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AND MECHANISMS OF
CARCINOGENESIS
EDITED BY ROBERT A. BAAN,
BERNARD W. STEWART, AND KURT STRAIF
IARC SCIENTIFIC
PUBLICATION NO. 165
TUMOUR SITE CONCORDANCE
AND MECHANISMS OF
CARCINOGENESIS
EDITED BY ROBERT A. BAAN,
BERNARD W. STEWART, AND KURT STRAIF
IARC SCIENTIFIC
PUBLICATION NO. 165
Published by the International Agency for Research on Cancer,
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About the cover: The background image (credit: Qweek/E+/Getty Images) reflects the concept of “overlap” discussed in this
volume, where agents cause tumours in the same target organs in humans and in experimental animals (see Chapter 21 and
Annex 1). The bar graph (credit: Daniel Krewski) shows a “mechanistic profile” of the 86 carcinogens included in the analysis
described in Chapter 22. The 10 bars represent the key characteristics (see Chapter 10); the height of a bar indicates the
number of agents that display that particular characteristic. Genotoxicity (the second bar from the left) is the most
prominent characteristic.
Tumour site concordance and mechanisms of carcinogenesis / edited by Robert A. Baan, Bernard W. Stewart, Kurt Straif
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Consensus statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix
Part 1
Concordance between cancer in humans and in experimental animals
Chapter 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Electrophilic agents
Chapter 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Aromatic amines and aristolochic acids
Chapter 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Arsenic and metals
Chapter 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Arsenic and metals
Chapter 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Arsenic and metals
Chapter 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Anticancer agents: qualitative and quantitative aspects
Chapter 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Polycyclic aromatic hydrocarbons and associated occupational exposures
Chapter 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Benzene and haematological cancers
Chapter 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Human tumour viruses
Part 2
Mechanisms of carcinogenesis
Chapter 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Key characteristics of carcinogens
Chapter 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks
Chapter 17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Inflammation
Part 3
Statistical analyses of concordance and key characteristics
Chapter 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Analysis of tumour site concordance
Annex 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Development of a data set on tumours and tumour sites in humans and in experimental animals for Group 1 agents
identified up to and including Volume 109 of the IARC Monographs
Contributors v
Vincent J. Cogliano Mark A. Hill Christopher J. Portier (April
Integrated Risk Information System Radiation Biophysics Group meeting only)
(IRIS) Gray Institute for Radiation National Center for Environmental
National Center for Environmental Oncology and Biology Health
Assessment University of Oxford Agency for Toxic Substances and
U.S. Environmental Protection Oxford, United Kingdom Disease Registry
Agency Centers for Disease Control and
Washington, DC, USA Charles William Jameson Prevention
CWJ Consulting, LLC Atlanta, GA, USA
David M. DeMarini Cape Coral, FL, USA
Integrated Systems Toxicology Jerry M. Rice
Division Agnes B. Kane Georgetown University Medical
U.S. Environmental Protection Department of Pathology and Center
Agency Laboratory Medicine Department of Oncology
Research Triangle Park, NC, USA Brown University Lombardi Comprehensive Cancer
Providence, RI, USA Center
Bice Fubini Washington, DC, USA
Department of Chemistry Robert J. Kavlock
Interdepartmental Center “G. National Center for Computational Ivan I. Rusyn
Scansetti” for Studies on Asbestos Toxicology Environmental Sciences and
and other Toxic Particulates U.S. Environmental Protection Engineering
Faculty of Pharmacy Agency Gillings School of Global Public
University of Turin Research Triangle Park, NC, USA Health
Turin, Italy University of North Carolina
Daniel Krewski Chapel Hill, NC, USA
Bernard D. Goldstein R. Samuel McLaughlin Centre for
Department of Environmental and Population Health Risk Assessment Martyn T. Smith (November
Occupational Health School of Epidemiology, Public meeting only)
University of Pittsburgh Health and Preventive Medicine Division of Environmental Health
Pittsburgh, PA, USA University of Ottawa Sciences
Risk Sciences International School of Public Health
Stephen S. Hecht Ottawa, Ontario, Canada University of California Berkeley
Masonic Cancer Center Berkeley, CA, USA
University of Minnesota Paul F. Lambert
Minneapolis, MN, USA McArdle Laboratory for Cancer Leslie Stayner
Research Division of Epidemiology and
Uwe Heinrich (unable to attend) University of Wisconsin School of Biostatistics
Fraunhofer Institute of Toxicology Medicine and Public Health School of Public Health
and Experimental Medicine Madison, WI, USA University of Illinois at Chicago
Hanover, Germany Chicago, IL, USA
Ronald L. Melnick
Kari Hemminki Ron Melnick Consulting, LLC Bernard W. Stewart (Observer at
German Cancer Research Center Chapel Hill, NC, USA April meeting)
(DKFZ) Cancer Control Program
Heidelberg, Germany South Eastern Sydney Public Health
Unit
Randwick, NSW, Australia
vi
Robert L. Ullrich Representatives Observer for the Centre Léon
UTMB Cancer Center Bérard
University of Texas Medical Branch Representative of the French Béatrice Fervers
Galveston, TX, USA Agency for Food, Environment and Department of Cancer and the
Occupational Health Safety Environment
Harri Vainio Cécile Michel (November meeting Centre Léon Bérard
Finnish Institute of Occupational only) University of Lyon
Health French Agency for Food, Lyon, France
Helsinki, Finland Environment and Occupational
Observer for the R. Samuel
Health Safety (ANSES)
McLaughlin Centre for Population
Paolo Vineis (April meeting only) Maisons-Alfort, France
Health Risk Assessment
Department of Environmental Pascale Lajoie (November meeting
Epidemiology Representative of the World Cancer
only)
Imperial College London Research Fund International
R. Samuel McLaughlin Centre for
St Mary’s Campus Martin Wiseman (April meeting
Population Health Risk Assessment
London, United Kingdom only)
University of Ottawa
World Cancer Research Fund
Ottawa, Ontario, Canada
Michael P. Waalkes International
Department of Epidemiology
