Asakawa and Ludwiczuk 2017) sweet bay (Laurus nobilis), and Magnolia spp.
which has caused airborne dermatitis in foresters In a survey of Danish greenhouse workers,
19% reported skin or mucosal symptoms related
to compositae and 10% exhibited positive patch
tests to Compositae mix or sesquiterpene lactone
mix (Paulsen et al. 1998).
Typically, Compositae dermatitis presents in
the elderly male hobby gardener growing chry-
santhemums (xDendranthema), although occupa-
tional dermatitis affects a younger population with
a greater female predominance (Paulsen et al.
1998). Chrysanthemums are “disbudded” manu-
ally in nurseries; the operative removes the central
growth point manually to achieve a more bushy
plant. Compositae dermatitis may initially affect
Fig. 10 Rhus succedaneum. (Courtesy of Dr. Sheila
Powell) the hands and arms, but typically spreads to the
Fig. 11 Rhus verniciflua
Fig. 12 Allergic dermatitis

from Rhus toxicodendron
1070 C. R. Lovell
phenylene diamine (Chew et al. 2010), also pre-

dispose to chronic actinic dermatitis. If the indi-
vidual avoids the allergen, the photosensitivity
can improve with time. True photosensitivity
to Compositae may occur in individuals exposed
to Parthenium hysterophorus (Kar et al. 2009;
Rai et al. 2016).
In addition to gardeners, farmers and florists,
herbalists, and food handlers may become sensi-
tized to Compositae extracts in medicines and
aromatherapy oils and vegetables such as lettuce,
chicory, and artichokes.
A diagnosis of compositae dermatitis can
usually be made with a positive patch test to
the sesquiterpene lactone (SL) mix, which con-
tains three molecularly dissimilar lactones,
alantolactone, found in Inula helenium
(Fig. 15) and costunolide and dehydrocostus lac-
tone (each 0.1%) in petrolatum. However,
European studies have shown that this mix
fails to detect allergy to some compositae such
as dandelion (Taraxacum officinale), and sensi-
tivity was increased by adding a mixture
of compositae plant extracts (Compositae
mix) (von der Werth et al. 1999). However,
Fig. 13 Grevillea cv Robyn Gordon Compositae mix carries a small risk of active
sensitization and may produce irritant reactions
face and neck, imitating photosensitivity but at 6%. Paulsen and Andersen (2011) advocate
involving skin folds and “Wilkinson’s triangle” testing the SL mix together with parthenolide
behind the ears (Fig. 14). The facial skin (0.1% or possibly 0.033%) in the baseline
often becomes thickened and furrowed (leonine series to improve the detection rate. However,
facies). Rarely, the patient may become even the addition of parthenolide does not
erythrodermic, notably in patients exposed to detect all cases of Parthenium dermatitis
Parthenium hysterophorus (Agarwal et al. 2008; (Mahajan et al. 2014).
Agarwal and D’Souza 2009). In temperate cli-
mates, the eruption is seasonal, when the plants
are in maximal growth. Systemic contact derma- 6.4.3 Primulaceae
titis can occur in topically sensitized individuals The typical streaky eruption on the hands and arms
(Paulsen 2017). induced by allergy to Primula obconica is now
Later, the patient may develop true photosen- becoming rare in northern Europe, since the devel-
sitive eczema (chronic actinic dermatitis), con- opment of new cultivar strains such as “Touch me”
firmed on phototesting (Beach and Pratt 2009). It and “Libre” which are almost primin free
has been postulated that sesquiterpene lactones (Connolly et al. 2004; Zachariae et al. 2007).
react with thymine/thymidine to form [2 + 2] Scattered case reports still occur. The eruption
photoadducts in high yields, perhaps explaining may mimic erythema multiforme or herpes simplex
the transition from contact allergy to photosensi- and can present with facial involvement due to
tivity (Lepoittevin and Berl 2009). However, airborne allergen. Primula dermatitis mostly affects
other allergens, including colophony and para- amateur growers although florists and professional
70 Plants 1071
Fig. 14 Airborne allergic contact dermatitis from

compositae in an Ethiopian farmer
Fig. 15 Inula helenium
gardeners are also affected. Other species of Prim-
ula, including P. auricula, are cultivated by alpine
gardeners and nurserymen and can induce a similar Common ivy (Hedera helix cvs) (Fig. 16) is
pattern of dermatitis; the allergen(s) are currently botanically unrelated to poison ivy (Rhus). How-
undetermined, although primin is not the culprit. ever, it is an important and probably under-
Some growers report becoming tolerant to the recorded cause of allergic contact dermatitis in
plants after repeated handling (Aplin and Lovell gardeners and greenhouse workers. Currently,
2001). ivy is grown intensively for use as a houseplant.
The major allergen is falcarinol, which is also
found in carrots and celery, causing allergy in
6.4.4 Other Plant Allergens food handlers. The dermatitis can be florid
Alstroemeria cultivars are a significant cause (Fig. 17) and edematous, with facial involve-
of allergic dermatitis in florists (see ▶ Chap. ment (Paulsen et al. 2010). Unfortunately
153, “Florists”). The allergen, tuliposide A, is falcarinol is not currently available as a screen-
also found in tulip bulbs (Tulipa cvs). ing allergen. Colophony (rosin) is the sticky
Fingertip dermatitis from bulbs can be irritant amber-colored material derived by “tapping”
or allergic or both (Hassan et al. 2017). Garlic the sap from conifers (Fig. 18). It is used widely
(Allium sativum) bulbs characteristically cause a as an adhesive and grip enhancer or antislip
fissured hyperkeratotic eruption on the fingertips agent.
of the nondominant hand in chefs, although it can Lichens are dual organisms, reflecting a sym-
cause a more widespread eruption. The major biotic relationship between an alga and a fungus.
allergen is diallyl disulfide (Bordel-Gomez and Lichens may cause allergic dermatitis in for-
Mirando-Romero 2008). esters and lumberjacks. Several species are
1072 C. R. Lovell
Fig. 16 Ivy leaf

Fig. 18 Collecting rosin from pine trees
7 Occupations at Risk
A bewildering array of occupations are at risk of

plant dermatoses (Rycroft 1993). The major ones
are listed in Table 1. Outdoor workers such as
gardeners, farmers, construction workers, and for-
esters predominate. Food handlers and bartenders
are exposed to fruit (especially citrus) and vege-
tables including capsicum (Lambrecht and
Goossens 2015) and lettuce (Paulsen and Ander-
Fig. 17 Bullous allergic contact dermatitis from Hedera sen 2016) and may present with protein contact
helix dermatitis (e.g., Assarian and Nixon 2015). Bee-
keepers may be sensitized to propolis, the glue
used in perfumery, e.g., oakmoss (Schalock derived from poplar tree buds, and used by bees to
2009), and positive patch test reactions to fra- construct honeycombs. Cosmetic handlers, mas-
grance mix 1 may reflect occupational sensitiza- seuses, and aromatherapists become sensitized to
tion to lichens in farmers (Bilcha et al. 2010). essential oils derived from plants, and these oils
Other plant allergens are listed in Table 4 and are also increasingly used in herbal medicines.
outlined in ▶ Chaps. 153, “Florists” and ▶ 158, Tobacco handlers can be sensitized to tobacco
“Gardeners.” leaf; the allergen is unknown but is not nicotine
70 Plants 1073
(Bonamonte et al. 2016). Even office workers can disease due to lupin allergy. Clin Exp Allergy
be sensitized to “green” plants such as Ficus 40:1467–1472
Chew A-C, Bashir SJ, Hawk JLM et al (2010) Contact and
benjamina and Schefflera. photocontact sensitization in chronic actinic dermatitis;
a changing picture. Contact Dermatitis 62:42–46
Christensson JB, Matura M, Gruvberger B et al (2010)
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(2010) Novel plant metalloproteinase from Dieffen- plant food profilin allergens show equivalent IgE reac-
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Paulsen E (2017) Systemic allergic contact dermatitis caused Compositae mix is a more sensitive test for compositae
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from common ivy (Hedera helix L. subsp. helix) in
Further Reading
Europe: past, present, and future. Contact Dermatitis
62:201–209 Avalos J, Maibach HI (2000) Dermatologic botany.
Pradalier A, Leriche E, Trinh C, Molitor JL (2004) Le CRC Press, Boca Raton
retour de l’enfant prodigue ou l’allergie au ficus. Eur Benezra C, Ducombs G, Sell Y, Foussereau J (1985) Plant
Ann Allergy Clin Immunol 36:326–329 contact dermatitis. BC Decker, Toronto
Rai R, Thomas M (2016) Photopatch and UV-irradiated Hausen BM (1988) Allergiepflanzen Pflanzenallergene:
patch testing in photosensitive dermatitis. Indian Handbuch u. Atlas d.allergie-induzierenden Wild- und
Dermatol Online J 7:12–16 Kulturpflanzen Teil 1. Kontaktallergene. Ecomed,
Reynolds NJ, Burton JL, Bradfield JWB et al (1991) Weed Landsberg, Munchen
wacker dermatitis (letter). Arch Dermatol 127:1419–1420 Lovell CR (1993b) Plants and the skin. Blackwell
Rycroft RJG (1993) The individual at risk. In: Lovell CR Scientific, Oxford
(ed) Plants and the skin. Blackwell Scientific, Mitchell J, Rook A (1979) Botanical dermatology. Plants
Oxford, pp 6–15 and plant products injurious to the skin. Greengrass,
Rycroft RJG, Lovell CR, Harries PG et al (1987) Occupa- Vancouver
tional irritant contact dermatitis from chicory. Bolletino Ott A (1991) Haut und Pflanzen. Gustav Fischer Verlag,
di Dermatologia Allergologica e Professionale 2:77–82 Stuttgart
Spices
71
Stefanie E. Pentinga
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1075
3 Origin and Sensitizing Constituents of Spices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
4 Delayed Type Contact Dermatitis to Spices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
5 Immediate Type Contact Dermatitis to Spices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
6 Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1076
7 Skin Tests with Spices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
Spices · Contact dermatitis · Allergy ·
Dermatitis · Employee Spices can elicit dermatitis. For more than
50 years, there are publications on this subject
(Anliker et al. 2002; Brancaccio and Alvarez
1 Core Messages 2004; Bruynzeel and Prevoo 1990; Brouwer
et al. 2009; Chan and Mowad 1998; Cooper and
• Spices can elicit dermatitis in employees Cooper 1996; Dooms-Goossens et al. 1990;
• Most involved skin sites in allergic contact Foti et al. 1997; Futrell and Rietschel 1993; Hata
dermatitis to spices are the palmar site of the et al. 1997; Hjorth 1961; Hjorther et al. 1997;
hands, the fingertips, the face, and the mouth. Kanerva et al. 1996; Kanny et al. 1994; Liddle
But dermatitis can occur anywhere at the skin. et al. 2006; Meding 1993; Meding et al. 2003;
• Epicutaneous and intracutaneous tests with Niinimaki 1984, 1987, 1995, 2010; Niinimaki
spices can be useful diagnostic tools. et al. 1995; Pentinga et al. 2008; Pons-Guiraud
1996; Prevoo and Bruynzeel 1990; Steurich 1996;
S. E. Pentinga (*)
Department of Dermatology, St. Antonius Hospital,
Utrecht, The Netherlands
e-mail: S.Pentinga@antoniusziekenhuis.nl