Inorganic Toxicology Group London, United Kingdom
Queens University
National Toxicology Program Kingston, Ontario, Canada
Laboratory
Division of the National Toxicology
Observers
Program IARC Secretariat
Observer for the R. Samuel
National Institute of Environmental
McLaughlin Centre for Population Robert Baan, Senior Visiting
Health Sciences
Health Risk Assessment Scientist (Co-Responsible Officer)
Research Triangle Park, NC, USA
Mustafa Al-Zoughool Lamia Benbrahim-Tallaa
R. Samuel McLaughlin Centre for Véronique Bouvard
Lauren Zeise
Population Health Risk Assessment Graham Byrnes
California Environmental Protection
University of Ottawa Fatiha El Ghissassi
Agency
Ottawa, Ontario, Canada Yann Grosse (Co-Responsible
Reproductive and Cancer Hazard
Department of Community and Officer)
Assessment
Environmental Health Neela Guha
Oakland, CA, USA
King Saud bin Abdulaziz University Zdenko Herceg (April meeting only)
for Health Sciences Marie-Pierre Lambert (April meeting
Riyadh, Saudi Arabia only)
Béatrice Lauby-Secretan
Observer for the R. Samuel Dana Loomis
McLaughlin Centre for Population Heidi Mattock
Health Risk Assessment Magali Olivier (April meeting only)
Michael Bird Ghislaine Scélo (April meeting only)
R. Samuel McLaughlin Centre for Chiara Scoccianti (April meeting
Population Health Risk Assessment only)
University of Ottawa Kurt Straif (Section Head)
Risk Sciences International Jiri Zavadil (November meeting only)
Ottawa, Ontario, Canada
Contributors vii
Additional Contributors Julian Little Administrative Assistance
School of Epidemiology, Public
The following people are co-authors Health and Preventive Medicine Sandrine Egraz
of chapters but were not present at University of Ottawa Elisabeth Elbers
the Workshop. Ottawa, Ontario, Canada Brigitte Kajo
Helene Lorenzen-Augros
Mélissa Billard M. Matilde Marques Annick Leroux
R. Samuel McLaughlin Centre for Department of Chemical and Karine Racinoux
Population Health Risk Assessment Biological Engineering Dorothy Russell
University of Ottawa Graduate Technical Institute
Ottawa, Ontario, Canada Technical University of Lisbon
Department of Epidemiology Production Team
Lisbon, Portugal
Queens University
Kingston, Ontario, Canada Karen Müller
Brittany Milton
English Editor
Risk Sciences International
Nicholas Birkett
Ottawa, Ontario, Canada
R. Samuel McLaughlin Centre for Sylvia Lesage
Population Health Risk Assessment Publishing Assistant
Jan M. Zielinski (deceased)
School of Epidemiology, Public
R. Samuel McLaughlin Centre for Elisabeth Elbers
Health and Preventive Medicine
Population Health Risk Assessment Publications Technician
University of Ottawa
School of Epidemiology, Public
Ottawa, Ontario, Canada
Health and Preventive Medicine Fiona Gould
University of Ottawa Publications Technician
Brian Collins
Healthy Environments and
Risk Sciences International
Consumer Safety Branch, Health Solène Quennehen
Ottawa, Ontario, Canada
Canada Publications Technician
Ottawa, Ontario, Canada
Kate Z. Guyton
National Center for Environmental
Assessment
Office of Research and
Development
U.S. Environmental Protection
Agency
Washington, DC, USA
viii
Acknowledgements
The two-part IARC Workshop on Tumour Site Concordance and Mechanisms of Carcinogenesis (held in April and
November 2012) was supported by grants from the European Commission (grant number VS/2012/0117) and from the
United States National Institute of Environmental Health Sciences (NIEHS).
Acknowledgements ix
Introduction Vincent J. Cogliano
The IARC Monographs to recommend agents for evaluation animals, and representative mech-
or re-evaluation. Otherwise, agents anistic and other relevant data, as
The IARC Monographs on the may be reviewed in response to an well as general information on the
Eval
uation of Carcinogenic Risks urgent public health need. agent and human exposure to it.
to Humans, published by the International, interdisciplinary Work The Working Group meets at IARC,
International Agency for Research ing Groups of expert scientists de- in Lyon, France, for eight days to
on Cancer (IARC) of the World velop each volume of the IARC
discuss the critical reviews and to
Health Organization, are a series Monographs. IARC selects partici-
develop consensus evaluations that
of scientific reviews that identify the pants in the Working Groups based
classify each agent into one of the
causes of cancer in humans. Since on their knowledge and experience,
following categories:
its inception in the early 1970s, the and absence of conflicting interests.
• carcinogenic to humans (Group 1);
IARC Monographs Programme has Working Group members general-
• probably carcinogenic to humans
evaluated more than 1000 chemical, ly have published research on the (Group 2A);
physical, and biological agents and carcinogenicity of the agents under • possibly carcinogenic to humans
classified almost 500 of these as review. IARC also gives considera- (Group 2B);
carcinogenic, probably carcinogenic, tion to demographic diversity among • not classifiable as to its carcinogen-
or possibly carcinogenic to humans. Working Group members and to icity to humans (Group 3);
Agents are identified as subjects a fair balance of scientific findings • probably not carcinogenic to hu-
for IARC Monographs evaluations and views. The IARC Monographs mans (Group 4).
based on evidence of human expo- are a worldwide endeavour that, Each volume of the IARC Mono-
sure and some evidence or suspi- graphs opens with the Preamble,
since 1971, has involved more than
which describes the objective and
cion of carcinogenicity. Agents may 1200 scientists from more than 50
scope of the IARC Monographs
be re-evaluated when substantial countries.
Programme, the scientific principles
new information becomes avail- For each agent, the Working
and procedures used in developing
able. Periodically, IARC convenes Group writes a critical review of the a Monograph, the types of evidence
Advisory Groups of experts from na- pertinent studies of cancer in ex- considered, and the scientific crite-
tional and international health agen- posed humans, cancer after admin- ria that guide the evaluations (IARC,
cies and from research institutions istration of the agent to experimental 2006).
xii
by Krewski et al.). It has long been To accommodate the different de- to determine whether there is coher-
recognized that concordance be- grees of precision with which cancer ence, which can be understood as
tween human and animal tumour sites have been identified (e.g. “liver concordance confirmed or discor-
sites is not evident for carcinogens cancer” for one agent and “hepato- dance explained.
of all types considered as a single cellular carcinoma” for another), the The chapters in this Scientific
category. Concordance can be ana- database uses designations that are Publication address what we have
lysed for a grouping of agents (e.g. more general in nature (“liver cancer” learned about some major mech-
aromatic amines) or for a cancer site in this example). Likewise, a detailed anisms for agents known to cause
(e.g. haematological cancers). Such list of 24 mechanistic events that was cancer in humans. The Consensus
analyses could explore the predictive initially proposed was subsequent- Statement was unanimously en-
value for human cancer of tumours in ly condensed to a set of 10 “key dorsed by the Workshop partici-
experimental animals, based on the characteristics” (see below). This pants. The chapters in Part 1 discuss
information collected to date. These level of aggregation is necessary to various groupings of carcinogenic
types of analyses may also identify avoid fragmenting the data into large agents, such as electrophilic agents,
human cancers for which there cur- numbers of categories with few data metals, constituents of tobacco
rently are no good animal models; points; this makes it possible to con- smoke, and human tumour viruses.
for these cancers, it might be advan- duct analyses across reasonable These chapters illustrate the types
tageous to focus on understanding numbers of agents. Further research of analysis that can be undertaken
mechanistic pathways to design new will change our understanding of for groups of carcinogenic agents,
experimental models that could iden- mechanistic events and will estab- including those that act at a com-
tify agents linked to these cancers. lish additional associations of agents mon site or through a common
The second data set contains the with mechanistic events in the future. mechanism.
information about established and Five additional human carcino- Chapter 10 (by Smith) discusses
our observation that all human carcin-
likely mechanistic events (see Al- gens, identified after the completion
ogens evaluated in Volume 100 (and
Zoughool et al., 2019 and Birkett et of Volume 100, are included in the
subsequent Monographs as men-
al., 2019). It is organized to facilitate data set: (i) diesel engine exhaust (re-
tioned above) display one or more of
the investigation of patterns across viewed in Volume 105; IARC, 2013),
what are called key characteristics of
mechanistic events and agents (ii) trichloroethylene (evaluated in
carcinogens: is electrophilic or can
(see the mechanistic analysis in Volume 106; IARC, 2014), (iii) poly-
be metabolically activated to elec-
Chapter 22, by Krewski et al.). Data chlorinated biphenyls (PCBs) and di-
trophiles; is genotoxic; alters DNA
can be aggregated for groupings of oxin-like PCBs (reviewed in Volume
repair or causes genomic instabil-
agents that involve common mech- 107; IARC, 2016b), and (iv) outdoor
ity; induces epigenetic alterations;
anistic events or common cancer air pollution and (v) particulate matter
induces oxidative stress; induces
sites. Such analyses could identify in outdoor air pollution (both evaluat-
chronic inflammation; is immunosup-
biomarkers that could be incorporat- ed in Volume 109; IARC, 2016a).
pressive; modulates receptor-medi-
ed into future epidemiological stud- The two data sets are linked. ated effects; causes immortalization;
ies. They also could identify popula- Concordance in the first data set and/or alters cell proliferation, cell
tions and developmental stages that may find support from the mech- death, or nutrient supply. Chapter 11
may be especially susceptible to the anistic information in the second. (by Stewart) places the key char-
occurrence of certain mechanistic Lack of concordance in the first data acteristics in the context of other
events. Ultimately, they could lead to set may or may not be explained by viewpoints, such as the hallmarks
the confident identification of human the mechanistic information in the of carcinogenesis. Subsequent
carcinogens based on mechanistic second. Accordingly, the analyses chapters in Part 2 discuss the role
information in the absence of ade- in this Scientific Publication do not of several of the key characteristics
quate cancer studies in humans or stop at a superficial analysis of con- individually, followed by chapters that
experimental animals. cordance or discordance. They seek discuss susceptibility.
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xiv
Consensus statement
This statement was unanimous- required sufficient evidence in hu- (in 2007), benzo[a]pyrene (in 2010),
ly endorsed by the participants in mans to classify an agent as carcino- aristolochic acid (in 2012), and etopo-
the Workshop on Tumour Site Con genic to humans (Group 1). Scientific side (in 2012). Mechanistic evidence
cordance and Mechanisms of Car understanding of the mechanisms was also important in classifying
cinogenesis, which was convened
of carcinogenesis, accompanied by the carcinogenicity of several other
by IARC on 16–18 April and 28–30
the development of assays for stud- agents between 2004 and 2010, and
November 2012 in Lyon.
ying mechanistic events, has led to in revising the classification of car-
Introduction new ways of identifying human car- cinogenicity for several additional
cinogens. Some examples are the agents in Volume 100.
The IARC Monographs Programme
following agents that were classified For Volume 100 of the IARC
is an international consensus ap-
as carcinogenic to humans: ethylene Monographs, a review was undertak-
proach to the identification of chem-
icals and other agents that may oxide (in 1994), based on strong ev- en during 2008–2009 of relevant in-
present carcinogenic hazards to idence of genotoxicity and limited formation on all the agents classified
humans. The Monographs assess epidemiological evidence in exposed in Group 1 (carcinogenic to humans)
the strength of the published sci- humans; 2,3,7,8-tetrachlorodiben- in Volumes 1–99. There was value
entific evidence for such identifica- zo-para-dioxin (in 1997), based on in a comprehensive review, because
tions, which are based primarily on about half of the agents classified
strong evidence of binding to the
epidemiological studies of cancer in Group 1 had last been reviewed
aryl hydrocarbon receptor and sub-
in humans and bioassays for car- more than 20 years earlier. Volume
sequent events; neutron radiation (in
cinogenicity in laboratory animals. 100 was organized in six parts, each
2000), based on the underlying radi-
Information that may be relevant to prepared by a separate Working
ation physics; benzidine-based dyes
the mechanisms by which the puta- Group, covering: pharmaceuticals
tive carcinogen acts is also consid- (in 2010), because these substances
(Volume 100A); biological agents
ered in making an overall evaluation are metabolized to a carcinogen in (Volume 100B); arsenic, metals,
of the strength of the total evidence humans; and several compounds for fibres, and dusts (Volume 100C);
for carcinogenicity to humans. which single-agent exposure does radiation (Volume 100D); person-
The use of mechanistic data to not exist because they are compo- al habits and indoor combustions
identify human carcinogens is accel- nents of (complex) mixtures, for ex- (Volume 100E); and chemical agents
erating. Initially, the IARC Monographs ample tobacco-specific nitrosamines and related occupations (Volume
xvi
that appears in this Scientific of systematic reviews of such The past practice of according
Publication in the analysis of evidence. The Workshop par- greatest concern to those agents
concordance between sites ticipants recommend that the demonstrated to be genotoxic,
where tumours arise in animals IARC Monographs Programme relative to agents whose carcino-
and in humans. use the key characteristics in its genicity appeared to be mediated
6. The Workshop participants also evaluations of carcinogenicity. by one or more other key char-
recommend that in future IARC 9. It is notable that in vivo or in vitro acteristics, appears to be overly
Monographs, the Evaluation mechanistic data are often avail- simplistic.