https://doi.org/10.1007/978-3-319-68617-2_70
1076 S. E. Pentinga
Swierczynska and Krecisz 1998; van den Akker There is a relation between delayed type aller-
et al. 1990; Vermaat et al. 2008; Wuthrich and gic contact dermatitis to spices and fragrances
Hofer 1984; Wuthrich and Dietschi 1985; Yagami (Bruynzeel and Prevoo 1990; Hjorth 1961). This
et al. 2009). Various types of skin reactions have is not remarkable, since both may contain identi-
been described. This chapter will focus on the most cal or related constituents (Niinimaki 2010). For
frequent types: immediate and delayed type aller- example, a flare-up of previous eczema in patients
gic contact dermatitis. Spices can provoke derma- allergic to Myroxylon pereirae (Balsam of Peru)
titis in employees with professions with frequent can be seen after ingestion of spices (Bruynzeel
contact with spices. They should especially be and Prevoo 1990; Hjorth 1961; Niinimaki 1984).
taken into consideration when assessing hand der- Myroxylon pereirae contains naturally occurring
matitis of employees exposed to spices (Niinimaki flavors such as cinnamic acid, cinnamaldehyde
2010). Furthermore, it is important to keep in mind cinnamic alcohol, methyl cinnamate, benzyl
that allergies to spices are frequently accompanied cinnamate, vanillin, and eugenol. (Walter et al.
by other aggravating factors, such as irritation. 2018)
Epicutaneous and intracutaneous tests with spices
can be useful diagnostic tools.
5 Immediate Type Contact
Dermatitis to Spices
3 Origin and Sensitizing
Constituents of Spices Immediate type contact dermatitis to spices is
characterized by contact urticaria. An immedi-
Spices are aromatic parts of plants, including ate pruritic response develops with erythema
seeds, fruits, roots, buds, flowers, and barks. A and edema at the site of skin contact. Paprika,
synonymous term, herb, is used for aromatic mustard, coriander, caraway seed, cayenne pep-
plants whose dried or fresh leaves or shoots are per, anise, dill, fennel, celery seed, garlic, onion,
used (Niinimaki 2010). Spices are commonly and parsley have been known to cause positive
added to a diversity of foods and drinks. And reactions in routine scratch or prick tests
also, spices, or their constituents, can be ingredi- (Niinimaki 1984).
ents of cosmetics. Many well-known fragrances Contact dermatitis to spices has been seen more
are ingredients of spices. Some examples are frequent in patients with birch or mugwort-pollen
cinnamaldehyde, cinnamic alcohol, eugenol, and allergy. These patients frequently also react to fresh
coumarin. fruits and vegetables, and therefore a term “celery-
carrot-mugwort-spice syndrome” has been used
(Niinimaki 2010; Wuthrich and Hofer 1984).
4 Delayed Type Contact
Dermatitis to Spices
6 Clinical Picture
Spices that most frequently cause delayed type
allergic contact dermatitis are ginger, cinnamon, Occupations in which employees are prone to
clove, nutmeg, and cayenne pepper (Pentinga develop contact allergy to spices are chefs, bakers,
et al. 2008, Unpublished work). Furthermore, caterers, food industry workers, kitchen assis-
many other spices have been reported in case tants, coffee-room assistants, food handlers, and
reports in literature in association with delayed housewives (Brancaccio and Alvarez 2004).
type contact dermatitis: paprika, vanilla, laurel, Spices can elicit allergic and irritant contact
cardamom, and more (Chan and Mowad 1998; dermatitis, through direct skin contact and some-
Dooms-Goossens et al. 1990). times by ingestion and subsequent vascular
71 Spices 1077
distribution to the skin. The clinical picture consists testing for spices. The selection of spices used in
of a combination of a polymorph eruption with one tests is dependent on the worker’s exposure his-
or more of the following features: erythema, vesi- tory (Niinimaki 2010).
cles, squamae, papules, and sometimes pustules. In Table 1 shows a battery of patch test materials
immediate type contact dermatitis, an urticarial for testing of allergic contact dermatitis to ordi-
reaction predominates at first, afterwards a more nary spices. Figure 1 shows a positive patch test to
polymorph skin eruption can be seen. cinnamon and fragrances.
Skin reactions can occur anywhere on the body
(Pentinga et al. 2008). In many cases, the hands are Table 1 Series of patch tests with spices and their con-
affected, in particular the palms and the fingers. For centrations (Pentinga et al., 2010, Unpublished work)
example, garlic dermatitis has a typical distribution Spices Concentration, in petrolatum (%)
on the fingertips of the nondominant hand (Burgess Ginger 30
1952; Brancaccio and Alvarez 2004; Brouwer et al. Cinnamon 30
2009; Niinimaki 2010; Pentinga et al. 2008). Often Clove 30
spices are among the many aggravating factors in Nutmeg 30
chronic hand dermatitis. Furthermore, the mouth Cayenne pepper 30
Dill 30
and the face can be affected (Brancaccio and Alva-
(Diallyl disulfide) 1
rez 2004). But other locations may occur, such as
Fennel 30
the anogenital skin and mucosa (Pentinga et al.
Curcuma 30
2008, Unpublished work; Vermaat et al. 2008).
Coriander 30
Cummin 30
Cardamon 30
7 Skin Tests with Spices White pepper 30
Garlic 30
Since immediate and delayed type reactions to Fenugreek 30
spices can occur, both intracutaneous skin prick Onion 30
and epicutaneous patch tests can be used in allergy
Fig. 1 Positive patch test

to cinnamon and fragrances:
cinnamyl alcohol, eugenol,
isoeugenol, Myroxylon
pereirae (Balsam of Peru),
and cinnamaldehyde
1078 S. E. Pentinga
References Meding B, Wrangsjo K, Brisman J, Jarvholm B (2003)