section for evidence of carci- able in humans. In most cases, 12. The objective of the IARC Mono
nogenicity in experimental an- when animal data are available graphs Programme is to identi-
imals be expanded to include for a key characteristic, human fy carcinogenic hazards, not to
additional information for agents data for that characteristic are exhaustively list all mechanistic
generally available, too. This events and pathways that might
evaluated as exhibiting sufficient
supports the notion that carcin- contribute to carcinogenesis.
evidence. For such agents, an
ogens show their characteristics Future coverage of mechanis-
additional sentence after the
across species. tic data should increase as the
relevant evaluation should refer
10. There should be no expec- retrieval of such data becomes
to the recognized site or sites
tation that all, or even most, more systematic and the key
of tumorigenesis, by using the
key characteristics operate characteristics are used as a
specification system described
for any human carcinogen. No framework for organization and
in the chapter on concordance
key characteristic is neces- analysis of mechanistic data.
analysis (Chapter 21, by Krewski
sary for carcinogenesis, and 13. Descriptive statistics of mecha-
et al.).
negative results for one or nisms identified to date may not
more key characteristics are be representative of future eval-
Mechanisms involved in
not an argument against the uations. Although genotoxicity
human carcinogenesis
potential carcinogenicity of is the key characteristic most
7. With increasing scientific un- an agent. Observation of one exhibited by the human carcin-
derstanding and availability of or more key characteristics in ogens identified to date, this
information on mechanisms of exposed humans can increase may reflect the relatively great-
carcinogenesis, it is expected the biological plausibility of er attention paid in the past to
that the IARC Monographs will less-than-sufficient evidence the investigation of genotoxic
make even greater use of mech in humans. Observation of agents. Future evaluations of car-
anistic data in identifying human one or more key characteris- cinogenic agents may involve a
carcinogens. tics in experimental animals larger set of mechanistic events
8. Until now, there has been no can increase confidence and pathways that are not yet
generally accepted method for in the human relevance of well developed or understood.
organizing mechanistic data less-than-sufficient evidence Accordingly, future shifts in the
pertinent to the identification in experimental animals. In distribution of the key character-
of carcinogenic hazards to interpreting the biological rel- istics are to be expected. This
humans. The key character- evance of information pertain- does not detract from the value
istics presented here offer a ing to the key characteristics, of using these characteristics
promising foundation for the it is important to consider as- now in evaluations of carcino-
structured evaluation of mech- pects of metabolism and kinet-
genic hazards.
anistic information, and this ics in extrapolating between in
should increase the utility of vitro and in vivo systems.
mechanistic evidence in future 11. A human carcinogen may dis-
identifications of carcinogenic play multiple key characteristics
hazards and the transparency that may interact with each other.
Abbreviations xix
CYP450 cytochrome P450
DCVC 1,2-dichlorovinyl-cysteine
DCVG (1,2-dichlorovinyl)glutathione
DDT dichlorodiphenyltrichloroethane
DES diethylstilbestrol
DMA(V) dimethylarsinic acid
DMBA 7,12-dimethylbenz[a]anthracene
DOHaD developmental origins of health and disease
DSBs double-strand breaks
eBL endemic Burkitt lymphoma
EBNA EBV nuclear antigen 1
EBV Epstein–Barr virus
EGF epidermal growth factor
EH epoxide hydrolase
ENCODE Encyclopedia of DNA Elements
ENU N-nitrosoethylurea
EPA United States Environmental Protection Agency
ER estrogen receptor
ERK extracellular signal-regulated kinase
ERα estrogen receptor alpha
F-344 Fischer 344
FANC/BRCA Fanconi anaemia complementation groups/breast cancer A
FISH fluorescence in situ hybridization
GLP good laboratory practice
GSH glutathione
GST glutathione S-transferase
GSTM1 glutathione-S-transferase M1
GTP guanosine-5′-triphosphate
GWAS genome-wide association study
H 2 O2 hydrogen peroxide
Hb haemoglobin
HBsAg hepatitis B surface antigen
HBV hepatitis B virus
HBx HBV X protein
HCC hepatocellular carcinoma
HCV hepatitis C virus
HER human epidermal growth factor receptor
HIF-1α hypoxia-inducible transcription factor 1 alpha
HIV human immunodeficiency virus
HIV-1 human immunodeficiency virus type 1
HMGB1 high-mobility group box 1 protein
HNSCC head and neck squamous cell carcinoma
HPB 4-hydroxy-1-(3-pyridyl)-1-butanone
HPV human papillomavirus
Hsp90 heat shock protein 90
HSV-1 herpes simplex virus type 1
HTLV-1 human T-cell lymphotropic virus type 1
IARC International Agency for Research on Cancer
ICD International Classification of Diseases
IGF-1 insulin-like growth factor 1
xx
IgM immunoglobulin M
IL-1α interleukin 1 alpha
InChI International Chemical Identifier
IRIS Integrated Risk Information System
IUPAC International Union of Pure and Applied Chemistry
JNK c-Jun N-terminal kinase
K14 keratin 14
KEGG Kyoto Encyclopedia of Genes and Genomes
KSHV Kaposi sarcoma-associated herpesvirus
LANA latency-associated nuclear antigen
LET linear energy transfer
LMP latent membrane protein
lncRNA long non-coding RNA
MALT mucosa-associated lymphoid tissue
MAPK mitogen-activated protein kinase
methyl-CCNU 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea
MHV-68 Murid herpesvirus 68
miRNA microRNA
MMA monomethylarsenic
MMA(III) monomethylarsinous acid
MMPs matrix metalloproteinases
MN micronuclei
MNNG N-methyl-N′-nitro-N-nitrosoguanidine
MOCA 4,4′-methylenebis(2-chloroaniline)
NAB N′-nitrosoanabasine
NAD+ oxidized nicotinamide adenine dinucleotide
NADH reduced nicotinamide adenine dinucleotide
NADPH nicotinamide adenine dinucleotide phosphate
NAT N′-nitrosoanatabine
NDEA N-nitrosodiethylamine
NDMA N-nitrosodimethylamine
NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells
NHL non-Hodgkin lymphoma
NK natural killer
NNAL 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
NNK 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
NNN N′-nitrosonornicotine
•
NO nitric oxide
NPV negative predictive value
NQO1 NAD(P)H:quinone oxidoreductase 1
Nrf 2 nuclear factor erythroid 2-related factor 2
O2•− superoxide
OAT organic anion transporter
•
OH hydroxyl radical
PAHs polycyclic aromatic hydrocarbons
PCB 77 3,3′,4,4′-tetrachlorobiphenyl
PCB 118 2,3′,4,4′,5-pentachlorobiphenyl
PCB 126 3,3′,4,4′,5-pentachlorobiphenyl
PCB 128 2,2′,3,3′,4,4′-hexachlorobiphenyl
PCB 153 2,2′,4,4′,5,5′-hexachlorobiphenyl
Abbreviations xxi
PCBs polychlorinated biphenyls
PCNA proliferating cell nuclear antigen
PeCDF 2,3,4,7,8-pentachlorodibenzofuran
PGHS-2 prostaglandin-endoperoxide synthase 2
PGRMC1 progesterone receptor membrane component 1
PI3K phosphoinositide 3-kinase
PPAR peroxisome proliferator-activated receptor
PPV positive predictive value
PR progesterone receptor
RET/PTC rearranged during transfection/papillary thyroid carcinoma
SCC squamous cell carcinoma
SCE sister chromatid exchange
SCID severe combined immunodeficiency
SIV simian immunodeficiency virus
SREBP1c sterol regulatory element-binding protein 1c
STAT3 signal transducer and activator of transcription 3
SULT1B1 sulfotransferase family cytosolic 1B member 1
SV40 simian virus 40
TCDD 2,3,7,8-tetrachlorodibenzo-para-dioxin
TCE trichloroethylene
TCF8 transcription factor 8
TD50 dose rate (in mg/kg body weight/day) that is estimated to reduce the proportion of
tumour-free animals by 50%
TGF-β transforming growth factor beta
TNF-α tumour necrosis factor alpha
ToxCast Toxicity Forecaster
TPA 12-O-tetradecanoylphorbol-13-acetate
UDP uridine-5′-diphosphate
UV ultraviolet
vFLIP viral Fas-associated death domain-like IL-1-converting enzyme inhibitory protein
vGPCR viral G protein-coupled receptor
WHO World Health Organization
xxii
CHAPTER 1
PART 1
part 1.
concordance between cancer in humans and in experimental
animals
chapter 1.
Electrophilic agents
James A. Bond and Ronald L. Melnick
Introduction or mice and, except for ethylene chloride), the lung (sulfur mustard),
oxide, sufficient evidence of carci- the lymphohaematopoietic system
In this chapter, electrophilic agents nogenicity from studies of exposed (benzene, 1,3-butadiene, and eth-
include direct-acting electrophilic humans. For ethylene oxide, there ylene oxide), nasal tissue (formal-
chemicals and chemicals that are was limited evidence of carcinogen- dehyde), and the kidney (TCE). For
metabolized to reactive electro- icity in humans, but the classification bis(chloromethyl)ether (BCME), the
philes. All of the chemicals discussed of this chemical was raised to carci- lung and the nasal cavity were iden-
here are IARC Group 1 agents and nogenic to humans (Group 1) based tified as target organs in humans
as such can be characterized as on strong mechanistic evidence and rats, respectively. In addition,
carcinogenic to humans. Relevant of mutagenicity and clastogenici- angiosarcomas of the liver, which
carcinogens discussed in this chap- ty, including the induction of sister are rare tumours, were identified in
ter do not include pharmaceutical chromatid exchange (SCE), chro- humans, rats, and mice exposed to
drugs classified in Group 1, which mosomal aberrations (CA), and mi- vinyl chloride.
otherwise typically include alkylating cronuclei (MN) in workers exposed In several instances, tumour sites
cytotoxic agents. to ethylene oxide. identified in animals were not de-
Tumour sites identified in previous Among this group of chemicals, tected in epidemiological studies of
IARC evaluations of the carcinogen- there is remarkable concordance in exposed workers. These apparent
icity of several non-pharmaceutical tumour sites with sufficient evidence discrepancies may be due to dif-
organic compounds in humans and or limited evidence of carcinogenicity ferences in susceptibility between
laboratory animals are shown in in humans and sufficient evidence of humans and certain animal mod-
Table 1.1. For each of these agents, carcinogenicity in rats and/or mice, els, differences in exposure con-
there was sufficient evidence of car- for example for the liver (aflatoxins, ditions between studies in animals
cinogenicity from studies in rats and/ trichloroethylene [TCE], and vinyl and in humans, or limitations in
2
Agent Humans Rats Mice
CHAPTER 1
PART 1
risk at particular sites. For example, the parent chemical or a metabolite other critical macromolecules or re-
the finding that mammary gland tu- thereof. All of these agents either ceptors are also important, because
mours were induced in female mice exist as direct-acting electrophilic these interactions can initiate the car-
exposed to benzene, 1,3-butadiene, species or can be metabolized to cinogenic process or affect its pro-
or vinyl chloride, whereas breast can- reactive electrophilic species. It is gression. Determinants for metabol-
cer risk was not elevated in exposed generally accepted that the abili- ism or molecular interactions are
workers may be due to the fact that ty of these electrophiles, whether dependent on the exposure history
women were not included in many alkylating agents, epoxides, or qui- (including the intensity, duration,
occupational cohort or case–control nones, to react with nucleophiles, frequency, and route or routes of
studies of these agents, sometimes such as DNA, is key to the carci- exposure, and the life stage of the
because there were very few or no nogenicity of this group of agents exposed individual) and may differ
women in relevant workforces, or (Table 1.1 and Table 1.2). according to the specific genotype of
because they were exposed to much Because of the diversity in the the individual (i.e. genetic polymor-
lower concentrations. In contrast, for biochemical and physical properties phisms in metabolic enzymes).
hospital-based sterilization workers of organic electrophilic compounds,
exposed to ethylene oxide, among it is useful to first examine, in a gen- Absorption
whom there is a high proportion of eral way, factors that are important
for their absorption, distribution, Organic compounds can be ab-
women, increases in breast cancer
metabolism, and elimination. These sorbed after inhalation, dermal ex-
incidence were observed. Exposure
factors include, but are not limited posure, or ingestion. The sites and
to ethylene oxide increased the inci-
to, (i) physiological, (ii) chemical, extent of absorption depend on the
dence of mammary gland tumours
and (iii) metabolic determinants. physicochemical characteristics of
in female mice but not in male mice.