Hand eczema in 45 bakers – a clinical study. Contact
Anliker MD, Borelli S, Wuthrich B (2002) Occupational Dermatitis 48(1):7–11
protein contact dermatitis from spices in a butcher: a Niinimaki A (1984) Delayed-type allergy to spices. Con-
new presentation of the mugwort-spice syndrome. tact Dermatitis 11(1):34–40
Contact Dermatitis 46(2):72–74 Niinimaki A (1987) Scratch-chamber tests in food handler
Brancaccio RR, Alvarez MS (2004) Contact allergy to dermatitis. Contact Dermatitis 16(1):11–20
food. Dermatol Ther 17(4):302–313 Niinimaki A (1995) Double-blind placebo-controlled per-
Bruynzeel DP, Prevoo RL (1990) Patch tests with some oral challenges in patients with delayed-type allergy to
spices. Dermatol Clin 8(1):85–87 balsam of Peru. Contact Dermatitis 33(2):78–83
Brouwer L, Pentinga SE, Rustemeyer T (2009) Niinimaki A (2010) Spices. In: Kanerva L, Elsner P,
Kruidenallergie, onderschat het niet! Ned Tijdschr Wahlberg JE, Maibach HI (eds) Handbook of occupa-
Voor Allergie en Astma 9(6):192–7 tional dermatology, 1st edn. Springer, Berlin, pp 767–770
Burgess JF (1952) Occupational dermatitis due to onion Niinimaki A, Hannuksela M, Makinen-Kiljunen S (1995)
and garlic. Can Med Assoc J 66(3):275 Skin prick tests and in vitro immunoassays with native
Chan EF, Mowad C (1998) Contact dermatitis to foods and spices and spice extracts. Ann Allergy Asthma
spices. Am J Contact Dermat 9(2):71–79 Immunol 75(3):280–286
Cooper RL, Cooper MM (1996) Red pepper-induced Pentinga SE, Bruynzeel DP, Rustemeyer T (2008) Een kok
dermatitis in breast-fed infants. Dermatology 193 die allergisch is voor zijn eigen gerechten. Ned Tijdschr
(1):61–62 Voor Allergie en Astma 8(4):132–5
Dooms-Goossens A, Dubelloy R, Degreef H (1990) Con- Pons-Guiraud A (1996) Contact dermatitis caused by food.
tact and systemic contact-type dermatitis to spices. Ann Dermatol Venereol 123(4):285–291
Dermatol Clin 8(1):89–93 Prevoo RL, Bruynzeel DP (1990) Epicutane tests en
Foti C, Carino M, Cassano N, Panebianco R, Vena GA, krasjes met tests met kruiden. Bull Contact Dermatosen
Ambrosi L (1997) Occupational contact urticaria from 1(4):120–123
paprika. Contact Dermatitis 37(3):135 Steurich FG (1996) A case of allergy to frogs legs. Allergy
Futrell JM, Rietschel RL (1993) Spice allergy evaluated by 51(11):852–853
results of patch tests. Cutis 52(5):288–290 Swierczynska MK, Krecisz B (1998) Occupational skin
Hata M, Sasaki E, Ota M, Fujimoto K, Yajima J, Shichida T changes in persons working in contact with food spices.
et al (1997) Allergic contact dermatitis from curcumin Med Pr 49(2):187–190
(turmeric). Contact Dermatitis 36(2):107–108 van den Akker TW, Roesyanto-Mahadi ID, van
Hjorth N (1961) Eczematous allergy to balsams, allied Toorenenbergen AW, van Joost T (1990) Contact
perfumes and flavouring agents, with special reference allergy to spices. Contact Dermatitis 22(5):267–272
to balsam of Peru. Acta Derm Venereol Suppl (Stockh) Vermaat H, Smienk F, Rustemeyer T, Bruynzeel DP,
41(46):1–216 Kirtschig G (2008) Anogenital allergic contact derma-
Hjorther AB, Christophersen C, Hausen BM, Menne T titis, the role of spices and flavour allergy. Contact
(1997) Occupational allergic contact dermatitis from Dermatitis 59(4):233–237
carnosol, a naturally-occurring compound present in Walter A, Seegraber M, Wollenberg A (2018) Food-related
rosemary. Contact Dermatitis 37(3):99–100 contact dermatitis, contact urticarial, and atopy patch
Kanerva L, Estlander T, Jolanki R (1996) Occupational test with food. Clin Rev Allergy Immunol. https://doi.
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Vegetables and Fruit
72
Andrea Bauer, Wolfgang Uter, and Christiane Szliska
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080
3 Irritant Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080
4 Allergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1080
5 Phototoxic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082
6 Photoallergic Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
7 Contact Urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
8 Immunologic Contact Urticaria (ICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
9 Non-immunologic Contact Urticaria (NICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
10 Protein Contact Dermatitis (PCD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Keywords
Occupational contact dermatitis · Vegetables ·
Fruits · Allergy · Irritation
A. Bauer (*)
Department of Dermatology, University Allergy Center,
University Hospital Carl Gustav Carus, Technical 1 Core Messages
University of Dresden, Dresden, Germany
e-mail: andrea.bauer@uniklinikum-dresden.de • Workers under risk are farmers, gardeners,
W. Uter bakers, pastry cooks, food handlers, cooks,
Department of Medical Informatics, Biometry and and food processing industry workers.
Epidemiology, University of Erlangen/Nürnberg, • Skin symptoms in occupational food handling
Erlangen, Germany
e-mail: wolfgang.uter@imbe.med.uni-erlangen.de; normally appear on the hands but may also
wolfgang.uter@fau.de develop on the face by direct skin contact or
C. Szliska aerogen exposure.
Department of Dermatology, Bethesda Hospital,
Freudenberg, Germany

https://doi.org/10.1007/978-3-319-68617-2_71
1080 A. Bauer et al.
• Clinical manifestations appear as irritant/ In food industry apprentices’ cumulative

allergic contact dermatitis, phototoxic/photo- prevalence of irritant hand dermatitis during the
allergic contact dermatitis, contact urticaria 3 years of training was as high as 41.3% (Bauer et
(immunologic/non-immunologic), and protein al. 1998). Mainly wet work in general but also
contact dermatitis. specific tasks like fruit handling >4 h a day were
significantly associated with an elevated risk
(Bauer et al. 2001).
The majority of irritant reactions to vegetables
2 Introduction
and fruit after direct skin contact are caused by
calcium oxalate, isothiocyanates, diterpene esters,
Skin exposure to vegetables and fruits is common
alkaloids, glycosides, and proteolytic enzymes
in many occupational settings of the food
(Modi et al. 2009). Fruits and vegetables commonly
processing industries. Workers under risk are
causing irritant contact dermatitis are garlic, onion,
farmers, gardeners, bakers, pastry cooks, food han-
potatoes, citrus fruits, pineapple, radish, horserad-
dlers, cooks, kitchen staff, restaurant service per-
ish, kale, cauliflower, cabbage, broccoli, Brussel
sonnel, and food processing industry workers.
sprouts, and carrots (Chan and Mowad 1998;
Skin reactions to food ingredients are common
Bahna 2004; Brancaccio and Alvarez 2004; Modi
and may be irritant or allergic. Allergic reactions
et al. 2009). Irritant contact dermatitis of the finger-
show a wide spectrum from immediate-type to
tips in cooks is often caused by garlic, a member of
delayed-type reactions (Table 1).
the Alliaceae family. If garlic is applied under
Skin symptoms in occupational food handling
occlusion, burns may result (Rafaat and Leung
normally appear on the hands but may also develop
2000; Esfahani and Chamlin 2017). Irritant
on the face by direct skin contact or airborne expo-
contact dermatitis to potatoes is common
sure. Systemic reactions are possible
(Bruce 1986) (Table 2). Proteolytic enzymes in
pineapples (bromelin) and papaya fruits (papain)
irritate the skin by impairing the epidermal barrier
3 Irritant Contact Dermatitis by proteolysis and increased capillary permeability
(Polunin 1951; Hausen 1988). Allyl iso-
The most common adverse food reaction in the thiocyanates, which are strong irritants, are respon-
occupational context is irritant contact dermatitis sible for irritant hand dermatitis caused by radish,
on the hands and on the face after direct skin horseradish, kale, cauliflower, cabbage, broccoli,
contact due to the irritative potential of many and Brussel sprouts (Gaul 1964; Mitchell and Jor-
food ingredients (Chan and Mowad 1998; dan 1974; Brancaccio and Alvarez 2004; Milanesi
Bahna 2004; Brancaccio and Alvarez 2004). and Gola 2016). Allyl isothiocyanates are degrada-
Occupations prone for irritant contact dermatitis tion products of sinigrin and gain their irritant
of the hands are food industry workers, food han- potential after solution in water (Amado and Jacob
dlers, bakers, pastry cooks, cooks, kitchen staff, 2007). The first case of a severe bullous irritant
farmers, and gardeners. reaction to celery leafs used for self-treatment of
knee pain was reported recently from Turkey
Table 1 Skin reactions from vegetables and fruit (Ermertcan et al. 2007).
Irritant contact dermatitis
Allergic contact dermatitis
Phototoxic contact dermatitis 4 Allergic Contact Dermatitis
Photoallergic contact dermatitis
Contact urticaria Allergic contact dermatitis to fruits and vegetables
Immunologic contact urticaria is uncommon. In most of the cases, sensitizations
Non-immunologic contact urticaria to oleoresins seem to be causative (Wüthrich
Protein contact dermatitis 1998; Chan and Mowad 1998). Native vegetables
72 Vegetables and Fruit 1081
Table 2 Fruit and vegetables containing irritant ingredients

Family Species Name Irritants
Alliaceae Allium sativum L. Garlic Leek oils (mono-, di-, polyalkylsulfides)
Allium cepa L. Onion
Rutaceae Citrus spp. Citrus fruits Fruit acids
Ananas comosum Pineapple Bromelain
Cruciferae/ Brassica, Sinapis, Rhaphanus Sinigrin allylisothiocyanate
Brassicaceae species
Brassica oleracea var. italica Broccoli
Brassica oleracea var. botrytis Cauliflower
L.
Brassica oleracea var. Brussels
gemmifera sprouts
Raphanus sativus Radish
Cochlearia armoracia L. Horse radish
Polygonaceae Rheum rhabarbarum L. Rhubarb Plumbagin, oxalic acid,
anthrachinonglycosides
Solanaceae Solanum tuberosum Potato Capsaicin
Capsicum annuum L. Paprika
Apiaceae/ Apium graveolens L. Celery
Umbelliferae
and fruit brought in by the patients had been propyldisulfide, and allicin (Papageorgiou et al.
patch tested, according to the documentation, 1983; Lembo et al. 1991). Employees in the
in 74 patients in departments of the IVDK catering and food industry are commonly affected
(www.ivdk.org) between 2010 and 2016, i.e., in (McFadden et al. 1992). Lembo et al. (1991)
a minute fraction of all patients tested in that reported 5.2% of 155 consecutive patients
period (n = 89,204). This may be due to the affected by eczemas and 12.9% out of 62 house-
fact that fresh material is mostly tested in a prick wives reacting to fresh garlic (patch tested as is),
(-to-prick) or scratch test, to diagnose immediate- respectively (Lembo et al. 1991). In sensitized
type contact allergy. In 10 of the 74 patch-tested patients, systemic allergic contact dermatitis may
patients, positive reactions at day (D) 3 or 4, occur after ingestion of garlic and onion (Veien
mostly +, were observed. In three patients and 1997). Cross-reactivity between garlic and onion
patches, respectively, ++ or +++ reactions were is discussed controversially so far (van Ketel and
observed: in one patient to both parsley and pars- de Haan 1978; Bleumink and Nater 1973; Sinha
ley root; in another to parsley and a number of et al. 1977).
other vegetables, including chicory; and in Other vegetables from the Alliaceae, Aster-
another to pineapple. Moreover, weak positive aceae/Compositae, and Cruciferae/Brassicaceae
reactions on D3/D4 were seen to carrot in two families reported to cause ACD are asparagus,
cases, to potato, and, interestingly, to fondant artichoke, chicory, lettuce, endive, cabbage, broc-
(sugar glazing) on D4 only (IVDK, internal report coli, cauliflower, celery, carrot, and sunflower
# 6, 2017). seeds (van Ketel and de Haan 1978; Malten
According to the literature, garlic and onion 1983; Krook 1973; Hausen and Wolf 1996;
seem to be the most common sensitizers (Adams Sánchez-Guerrero and Escudero 1998; Chan and
1990; van Ketel and de Haan 1978; McFadden Mowad 1998; Kimmig and Klauder 1956;
et al. 1992; Hjorth and Roed-Petersen 1976). Vickers 1941; Murdoch and Dempster 2000;
Fingertip dermatitis on the first three finger tips Kanerva 1996a, b; Rademaker and Yung 2000;
is the most common presentation (Jappe et al. Paulsen et al. 2015). Allergic contact dermatitis to
1999). Major allergens are diallydisulfide, allyl asparagus was first reported in literature in 1880
(Güntz 1880). Before automation took place in all of them employed in food occupations and
asparagus processing industry, workers in canning suffering from hand dermatitis. Positive patch
factories were most commonly affected. Today, test reactions were seen to tomato, lettuce, and
asparagus farmers, cooks, and food handlers are at carrot. Moreover, paprika elicited a weak allergic
risk. 1,2,3-Trithiane-5-carboxylic acid, a plant patch test reaction in two patients (Kanerva
growth inhibitor occurring mainly in the early 1996b) and caused occupational allergic contact
phases of asparagus growth, is the main allergen dermatitis in a potato chips factory worker
causing asparagus-induced allergic contact der- (Lambrecht and Goossens 2015).
matitis, which was identified by Hausen and Urushiol and 5-alkenyl resorcinols are
Wolf in 1996 (Hausen and Wolf 1996). responsible for mango dermatitis caused by
Other vegetables reported to cause allergic con- the sap, pulp, and peel of the fruit (Calvert et al.
tact dermatitis are lettuce (Lactuca sativa), chicory 1996; Oka et al. 2004; Kim and Christiansen
(Cichorium intybus), and endive (Cichorium 2015). Cross-reactivity with other members of
endivia) (Friis et al. 1975; Helander 1984; Mitchell the Anacardiaceae family (poison ivy, poison
et al. 1989; Oliwiecki et al. 1991; Paulsen and oak) occurs due the cross-sensitivity of 5-
Andersen 2016). In 2002, Bauer et al. analyzed the alkenylresorcinols and urushiol. Hershko et al.
results of patch testing performed in 873 bakers, (2005) reported cases of allergic contact dermati-
cooks, and butchers suspected for occupational tis to mango in mango pickers, who never had
allergic contact dermatitis from 29 dermatological previous contact to mangos before but were
departments of the Information Network of Depart- exposed to poison ivy or poison oak (Hershko
ments of Dermatology (IVDK). Two hundred thir- et al. 2005). Allergic reactions to orange peel or
teen patients (24.4%) were diagnosed with orange oil are reported in the literature but do not
allergic contact dermatitis. Concerning vegetable play a prominent role in the occupational context
sensitization, significantly higher sensitization nowadays due to automation in the fruit canning
rates for compositae mix (6.8% vs. 2.4%) industry (Hausen 1988).
( p<0.05) were found in employees in the food Citrus fruits – besides their irritative and pho-
industry compared to the total test population, totoxic characteristics – may cause sensitization.
underlining the importance of the Asteraceae/ Limonene the main component of orange oil is a
Compositae family in the induction of occupa- weak sensitizer. Other components like citral, cit-
tionally relevant allergic contact dermatitis. ronellal, or linalyl acetate have a higher sensitiza-
Allyl isothiocyanate is not only an irritant but tion potential but are less important because of
may also act as allergen in horseradish, cabbage, their low concentrations (Hausen 1988). Recently,
broccoli, cauliflower, kale, and Brussel sprouts a case of lime contact dermatitis caused by sensi-
(Gaul 1964; Lerbaek et al. 2004). Sánchez- tization to geraniol, which is a minor component
Guerrero and Escudero reported on two patients of the peel oil, was reported (Swerdlin et al. 2010)
of contact dermatitis due to broccoli (greengro- (Table 3).
cery worker) and broccoli and cauliflower (green- Allergic contact dermatitis to potatoes is rarely
house worker), respectively (Sánchez-Guerrero reported (Bruce 1986; Carmichael et al. 1989)
and Escudero 1998).
Sporadic cases of allergic contact dermatitis to
falcarinol in carrot in food industry workers are 5 Phototoxic Contact Dermatitis
reported in the literature since many decades
(Vickers 1941; Kimmig and Klauder 1956; Phytophotodermatitis may be induced by various
Kanerva 1996b; Fouls and Sadhra 1990; Kawai photosensitizing agents in fruits and vegetables
et al. 2014). Cross-reactivity to celery has been after UV exposure (mainly UVA 320–400 nm) in
reported (Kimmig and Klauder 1956). Kanerva areas of the body exposed to photosensitizing
1996 reported on allergic contact dermatitis to fruits and vegetables (Bahna 2004; Brancaccio
food in five patients sensitized to different spices, and Alvarez 2004; Killig and Werfel 2008).
Table 3 Sensitizing ingredients in fruit and vegetables

Family Species Name Sensitizing substances
Asteraceae/ Lactuca sativa Lettuce Sesquiterpene lactones:
Compositae Cichorium intybus Chicory Lactucin, lactucopicrin
Cichorium endivia Endive
Cynara scolymus L. Artichoke Cynaropicrin
Cruciferae/ Brassica oleracea var. Broccoli Allyl isothiocyanates
Brassicaceae italica
Brassica oleracea var. Cauliflower
botrytis L.
Brassica oleracea var. Brussel
gemmifera sprouts
Cochlearia armoracia L. Horseradish Allyl-benzyl-isothiocyanate
Raphanus sativus Radish
Apiaceae/ Daucus carota Carrots Falcarinol
Umbelliferae Apium graveolens Celery
Pastinaca sativa L. Parsnip
Rutaceae Citrus sinensis L. Orange Limonene, citral, citronellal, linalyl acetate
Citrus limon L. Lemon
Citrus limetta Risso L. Lime
Citrus paradisi Macfad Grapefruit
Alliaceae Asparagus officinalis Asparagus 1,2,3 trithiane-5-carboxylic acid, asparagin,
coniferin, vanillin
Allium sativum L. Garlic Diallydisulfide, allyl propyldisulfide, allicin
Allium cepa L. Onion n.i.
Anacardiaceae Mangifera indica L. Mango 5-alkenyl resorcinols
Urushiol
Solanaceae Solanum lycopersicum Tomato Cinnamic acid
Commonly, members of the Rutaceae (lime, Occupations under risk are farmers, gardeners,
lemon, orange, bitter and bergamot orange, grape- vegetable harvest workers, and food handlers
fruit), Moraceae (fig tree), and Umbillifereae (cel- (Amado and Jacob 2007). The typical morphol-
ery, fennel, carrot, parsnip) are responsible for the ogy is acute pruritic, sometimes bullous, dermati-
reactions, because of psoralens (furocumarines) in tis healing with hyperpigmentations (Brancaccio
these fruits and vegetables inducing dermatitis and Alvarez 2004). Systemic phototoxic reaction
after UV exposure (Chan and Mowad 1998; is reported after ingestion of larger amounts of
Berkley et al. 1986; Seligman et al. 1987; Bowers celery root (Ljunggren 1990) (Table 4).
1999; Amado and Jacob 2007; Pathak 1986;
Aberer 1992; Marcos and Kahler 2015; Friedman
et al. 2016). Infection of the vegetables with 6 Photoallergic Contact
the fungus species Sclerotinia sclerotiorum Dermatitis
or other fungus species leads to increased levels
of psoralens resulting in more intense phyto- Photoallergic contact dermatitis arises after sensi-
phototoxic reactions. Severe cases of bullous con- tization to photoactivated allergens. Most reports
tact dermatitis were described in occupational in the literature concern garlic-induced photo-
settings in up to 26% of celery harvest workers allergic contact dermatitis. The relevant photo-
after contact to infected celery (Perone et al. 1964; allergen from garlic is diallyl disulfide (Scheman
Luppi and Bucci 1970; Birmingham et al. 1961; and Gupta 2001; Alvarez et al. 2003; Borrelli
Berkley et al. 1986; Beier and Oertli 1983). et al. 2007).
Table 4 Phototoxic ingredients in fruit and vegetables