Examples of physiological factors the compound. Highly reactive or-
Thus, limitations in human cancer
are alveolar ventilation rate, cardi- ganic chemicals typically interact
databases and sex-specific tumours
ac output, blood flow to organs, or- with tissues at the portal of entry,
in animal studies need to be consid-
gan volumes, and body mass and and toxicity and carcinogenicity are
ered in evaluations of site concor-
composition (e.g. percentage body often most evident at these sites.
dance for tumour induction between
fat). Examples of chemical factors Formaldehyde, for example, is a wa-
humans and animals.
include the stability and reactivity ter-soluble, reactive volatile organic
The carcinogenicity of organic
of the parent compound and its me- compound. After inhalation, form-
compounds and their organ specifici-
tabolites, partition coefficients that aldehyde interacts with the highly
ty in animal models and in humans
control the distribution of organic aqueous nasal mucosa, the first
are influenced by numerous factors.
compounds between blood and air respiratory tract tissue that is en-
This chapter focuses on factors
or blood and tissues, rates of uptake countered upon inspiration. In rats
that affect tissue dosimetry, factors
from the gastrointestinal tract, and chronically exposed to formaldehyde
that contribute to the multistep car-
absorption through the dermis. For vapours, the anterior portion of the
cinogenic process for each agent,
some organic chemicals, metabol- nasal cavity was the site of tumour
and factors that might account for
ic determinants such as the cellular induction.
interspecies and inter-individual
capacity for metabolism and the af- Sulfur mustard (also known as
differences in susceptibility.
finity of metabolic enzymes for the mustard gas) is another example of
Chemical disposition compound are critical, both in acti- a reactive volatile organic compound
vating the parent compound to the that can be absorbed after inhalation
The role of metabolism in the forma- putative carcinogenic electrophilic or through dermal exposure. It is a
tion of the putative carcinogenic inter- metabolite and in transforming the lipophilic substance that easily pene-
mediates of the non-pharmaceutical parent compound or the electrophilic trates into the skin and mucosal sur-
organic compounds that are carcino- intermediate into a metabolite that faces (Drasch et al., 1987; Somani
genic to humans is summarized in can be readily eliminated. Molecular and Babu, 1989), resulting in a high
degree of bioavailability. Sulfur mus- among the most potent animal and large blood–tissue interface of the
tard is a bifunctional alkylating agent human carcinogens known. The fact alveoli in that region. The blood–air
(IARC, 1987). Like for formaldehyde, that BCME and CMME are powerful partition coefficient is a key factor in
there is evidence that DNA alkylation alkylating agents provides moderate determining the maximum levels of
by sulfur mustard leads to forma- to strong evidence that they oper- the organic compound that can be
tion of cross-links, inhibition of DNA ate by a genotoxic mechanism. This attained in the blood at any given
synthesis and repair, and induction mechanism is likely to be similar to concentration of the compound in air.
of point mutations and chromo- that of other strong alkylating agents, For example, the blood–air partition
some-type and chromatid-type ab- involving modification of DNA and coefficients for the carcinogens vinyl
errations (ATSDR, 2003). Some of resultant mutations. BCME can chloride, 1,3-butadiene, benzene,
these changes are observed in nasal also be absorbed through the skin, and TCE are 1.2, 1.5, 7.8, and 10
tissue, consistent with the nose be- and studies in which mice were ex- respectively. At equivalent air con-
ing a target organ for sulfur mustard. posed to BCME by dermal applica- centrations, higher levels of benzene
BCME and chloromethyl methyl tion demonstrated that this agent is and TCE will be present in the blood
ether (CMME) are highly reactive or- a potent complete skin carcinogen, at steady state, compared with vinyl
ganic compounds that belong to the producing both papillomas and squa- chloride and 1,3-butadiene.
group of chloroalkyl ethers, which mous cell carcinomas (Van Duuren The organic compounds dis-
are flammable, volatile, colourless et al., 1969). cussed here can also be absorbed
liquids with highly irritating odours. Ethylene oxide is a water-soluble after oral exposure. Ingestion and
In water and aqueous biological volatile organic compound that is rel- subsequent oral absorption repre-
fluids, these substances are rapid- atively stable in aqueous solutions at sent the greatest potential route of
ly hydrolysed to form hydrochloric neutral pH (half-life, approximately exposure to non-volatile organic
acid, methanol, and formaldehyde 72 hours). Because it is completely compounds. Organic chemicals may
(Nichols and Merritt, 1973; National miscible with water, inhaled ethylene enter the body via food or in liquids.
Toxicology Program, 2004). The car- oxide will dissolve in the aqueous lin- Aflatoxin is a compound for which
cinogenic effects of BCME are re- ing of the respiratory tract and diffuse ingestion is considered the most
stricted to the epithelial tissue where into the blood. Thus, uptake of this important route of exposure. For ex-
exposure occurs, namely the lung organic compound will be substantial ample, human uptake of aflatoxins
for humans and respiratory tract tis- throughout the respiratory tract. in quantities of nanograms to micro-
sues for laboratory animals exposed Volatile organic compounds that grams per day occurs mainly through
to BCME by inhalation. This por- are not reactive or water-soluble are consumption of contaminated maize
tal-of-entry effect is consistent with generally absorbed into the blood, and peanuts, which are dietary sta-
the short half-life of BCME in aque- primarily in the pulmonary region of ples in some tropical countries.
ous media (ATSDR, 1989). BCME is the respiratory tract because of the Uptake of aflatoxin M1 in quantities
4
of nanograms per day occurs main- reactive exo-epoxide; binding of the to be metabolized via two CYP450
ly via consumption of aflatoxin-con- exo-epoxide to DNA, resulting in enzymes, rather than just one,
CHAPTER 1
PART 1
taminated milk, including breast milk the formation of DNA adducts; and and that the putative, high-affinity
(IARC, 2002). Once absorbed from miscoding during DNA replication, enzyme is active primarily at ben-
the gastrointestinal tract, aflatoxins which leads to development of mu- zene concentrations below 1 ppm
are transported via the hepatic por- tations, with eventual progression to (Rappaport et al., 2009). Whereas
tal blood to the liver, where they are tumours. Aflatoxin B1, the most com- CYP2E1 is the primary enzyme re-
metabolized. As discussed below, mon and potent of the aflatoxins, is sponsible for mammalian metabol-
metabolism is key to understanding metabolized predominantly in the ism of benzene at higher levels of
the carcinogenicity of aflatoxins. liver. In humans, CYP1A2, CYP2B6, exposure (Valentine et al., 1996;
CYP3A4, CYP3A5, and CYP3A7, Nedelcheva et al., 1999), CYP2F1
Metabolic activation or as well as the phase II enzyme glu- and CYP2A13 have been proposed
detoxification and elimination tathione-S-transferase M1 (GSTM1; as enzymes that metabolize ben-
see below) are hepatic enzymes zene at environmental levels of expo-
Metabolism plays a key role in both that mediate aflatoxin metabolism. sure, i.e. below 1 ppm (Powley and
the activation and the detoxification In humans, the relative contribution Carlson, 2000; Sheets et al., 2004;
of many organic compounds. The of these enzymes in vivo depends Rappaport et al., 2009).
first step, generally called phase I not only on their affinity but also A large proportion of benzene
metabolism, is oxidation to a meta- on their expression level in the liv- oxide spontaneously rearranges to
bolic intermediate. This intermediate er, where CYP3A4 is predominant, phenol, which is either eliminated via
becomes the substrate for the sec- mediating the formation of the afla- phase II conjugation or further metab-
ond step, phase II, in which it is en- toxin B1 exo-epoxide and aflatoxin olized to hydroquinone and 1,4-ben-
zymatically hydrolysed or conjugated Q1. In humans, as in other species, zoquinone. The remaining benzene
with one of a variety of biological sub- the DNA binding and carcinogenicity oxide is either hydrolysed to produce
strates, such as sulfate, glucuronic of aflatoxin B1 result from its con- benzene-1,2-dihydrodiol (catechol),
acid, or glutathione (GSH). Phase II version to the exo-8,9-epoxide by which is further oxidized to 1,2-ben-
reactions increase the water solubil- CYP3A4 (Essigmann et al., 1982). zoquinone, or conjugated with GSH
ity of the chemical, which facilitates This epoxide is highly reactive and to produce S-phenylmercapturic
its excretion in urine, or increase the is the main mediator of cellular injury acid. Metabolism of the oxepin tau-
molecular weight, so that the agent (McLean and Dutton, 1995). In con- tomer of benzene oxide is thought to
is more readily eliminated in bile. trast, CYP1A2 can generate some open the aromatic ring; this yields the
Phase I metabolism of organic com- exo-epoxide but also a high propor- reactive muconaldehydes and mu-
pounds can also result in formation tion of endo-epoxide and aflatoxin conic acid. Benzene oxide, the ben-
of reactive intermediates that can M1. Aflatoxins M1 and Q1, produced zoquinones, the muconaldehydes,
spontaneously interact with critical from aflatoxin B1 by CYP1A2 and and the benzene dihydrodiol epox-
macromolecules. For many organic CYP3A4, respectively, are present ides (formed from CYP450-mediated
chemicals, this is the first key step in in the urine of individuals exposed oxidation of benzene dihydrodiol)
the carcinogenic process. to aflatoxins (Ross et al., 1992; Qian are electrophiles that react readily
Cytochrome P450 (CYP450) is et al., 1994). with peptides, proteins, and DNA
the collective name of the family of Benzene is also a substrate for (Bechtold et al., 1992; McDonald
enzymes responsible for the initial CYP450 enzymes. In common with et al., 1993; Bodell et al., 1996;
phase I metabolism of many organ- other compounds discussed in this Gaskell et al., 2005; Henderson et al.,
ic compounds. Metabolic activation section, benzene must be metabo- 2005; Waidyanatha and Rappaport,
by various CYP450 isozymes is lized to become carcinogenic (Ross, 2005), thereby interfering with cellu-
a key first step in the carcinogen- 2000; Snyder, 2004). The initial lar function (Smith, 1996). The role of
ic process for aflatoxin, benzene, metabolic step involves CYP450- these different metabolites in the car-
1,3-butadiene, TCE, and vinyl chlo- dependent oxidation to benzene ox- cinogenicity of benzene remains un-
ride. For example, in the mechanism ide, which exists in equilibrium with clear, but formation of benzoquinone
of carcinogenicity of aflatoxins, the its tautomer oxepin. It has been re- from hydroquinone via myeloperoxi-
key steps involve: metabolism to a ported that benzene is most likely dase in the bone marrow has been
6
species at higher exposures, but at dehyde dehydrogenase, and cat- is converted (i) by enzymatic and
lower exposures oxidation is limited alase, as well as CYP2E1. One- non-enzymatic hydrolysis to ethyl-
CHAPTER 1
PART 1
by the hepatic blood flow. carbon metabolism not mediated by ene glycol, which is partly excreted
Conjugation with GSH is another CYP450 is central to many biologi- as such and partly metabolized fur-
important metabolic pathway for TCE, cal processes. In aqueous solution, ther via glycolaldehyde, glycolic acid,
resulting in the formation of short- formaldehyde is rapidly converted and glyoxylic acid to oxalic acid, for-
lived and reactive metabolites. The to its dihydroxy form, methanediol mic acid, and carbon dioxide; and
initial conjugation reaction occurs (CH2(OH)2, also known as formalde- (ii) by conjugation with GSH.
primarily in the liver to form (1,2-di- hyde hydrate or methylene glycol), Sulfur mustard, BCME, and
chlorovinyl)glutathione (DCVG). which is in dynamic equilibrium with CMME can also react spontaneous-
Subsequent processing of DCVG formaldehyde.
ly with biological molecules without
occurs primarily in the kidney, which the need for metabolic activation.