Family Species Name Photoactive substances
Rutaceae Citrus bergamia Bergamot Bergaptol, 5-MOP, 5-geranyloxypsoralen
Risso et Poit. lime
Citrus limetta Risso Lime 5-geranyloxypsoralen, bergaptol, 5,8-
DiMOP
Citrus paradisi Macfad. Grapefruit Bergamottin, bergaptol
Citrus sinensis (L.) Osb. Orange Psoralens, bergaptol, xanthyletin
Citrus limon (L.) Burm Lemon Psoralens,5-MOP, oxypeucedanin
Fil.
Apiaceae/ Apium graveolens L. Celery Psoralen, 5-MOP, 8-MOP
Umbelliferae Daucus carota L. Carrot 5-MOP, 8-MOP
Pastinaca sativa L. Parsnip 5-MOP, 8-MOP, imperatorin
Foeniculum vulgare Fennel 5-MOP, 8-MOP
Moraceae Ficus carica L. Fig tree Psoralen, 5-MOP, 8-MOP
MOP Methoxypsoralen
contact urticaria (and protein contact dermatitis) to

7 Contact Urticaria
vegetables were observed (i.e., 0.8%) (Kanerva
1995, 1996a). Chefs, cooks, and cold buffet
The contact urticaria (syndrome) (immediate-type
managers showed the highest incidence of occupa-
contact reactions), first defined as a biological
tional contact urticaria cases followed by farmers,
entity in 1975 by Maibach und Johnson, com-
domestic animal attendants, bakers, and nurses (40
prises a heterogeneous spectrum of inflammatory
persons out of 815). A recent systematic review of
reactions that usually appear within minutes after
the literature summarized all reported occupational
cutaneous or mucosal contact with the eliciting
cases of CU in the food industry. Vegetables and
agent although delayed-type reactions are some-
fruit ranked second on the hit list of allergens
times observed (van Krogh and Maibach 1982).
causing CU (Lukacs et al. 2016).
The term “syndrome” means either localized or
generalized clinical manifestations involving also
organs other than the skin, such as the respiratory
or the gastrointestinal tract. 8 Immunologic Contact Urticaria
Moreover, immunologic contact urticaria (ICU)
(ICU) and non-immunologic contact urticaria
(NICU) reactions can be distinguished patho- ICU is due to immediate-type hypersen-
physiologically but usually not clinically. sitivity (IgE-mediated). This can be clinically
Thus, typical symptoms can occur with or manifested by localized urticaria which may
without sensitization. In both ICU and spread beyond the area of contact. Vegetables
NICU, contact urticaria appears as a wheal- and fruits are common causes of occupational
and-flare reaction. Contact urticaria is usually and nonoccupational ICU (Amaro and Goossens
rapid in onset and accompanied by intensive 2008). ICU may progress to angioedema and
pruritus. can be accompanied by systemic symptoms
Valid estimates regarding the prevalence of including rhinitis, asthma, and anaphylactic
fruit- and vegetable-related ICU or NICU, in gen- shock (Table 5). The diagnosis often can be
eral, and ICU or NICU due to specific triggers in confirmed by measurements of specific IgE
particular are scarce in the literature, beyond case antibodies or an open application test with
reports. In Finland in a 7-year period (1990–1996) reading after 20 min. Prick-to-prick testing with
out of 1205 cases, ten persons with occupational fresh food can be helpful.
Table 5 The contact urticaria syndrome Most commonly PCD manifests as chronic
Stage 1 Localized urticaria recurrent eczematous hand dermatitis (Cronin
Dermatitis 1987). Patients complain of itching and/or
Nonspecific symptoms (itching, tingling, stinging within 30 min upon contact with an
burning, etc.) offending allergen. PCD is considered to be a
Stage 2 Generalized urticaria combination of immediate type I and delayed
Cutaneous and extracutaneous reactions type IV allergic responses (Janssens et al. 1995;
Stage 3 Rhinoconjunctivitis Bahna 2004; Brancaccio and Alvarez 2004; Killig
Orolaryngeal symptoms
and Werfel 2008).
Bronchial asthma
Employees in the food industry, especially
Stage 4 Anaphylactic symptoms
food handlers and chefs, often suffering from
epidermal barrier function perturbation due to
high loads of wet work, are at high risk for sensi-
9 Non-immunologic Contact tization due to the fact that they handle raw food
Urticaria (NICU) during their entire working day (Janssens et al.
1995; Hjorth and Roed-Petersen 1976; Veien et al.
NICU is more common and is caused by agents 1983; Chan and Mowad 1998; Amaro and
that directly stimulate the release of vasoactive Goossens 2008). Recent studies and reviews
substances like histamine from mast cells. concerning the subject showed seafood, eggs,
Other mediators may be involved such as and flour to be the most common allergens.
substance A, bradykinin, and possibly leukotri- Other relevant allergens were fresh fruit and veg-
enes and prostaglandines. NICU typically etables as well as spices and meat (Bahna 2004;
causes mild localized reactions that clear Brancaccio and Alvarez 2004; Levin and
within hours. Agents causing NICU can be Warshaw 2008; Barbaud et al. 2015). Other risk
found widely in food. Open testing for factors under discussion are atopy and chronic
NICU can be performed by applying a small irritant hand dermatitis (Janssens et al. 1995).
amount of the presumed offending agent to Nowadays a lot of basic food such as potatoes
normal skin. (Martínez de Lagrán et al. 2009); tomato (Cronin
1987); lettuce (Alonso et al. 1993); delicacies as
asparagus (Sánchez et al. 1997) or exotic fruits like
10 Protein Contact Dermatitis melon (García et al. 2004) mango, kiwi, litchi,
(PCD) peach (Cuesta-Herranz et al. 1998), and apricot;
and vegetables are described as eliciting agents of
Originally described by Hjorth and Roed-Peterson occupational CU or PCD (Carino et al. 1997; Foti
in 1976, PCD is an eczematous reaction occur- et al. 1997; Gala Ortiz et al. 2000; Krook 1977;
ring after skin contact to high molecular Temsvari and Becker 1993) (Tables 6 and 7). Com-
weight proteins originating from plants and pared to the spectrum of vegetables and fruits
animals (Hjorth and Roed-Petersen 1976). causing ICU and NICU, it is indeed a smaller
Pathogenesis of the disease is not entirely range of foods (vegetables and fruit) being reported
understood. These proteins are thought to as causing delayed-type reactions (PCD) (Table 7).
penetrate especially through compromised Clinical studies have suggested that fruit and
skin and to elicit immediate urticarial and vegetable allergy is connected with birch pollen
vesicular reactions (type I) followed by a allergy (Hannuksela and Lahti 1977).
delayed (type IV) allergic reaction. Causative Hannuksela and Lathi (1977) tested 388 atopic
proteins are classified in four groups (group 1, patients with the scratch-chamber method and
fruits, vegetables, spices, plants; group 2, ani- demonstrated that 36% of subjects with hyper-
mal proteins; group 3, grains; group 4, enzymes) sensitivity to birch pollen had immediate positive
(Janssens et al. 1995). responses to many fruits and vegetables, mainly
Table 6 Fruit and vegetables causing occupational con- Table 7 Fruit and vegetables causing protein contact
tact urticaria (type I allergies) dermatitis (type IV allergies)
Fruits Vegetables Fruits Vegetables
Apple Artichoke Cherry Cabbage
Apricot Asparagus Kiwi Celeriac
Banana Beans Lemon (flesh, peel, oil) Chicory
Fig Cabbage Lime oil Cress
Grapefruit Carrots Mango Cucumber
Kiwi Cauliflower Orange (peel) Endive
Lemon Celery Garlic
Lime Chives Horseradish
Litchi Cucumber Kidney bean
Mango Endive l Leek
Melon Fennel Lettuce
Pear Garlic Onion
Pineapple Leek Potato
Plum Lettuce Radish
Pomegranate Onion Red pepper
Strawberry Parsley, paprika Shallot
Watermelon Potato Tomato skin
Shallots
Soybean
Spinach
and scratch-chamber testing should be performed
Tomato “in loco.”
In conclusion, cutaneous reactions to vegeta-
bles and fruits may be caused by irritant/allergic
apple, carrot, parsnip, and potato. Moreover, new contact dermatitis, phototoxic/photoallergic con-
type I sensitizations have been shown to be facili- tact dermatitis, contact urticaria (immunologic/
tated by enhanced percutaneous allergen resorp- non-immunologic), and protein contact dermatitis.
tion. Recently molecular-specific diagnostics
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Animals
73
Contents
1 Core Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
3 Non-allergic Skin Pathology from Animal Contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091
4 Allergy to Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
5 Diagnosis of Animal Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
6 Diagnostic Workup for Occupational Allergy Suspected to Be from Contact
with Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
7 Managing Symptoms of Contact Urticaria or (Protein) Contact Dermatitis
from Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
Abstract dermatitis (ACD). Contact urticaria (CU) can

Skin contact with animals and animal-derived be either immunologic (IgE-mediated) or
products occurs in numerous occupations, non-immunologic and refers to a wheal-and-
everyday life, and hobbies. Animal contact flare reaction appearing usually within 30 min
can cause allergic, irritant, or toxic skin reac- of contact with the causative agent. The clini-
tions, parasitic infestations, and zoonoses. Skin cal picture of protein contact dermatitis (PCD),
hazards, especially from insect, reptile, and although IgE-mediated, is chronic contact
marine life, differ greatly in different climatic eczema, but there can be acute phases of pru-
areas. Proteins of animal origin constitute a ritus and wheals within minutes of skin contact
major group of allergens able to cause with the causative animals or animal products.
immediate-type IgE-mediated contact urticaria High-risk occupations are those that work in
(CU) or protein contact dermatitis (PCD) direct or indirect contact with animals like
and less often delayed-type allergic contact farmers, veterinarians, health and animal care
workers, food industry, or in any occupations
dealing with natural environments. Any
P. Susitaival (*)
Department of Dermatology, North Carelia Central
proteins of animal origin are potentially sensitiz-
Hospital, Joensuu, Finland ing. This chapter concentrates on skin problems
e-mail: paivikki.berry@fimnet.fi

https://doi.org/10.1007/978-3-319-68617-2_72
1090 P. Susitaival
encountered from contact with live animals. Indi- 2 Introduction

vidually tailored skin tests for both immediate
and delayed allergies, and often also specific IgE Direct or indirect skin contact with animals and
in blood, are needed for diagnosing allergy to animal-derived products occurs in numerous occu-
animals or animal products. Commercial test pations, everyday life, and hobbies. Contact with
materials can give false-negative results. Skin mammals can cause allergic or irritant or skin reac-
tests should be made, if possible, with the same tions and parasitic infestations and be a source of a
materials and in the same format as have been multitude of zoonotic infections. Insects and other
causing the skin problems. invertebrates, snakes and marine/freshwater ani-
mals, and arthropods may cause allergic, irritant,
or toxic reactions by excreting, biting, or stinging.
Keywords Insects and other animals can also cause parasitic
Amniotic fluid · Animal proteins · Child care · infestations and act as vectors for microbial dis-
Contact urticaria · Dairy farming · Fish bait · eases. Skin hazards, especially from insect, reptile,
Fishing industry · Forestry · Health care · and marine life, differ greatly in different climatic
Insects · Laboratory animals · Marine life · areas. Proteins of animal origin constitute a major
Parasitic infestations · Patient-supplied group of allergens able to cause immediate-type
materials · Pet food · Protein contact IgE-mediated contact urticaria (CU) or protein con-
dermatitis · Research laboratories · Seafood · tact dermatitis (PCD) and, less often, delayed-type
Zoo animals · Zoonoses allergic contact dermatitis (ACD). Contact urticaria
(CU) can be either immunologic (IgE-mediated) or
non-immunologic and refers to a wheal-and-flare
1 Core Messages reaction appearing usually within 30 min of contact
with the causative agent. The clinical picture of
• Direct or indirect (e.g., allergens in the air) skin protein contact dermatitis (PCD), although
contact with animals can occur in numerous IgE-mediated, is chronic contact eczema, but
occupations. there can be acute phases of pruritus and wheals
• Animal contact can cause allergic, irritant, or within minutes of skin contact with the causative
toxic skin reactions, parasitic infestations, and animals or animal products.
zoonoses. Animal-related skin problems can be encoun-
• Skin hazards, especially from insect, reptile, tered in numerous industries including laboratory
and marine life, differ greatly in different cli- animal facilities, livestock farms (especially dairy
matic areas. farming), veterinary medicine, animal care, health
• Most common animal-related occupational and child care, research laboratories and zoos,
skin diseases in Northern Europe are mite fishing, gardening and forestry, and food industry.
infestations and allergic symptoms from The hazards, especially from insect, reptile, and
domestic or laboratory animals. marine life, differ greatly in different climatic
• Individually tailored skin tests for both imme- areas. This chapter concentrates on skin problems
diate and delayed allergies are needed in diag- encountered from contact with live animals.
nosing animal protein allergy. The most common animal-related occupa-
• Commercial skin test materials can give tional skin diseases in the Finnish Register of
false-negative results; therefore specific Occupational Diseases (2000–2014) were scabies
IgE measurements from blood are often mite infestations and PCD from cow dander
needed. allergy (Table 1). Scabies epidemics occur mainly
• Changing world brings new jobs with animal in health-care wards for chronic patients. Cow
allergens, e.g., growing insects for animal and dander was the main cause of occupational skin
human food. allergy in dairy farmers.
73 Animals 1091
Table 1 Animal-related registered occupational skin diseases in Finland in 2000–2014 (Finnish Register of Occupa-
tional Diseases)
Animal n Diagnoses Industry or occupations
Scabies mite 664 Scabies Health and child care
Cow 517 PCD, CU, ACD Dairy farming, veterinarians
Laboratory animals 22 CU, PCD Research, laboratory assistants, veterinarians
Storage mites 11 PCD, CU Farming, warehouses for food etc.
Swine 10 PCD Farming, abattoirs, animal transportation
Pediculus capitis 5 Pediculosis Child and health care
Fox, mink, furs 4 PCD Fur industry
Spiders 2 PCD Cattle farming
Dog 2 PCD Education, veterinary medicine
All 1237
ACD allergic contact dermatitis, PCD protein contact dermatitis, CU contact urticaria
3 Non-allergic Skin Pathology in humans. Ectoparasites like mites have been

from Animal Contact reported since the early twentieth century to
cause epidemics in humans (Rycroft and Kennedy
Contact with insects, arthropods, and also reptiles 1981; Betz et al. 1982; Letchford et al. 1994;
(e.g., spiders, mites, snakes) can occur in numer- Chung et al. 1998; Beck 1999; Centers for Disease
ous occupations as an environmental hazard (e.g., Control and Prevention 2005; Kelaher et al. 2005;
farming, forestry, gardening). Skin reactions Del Giudice et al. 2008). Pyemotes ventricosus
result from toxins or allergy to insects and their mite is an ectoparasite of insect (e.g., beetle) lar-
bites. Caterpillars and occasionally moths may vae, and quite extensive outbreaks have been
have irritating hairs, spines, venoms, and toxins reported in the USA and France connected to
that may cause stings, eczematous or papular straw- and wood-eating beetles (Betz et al. 1982;
dermatitis, and urticaria (Hossler 2009; Vega Del Giudice et al. 2008). The skin lesions are very
et al. 2011). There are several reports of a South- specific, and it seems that the vesicular rash is
ern European pine processionary caterpillar caused by the mites burrowing in the skin (Del
(Thaumetopoea pityocampa) causing epidemics Giudice et al. 2008). Eradication of the source of
of urticarial reactions in rural populations mostly mites, along with symptomatic treatment, is the
via airborne contamination (Vega et al. 2011). The treatment of choice in mite-induced rash.
mechanisms of these reactions are complex, some Marine and freshwater organisms, especially
of them probably immunological (Vega et al. in the tropics, frequently cause various skin
2011). Most species cause mild and self-limiting injuries and sometimes life-threatening systemic
reactions, but occasionally systemic or allergic toxicity (Ulrich et al. 2008; Haddad et al.
reactions can be severe. Treatment in most cases 2009; Tammaro et al. 2018). Numerous different
is symptomatic with prompt removal of offending mechanisms are involved from infestations
hairs or spines (Hossler 2009). There are reports (e.g., Vibrio vulnificus) and envenomations to
from India and China of epidemics of dermatitis zoonotic infections from fish or marine mammals
caused by a rove beetle Paederus fuscipes, which (e.g., Mycobacterium marinum or erysipeloid).
releases a vesicant pederin when crushed Mycobacterium marinum is responsible for “fish
(Gnanaraj et al. 2007; Huang et al. 2009). Head tank granuloma,” a chronic and sometimes dis-
lice or scabies epidemics have occurred in care abling skin infection, which is possibly the most
facilities (Holness et al. 1992; Finnish Register of frequent “atypical” cutaneous mycobacteriosis.
Occupational Diseases). Mites of numerous ani- Many invertebrates (e.g., corals, jellyfish, sea
mal species can cause transient or recurrent rashes anemones, sea urchins) and also venomous fish
1092 P. Susitaival
(e.g., stingrays) can cause dermatologic lesions Hollander et al. 1997; Susitaival et al. 2001;
varying from painful local physical or chemical Tauscher and Belsito 2002; Ruoppi et al. 2004;
trauma (erythema, vesicobullae, petechiae, necro- Muzembo et al. 2014; Palmberg et al. 2015). SPTs
sis) to systemic toxicity (Haddad et al. 2009). to laboratory animals have been positive in
Prompt removal of all foreign materials from the 15–21% of persons who work with animals in
lesions with tweezers or salt water soaks and laboratories and to cow in 5–14% of some farmer
inactivation of the venoms or nematocysts excret- populations (Slovak and Hill 1981; Cockroft et al.
ing toxins, e.g., with vinegar soaks, is the 1981; Rautalahti et al. 1987; Larmi et al. 1988;
suggested first aid in most cases of tropical marine Weissenbach et al. 1988; Iversen and Pedersen
environment accidents (Haddad et al. 2009). 1990; Ruoppi et al. 2004; Muzembo et al. 2014;
Palmberg et al. 2015). One fifth of surveyed Cal-
ifornia veterinarians reported skin symptoms
4 Allergy to Animals when handling some animal species (Susitaival
et al. 2001). It seems, according to the California
Proteins of animal origin constitute the largest veterinary survey, that animal species have a dif-
group of allergens causing contact urticaria ferent capacity to cause skin and respiratory
(CU) and protein contact dermatitis (PCD). symptoms. Rats, rabbits, cattle, and dogs more
High-risk industries include livestock farming often cause skin symptoms than cats and horses
(especially dairy farming), veterinary medicine, (Table 2, Susitaival et al. 2003).
animal care in veterinary clinics, zoos and Laboratory animals (rats, mice, guinea pigs,
research facilities, research, pet food and fish rabbits, hamsters, cats, dogs, toads) have been
bait industries, food industry, fishing, and forestry. reported to cause CU and other skin symptoms
Sensitization can lead to respiratory and or skin (Cockroft et al. 1981; Weissenbach et al. 1988;
symptoms (Helaskoski et al. 2017; Muzembo Rudzki 1975; Burrows 1979; Agrup and Sjöstedt
et al. 2014). Exposure can also be from airborne 1985; Aoyama et al. 1992; Karches and Fuchs
allergens (dander, urinary proteins, etc.) resulting 1993; Ruoppi et al. 2004). In a recent prospective
in skin symptoms on open skin areas (face, neck, Swedish study, one in five newly employed labo-
arms, etc.) as well as on animal contact areas. Any ratory animal workers became sensitized to labo-
proteins of animal origin can potentially be ratory animals during the first 2 years of
sensitizing. employment (Palmberg et al. 2015). Up to one
Most epidemiological studies of occupational third of those handling rats may get sensitized,
diseases from animal contact have been and multiple sensitization to different laboratory
conducted among people working with laboratory animals is common (Cockroft et al. 1981; Agrup
animals and mostly concerning respiratory allergy and Sjöstedt 1985; Weissenbach et al. 1988).
(Cockroft et al. 1981; Slovak and Hill 1981; Symptoms are often reported on scratched skin
Weissenbach et al. 1988; Agrup and Sjöstedt and especially from skin contact with rat/mouse
1985; Aoyama et al. 1992; Ruoppi et al. 2004; tails and urine (Cockroft et al. 1981; Agrup and
Ferraz et al. 2013; Muzembo et al. 2014; Sjöstedt 1985; Hollander et al. 1997). Handling
Palmberg et al. 2015). Some studies have sur- male rats has been reported to increase the risk of
veyed skin diseases in veterinarians or farmers allergy because of higher excretion of urinary pro-
(Susitaival et al. 2001; Tauscher and Belsito teins (Renström et al. 2001). Laboratory animal
2002; Susitaival et al. 1995). Risk factors for allergy has also been connected to severe worsen-
work-related animal allergy have been history of ing of atopic dermatitis (Bhabha and Nixon 2012).
atopy, any positive skin prick tests (SPTs), allergy Allergy to animal proteins (dander, hair,
to cats and dogs, preemployment total IgE >100 feathers, blood, amniotic fluid, saliva, etc.) from
kU/l, female sex, intensity of aeroallergen expo- various other mammalian species and birds has
sure, and length of exposure (Slovak and Hill been reported to cause PCD or CU or other skin
1981; Venables et al. 1988; Fuortes et al. 1996; symptoms (Epstein 1948; Schneider et al. 1960;
73 Animals 1093
Table 2 Skin and respiratory symptoms from common animals in California veterinarians, N = 1353 (Susitaival et al.
2003)
Skin symptoms Respiratory symptoms
Symptoms from N % of 1353 % of all symptoms from the speciesa
Any animal 538 40 48 78
Cat 353 26 20 92
Horse 93 7 32 80
Dog 263 19 53 66
Rabbit 30 2 63 87
Cattle 89 7 79 40
Rat 18 1 100 6
a
Overlapping – some have both skin and respiratory symptoms
Cockroft et al. 1981; Göransson 1981; van Ketel Insects (cockroaches, locusts, flour beetles,
and van Diggelen 1982; van der Mark 1983; caterpillars, silk worms and their cocoons, and
Degreff et al. 1984; Agrup and Sjöstedt 1985; fruit flies) and storage mites and spiders have
Kalveram et al. 1986; Camarasa 1986; Prahl and also been reported to cause CU/PCD (Kanerva
Roed-Petersen 1979; Hjorth and Roed-Petersen et al. 1995; Monik 1988; Lopata et al. 2005;
1980; Hansen and Petersen 1989; Aoyama et al. Alanko et al. 2000; Vega et al. 2004; Jones et al.
1992; Susitaival et al. 1995; Valsecchi et al. 2003; 2016; Gowda et al. 2016, Estévez 2006; Finnish
Herzinger et al. 2005; Buckle and Devos 2007; Institute of Occupational Health). Insect allergies
Swiderska-Kiełbik et al. 2011; Renström et al. may become more recognized in industries
2011; Polovic et al. 2013). Also, delayed allergy involving pet food (Bregnbak et al. 2013;
to animal proteins has been documented in several Renström et al. 2011) and possibly, in the future,
reports (Epstein 1948; Roth 1968; Malanin and insect food for humans. PCD/CU has been
Kalimo 1992; Susitaival et al. 1995; Timmer and reported from several insects and larvae used for
Coenraads 1996; Kanerva and Estlander 1997; fish bait or fish food (De Jaegher and Goossens
Mahler et al. 1998; Ljubojevic et al. 2007). Cow 1999; Purello-D’Ambrosio et al. 1995; Virgili
dander allergy is the most common cause of occu- et al. 2001; Pazzaglia et al. 2003; Siracusa et al.
pational PCD/CU in Finland (Kanerva and 2003). A common fish parasite (nematode)
Susitaival 1996). Anisakis simplex has also been reported to cause
Seafood allergy cases have been reviewed in CU/PCD although it more commonly causes gas-
several articles (Jeebhay et al. 2001; Lopata et al. trointestinal symptoms in those eating the fish
2010; Lukács et al. 2016). Many types of salt and (Conde-Salazar et al. 2002; Barbuzza et al.
freshwater fish and other sea life have been 2009). Photosensitivity with allergic contact der-
reported to cause CU or PCD, and many of the matitis has been reported from a bryozoan in
patients have been allergic to several types of fishermen on the English Channel (Clin et al.
shellfish and also bony fish (Jeebhay et al. 2001; 2008).
Lopata et al. 2010; Lukács et al. 2016; Kanerva
and Pajari-Backas 1999). The prevalence of occu-
pational CU/PCD in seafood processing workers 5 Diagnosis of Animal Allergy
has been estimated to be somewhere between 3%
and 11%, but controlled population studies are Farmers, veterinarians, and others working with
lacking. Allergy to fish and molluscs (e.g., animals may have worked with the animals for
squid) is less common than allergy to shellfish years before starting to have skin symptoms. CU
(crustaceans). In many cases, the seafood causing or PCD from animal proteins is often accompa-
CU/PCD also causes respiratory symptoms but is nied by respiratory symptoms, and the respiratory
well tolerated as food. symptoms may precede skin symptoms by years
1094 P. Susitaival
(Aoyama et al. 1992; Nienhaus et al. 2005; fresh materials. In those instances also, in vitro
Spiewak et al. 2000; Spiewak 2004; Barbuzza in-house methods like ELISA or ImmunoSpot can
et al. 2009; Helaskoski et al. 2017; Muzembo be used to detect immediate allergy to the
et al. 2014). Skin tests for immediate allergy suspected material (Laukkanen et al. 2005).
(e.g., SPT) or specific IgE have been positive
with animal dander, hair, amniotic fluid, serum,
blood, organs, milk, and saliva (Rudzki 1975; 6 Diagnostic Workup
Prahl and Roed-Petersen 1979; Hjorth and Roed- for Occupational Allergy
Petersen 1980; Slovak and Hill 1981; Degreff Suspected to Be from Contact
et al. 1984; Agrup and Sjöstedt 1985; Falk et al. with Animals
1985; Kalveram et al. 1986; Weissenbach et al.
1988; Karches and Fuchs 1993; Buckle and History: present skin disease, association to ani-
Devos 2007; Valsecchi et al. 2003). Cross sensi- mal contact, history of atopy and previous skin
tivity is common, especially with mammalian diseases, and detailed description of work and
serum albumins, most commonly between dog, hobbies for other possible causative agents.
cat, pig, and horse (Alvarez-Perea et al. 2014). Status: Contact urticaria or (protein) contact
Diagnosis should be based on a detailed history dermatitis:
of skin disease and work, skin tests, skin prick
tests (SPTs), specific IgE in blood (e.g., RASTs), Type I skin tests/laboratory for immediate allergy
and open provocation tests when needed. Skin with commercial and other (patient-provided)
tests should include all possible allergens animal materials: skin prick tests, specific IgE
according to the patient history. SPTs and specific in blood (e.g., RASTs), open application tests
IgE measurements with animal danders generally or provocation tests, scratch tests, ELISA, or
reveal immediate allergy to animals. However, it (multiallergen) ImmunoSpot
is important to realize that the sensitivity of SPT If negative ! Patch tests for delayed allergy with
solutions from different manufacturers can vary animal materials (30 min, 48 h, and 96 h
considerably causing possibly false negatives readings)
(van Kampen et al. 2013). Also, dander or hair
are not always the best source of allergens. The If all available skin testing or blood work does
allergens may also be found in urine (in mice and not reveal the cause or cannot be performed, the
rats) or saliva (in, e.g., dogs, Polovic et al. 2013). patient history and the effect of skin protection
Especially with animal allergens, the cutting point (and provocation) from suspected aggravating
of a positive SPT reaction should probably be factors should help to reach a diagnosis and iden-
more like 1.5 mm than the 3 mm usually used tify necessary preventive and protective
(van Kampen et al. 2013). More than one method measures.
for diagnosis is often necessary to avoid false
negatives if the history and SPT results do not
agree. 7 Managing Symptoms
If specific IgE measurements and SPTs both of Contact Urticaria or (Protein)
with commercial series and natural animal mate- Contact Dermatitis
rials are negative, the next step is patch tests with from Animals
the same materials both for immediate (30 min)
and delayed (48 h and 96 h) reactions. For allergy For the prevention of contact urticaria and derma-
to uncommon animal allergens, or other sub- titis, and other causes of skin diseases and zoo-
stances with no commercial test materials (like notic infections from animal contact, training of
animal fluids), the diagnostic skin tests can be workers in prevention and utilization of protective
done with patient-supplied materials, e.g., fresh measures is needed. There are studies showing
animal dander/hair. In such cases, attention should that there is room for improvement in that
be paid to contagious diseases possibly present in area (Ferraz et al. 2013; Muzembo et al. 2014).
73 Animals 1095
The recent change in research facilities from using Beck W (1999) Farm animals as disease vectors of para-
rats to genetically modified mice in ventilated sitic epizonooses and zoophilic dermatophytes and
their importance in dermatology. Hautarzt 50(9):
sealed cages decreases the airborne levels of aller- 621–628
gens in laboratory animal facilities, decreasing the Betz TG, Davis BL, Fournier PV, Rawlings JA, Elliot LB,
airborne allergens (Feary and Cullinan 2016). Baggett DA (1982) Occupational dermatitis associated
Workers handling animals should be taught with straw itch mites (Pyemotes ventricosus). JAMA
247(20):2821–2823
about the specific risks for skin diseases and pos- Bhabha FK, Nixon R (2012) Occupational exposure to
sible zoonotic infections and encouraged to use laboratory animals causing a severe exacerbation of
protective vinyl or low-protein latex gloves even atopic eczema. Australas J Dermatol 53(2):155–156
prior to the development of skin symptoms in Bregnbak D, Friis UF, Zachariae C, Menné T, Johansen JD
(2013) Protein contact dermatitis caused by worms and
traditionally “bare-handed” jobs. Atopy is a risk insects used to feed exotic birds. Contact Dermatitis
factor for IgE-mediated animal allergy and skin 70:64–66
symptoms from animals, and atopic workers Buckle DM, Devos SA (2007) Hand and forearm derma-
should be monitored regularly for respiratory toses among veterinarians. J Eur Acad Dermatol
Venereol 21:360–363
and skin symptoms. Burrows D (1979) Urticaria from rats. Contact Dermatitis
CU symptoms are often relieved by washing 5:122
the skin soon after contact and using antihista- Camarasa JG (1986) Contact eczema from cow saliva.
mines regularly. Protein contact dermatitis sub- Contact Dermatitis 15(2):117
Centers for Disease Control and Prevention (CDC) (2005)
sides in weeks when the skin is protected from Outbreak of pruritic rashes associated with mites-
contact with the animal allergen using protective Kansas, 2004. MMWR Morb Mortal Wkly Rep
gear. Motivation for strict protection with clothing 54(38):952–955
and protective gloves is imperative, even though Chung SL, Hwang SJ, Kwon SB, Kim DW, Jun JB, Cho
BK (1998) Outbreak of rat mite dermatitis in medical
often first considered impossible by, e.g., farmers. students. Int J Dermatol 37(8):591–594
Protecting the face and neck from exposure to Clin B, Stosse-Guevel C, Marquignon MF, Verneuil L,
airborne allergens with the use of powered hooded Letourneux M (2008) Professional photosensitive
respirators can be effective. It is important to eczema of fishermen by contact with bryozoans: dis-
abling occupational dermatosis. Int Marit Health 59
advise those handling animals to change, store, (1–4):45–52
and wash their work clothes outside their living Cockroft A, McCarthy P, Edwards J, Andersson N (1981)
quarters. Dairy cattle-related PCD or CU tends to Allergy in laboratory animal workers. Lancet 1(8224):
heal if the cattle are mostly outside in natural 827–830
Conde-Salazar L, González MA, Guimaraens D (2002)
surroundings, e.g., in summer. Type I and type IV sensitization to Anisakis simplex
in 2 patients with hand eczema. Contact Dermatitis
46:361
De Jaegher C, Goossens A (1999) Protein contact derma-
References titis from midge larvae (Chironomus thummi thummi).
Contact Dermatitis 41:173
Agrup G, Sjöstedt L (1985) Contact urticaria in laboratory Degreff H, Bourgeois M, Naert C, Van de Kerckhove M,
technicians working with animals. Ta Derm Venereol Dooms-Goossens A (1984) Protein contact dermatitis
(Stockh) 65:111–115 with positive RAST caused by bovine blood and amni-
Alanko K, Tuomi T, Vanhanen M, Pajari-Backas M, otic fluid. Contact Dermatitis 11(2):129–130
Kanerva L, Havu K, Saarinen K, Bruynzeel DP Del Giudice P, Blanc-Amrane V, Bahadoran P, Caumes E,
(2000) Occupational IgE-mediated allergy to Tribolium Marty P, Lazar M, Boissy C, Desruelles F, Izri A,
confusum (confused flour beetle). Allergy 55:879–882 Ortonne J-P, Counillon E, Chosidov O, Delaunay P
Alvarez-Perea A, Caralli ME, Zubeldia JM, Baeza ML (2008) Pyemotes ventricosus dermatitis, southern
(2014) Pork-cat syndrome as a cause of occupational France. Emerg Infect Dis 14(11):1759–1761
asthma. J Investig Allergol Clin Immunol 24(3):209–211 Epstein S (1948) Milker’s eczema- an analysis of forty-two
Aoyama K, Ueda A, Manda F, Matsushita T, Ueda T, cases. J Allergy 19:333–341
Yamauchi C (1992) Allergy to laboratory animals: an Estévez MD (2006) Occupational contact urticaria-
epidemiological study. B J Ind Med 49(1):41–47 dermatitis by Tyrophagus putrescentiae. Contact Der-
Barbuzza O, Guarneri F, Galtieri G, Ganqemi S, Vaccaro M matitis 55(5):308–309
(2009) Protein contact dermatitis and allergic asthma Falk ES, Hektoen H, Thune PO (1985) Skin and respira-
caused by Anisakis simplex. Contact Dermatitis tory tract symptoms in veterinary surgeons. Contact
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1096 P. Susitaival
Feary J, Cullinan P (2016) Laboratory

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Swen Malte John

Jeanne Duus Johansen

With 349 Figures and 447 Tables

Thomas Rustemeyer Peter Elsner

ISBN 978-3-319-68615-8 ISBN 978-3-319-68617-2 (eBook)

contribution to ﬁght negligence regarding occupational dermatoses. In most

October 2019 Swen Malte John

Paulo MS et al (2019) WHO/ILO work-related burden of disease and injury:

The knowledge of occupational Dermatology has expanded – vibrantly – in

aspects of workers’ compensation for occupational contact dermatitis.

Part I General Aspects of Occupational Dermatology . . . . . . . . 1

1 Immunology and Barrier Function of the Skin . . . . . . . . . . . 3

3 Quality of Life (QoL) in Relation to Occupational Skin

4 Pharmacoeconomics of Occupational Diseases . . . . . . . . . . . 27

5 Occupational Dermatology: Ethical Aspects . . . . . . . . . . . . . 37

6 History of Occupational Dermatology . . . . . . . . . . . . . . . . . . 51

7 Classiﬁcation of Occupations ......................... 61

8 Surveillance in Occupational Contact Dermatitis . . . . . . . . . 69

9 Occupational Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

10 Other Occupational Skin Diseases . . . . . . . . . . . . . . . . . . . . . 97

11 Websites, Online Databases, and Sources of Information . . . 105

Part II Occupational Skin Diseases: Clinical . . . . . . . . . . . . . . . . . . 117

12 Contact Dermatitis due to Irritation . . . . . . . . . . . . . . . . . . . 119

29 Occupational Connective Tissue Disorders . . . . . . . . . . . . . . 393

Part III Causative Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491

35 Antiseptics and Disinfectants . . . . . . . . . . . . . . . . . . . . . . . . . 493

61 Adhesives and Glues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891

Part IV Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1261

83 Workplace Survey: Guiding Principles from

91 Skin Biopsy and Dermatopathology . . . . . . . . . . . . . . . . . . . . 1371

Part V Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397

93 Evidence-Based Management of Hand Eczema . . . . . . . . . . . 1399

Part VI Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505

102 Prognosis of Occupational Contact Dermatitis . . . . . . . . . . . 1507

Part VII Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1541

106 Prediction of Skin Irritation by Noninvasive

Part VIII Job Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1699

117 Aircraft Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1701

119 Aromatherapists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1715

138 Cheese Makers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1839

156 Fur Farming and the Fur Industry . . . . . . . . . . . . . . . . . . . . 1991

174 Metal Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2123

192 Shoe Manufacturers and Repairers . . . . . . . . . . . . . . . . . . . . 2295

Part IX Chemistry and Concentrations of Patch Test

201 Dictionary of Contact Allergens: Chemical Structures,

208 Sulfuric Acid Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2587

209 Contact Urticaria Syndrome: Occupational Aspects . . . . . . . 2595

210 Nonimmunologic Contact Urticaria . . . . . . . . . . . . . . . . . . . . 2629

Swen Malte John Department of Dermatology, Environmental Medicine and

Kristiina Aalto-Korte Occupational Medicine, Finnish Institute of Occupa-

Kerry E. Adam Faculty of Health Sciences, School of Health and Rehabil-

Keith William James Adam Medibank Health Solutions, Brisbane, QLD,

Tove Agner Department of Dermatology, Faculty of Health Science,

Iris S. Ale Department of Dermatology and Allergology, Republic University

Ayda Alhammadi Department of Dermatology, Hamad Medical Corpora-

Henning Allmers Department of Dermatology, Environmental Medicine and

Firas A. Al-Niaimi Department of Dermatology, Cumberland Inﬁrmary,

Agustin Alomar Servicio de Dermatología, Hospital de la Santa Creu i Sant

Klaus E. Andersen Department of Dermatology and Allergy Centre, Odense

Savina Aneja Department of Dermatology, Desk A-61, Dermatology-Plastic

Gianni Angelini Department of Biomedical Science and Human Oncology,

Gheorghe Bucur: deceased.

Jennifer Cahill Occupational Dermatology Research and Education Centre,