is a tumour target site in rats and hu- Direct-acting compounds
For example, the reactivity of sulfur
mans. In the kidney, DCVG can be
Some organic compounds discussed mustard with a wide variety of cel-
hydrolysed by γ-glutamyltransferase
here are sufficiently reactive that they lular macromolecules is well docu-
and cysteinylglycine dipeptidase to
do not require metabolic activation mented (IARC, 1975, 1987; ATSDR,
1,2-dichlorovinyl-cysteine (DCVC),
as the first step in the carcinogenic 2003). The presence of two chlorine
which may be N-acetylated to form
process. Formaldehyde reacts read- atoms makes it a strong bifunctional
a mercapturate or converted by
ily and reversibly with amino groups alkylating agent with a high chemi-
β-lyase to generate a reactive thi-
to form Schiff bases, and with sulf- cal reactivity (Dacre and Goldman,
olate that rearranges to form either
hydryl groups resulting in the forma- 1996). The chlorine atom is typically
chlorothioketene or chlorothioacetyl
chloride (Dekant et al., 1988; Völkel tion of S-hydroxymethylglutathione, released under formation of a car-
and Dekant, 1998). Chlorothioketene which is oxidized by ADH3 to bonium ion, which then undergoes
and chlorothioacetyl chloride are S-formylglutathione. S-formylglu- intramolecular cyclization to create a
highly reactive and chemically un- tathione is further metabolized by highly reactive compound. Formation
stable, and are thought to be the S-formylglutathione hydrolase to of the carbonium ion is facilitated
molecular forms responsible for ad- generate formate and GSH. Formate in aqueous solutions (Somani and
duct formation with nucleic acids in can also be formed non-enzymati- Babu, 1989); this explains the sensi-
the kidney (Müller et al., 1998a, b). cally (Hedberg et al., 2002). Because tivity of mucosal tissues, such as the
For both humans and rodents, the formaldehyde reacts non-enzymat- eye, to its effect (Solberg et al., 1997).
information on urinary excretion of ically with critical macromolecules Elevated concentrations of thiodigly-
stable end-products is much more (DNA and others), many of these en- col, the major hydrolysis product of
extensive for the oxidative pathway zymatic processes can be viewed as mustard gas, were detected in hu-
than for the GSH conjugation path- detoxification steps, especially those man urine after exposure to mustard
way. However, this is not an accurate that lead to incorporation of the com- gas vapour and aerosol (Jakubowski
indication of the overall flux through pound into the one-carbon pool. et al., 2000). BCME and CMME are
each pathway, because it does not Ethylene oxide is another di- rapidly hydrolysed in water and in
account for the formation of reactive rect-acting alkylating agent that re- aqueous biological fluids to form hy-
and chemically unstable metabolites acts with nucleophiles without the drochloric acid, methanol, and form-
via the GSH conjugation pathway. need for metabolic transformation. aldehyde (Nichols and Merritt, 1973;
As noted above, CYP450 en- The direct reaction of ethylene ox- National Toxicology Program, 2004).
zymes are not the only enzymes ide with DNA is thought to initiate
involved in the metabolism of organ- the cascade of genetic and related Molecular interactions (DNA
ic compounds. Formaldehyde, an events that lead to cancer (Swenberg adducts, genetic alterations,
important intermediate in one-car- et al., 1990). The pathways of ethyl- etc.)
bon metabolism, is a substrate for ene oxide metabolism can thus be
several enzymes, including cyto- considered detoxification pathways A common feature of the above-men-
solic ADH, mitochondrial ALDH, that increase the elimination of the tioned agents is that they either are
cytosolic GSH-dependent formal- parent chemical. Ethylene oxide direct-acting electrophiles or are
8
Table 1.3. Levels of evidencea in humans and animals of key characteristics of carcinogens
10
metabolites of 1,3-butadiene can effects of 1,3-butadiene and its me- oxide and/or by the rearrangement
also react at sites involved in base tabolites are induction of CA, SCE, product chloroacetaldehyde (Bonse
CHAPTER 1
PART 1
pairing and form adducts at the N3 and MN. et al., 1975). Both intermediates can
position of cytosine, at N1 and N6 of Genetic alterations in 1,3-butadi- bind to proteins, RNA, and DNA
adenine, and at N1 and N2 of guanine ene-induced tumours in mice are of (Guengerich and Watanabe, 1979).
(Selzer and Elfarra, 1996a, b, 1997; the same type as those frequently Vinyl chloride is mutagenic in bac-
Zhao et al., 1998; Zhang and Elfarra, involved in the development of a va- teria and mammalian cells. It is also
2004). An increase in the number of riety of human cancers. The K-Ras, clastogenic in vivo and in vitro, caus-
N1-trihydroxybutyladenine adducts H-Ras, p53, p16/p15, and β-cate- ing increases in the frequencies of
was detected in lymphocytes of work- nin mutations detected in tumours CA, SCE, and MN (IARC, 2008).
ers exposed to 1,3-butadiene (Zhao from exposed mice are probably The major DNA adduct formed from
et al., 2000). Alkylation of N1-adenine the result of the DNA reactivity and chloroethylene oxide is at the N7 po-
by epoxybutene followed by hydro- the genotoxic effects of 1,3-butadi- sition of guanine. In addition, etheno
lytic deamination forms the highly ene-derived epoxides. Other DNA- DNA adducts (1,N 6 -ethenoadenine,
alkylating metabolites of 1,3-butadi- 3,N4-ethenocytosine, N2,3-etheno-
mutagenic deoxyinosine (Rodriguez
ene (hydroxymethylvinylketone and guanine, and 1,N2-ethenoguanine)
et al., 2001), which codes for incor-
crotonaldehyde) may also contribute have been identified after in vitro in-
poration of cytosine during DNA rep-
to the mutagenicity and carcino- cubations with chloroethylene oxide,
lication, leading to the generation of
genicity of this compound. A con- and levels of these adducts are in-
A → G mutations. Diepoxybutane is
sistent pattern of K-Ras mutations creased in multiple organs of rats ex-
a bifunctional alkylating agent that
(G → C transversions at codon 13) posed to vinyl chloride by inhalation
can form monoadducts in DNA simi-
was observed at multiple organ sites (Ciroussel et al., 1990; Guengerich,
lar to those formed by epoxybutane-
of 1,3-butadiene-induced cancers 1992; Swenberg et al., 2000). The
diol, or DNA–DNA cross-links by
(Hong et al., 2000; Sills et al., 2001; etheno adducts, which may be in-
binding at the N7 position of guanine
Ton et al., 2007). Alterations in the volved in base-pair substitutions, are
of one DNA strand and at another
p53 gene in brain tumours in mice much more persistent than the N7-
site elsewhere in the DNA, such as
were mostly G → A transition muta- guanine adduct (Fedtke et al., 1990)
the N7 of another guanine or the N1 tions (Kim et al., 2005) that probably and have demonstrated miscoding
of an adenine (Goggin et al., 2009). arose from miscoding at apurinic potential in vitro and in vivo, causing
Depurination of these interstrand sites resulting from depurination of A → G transitions, A → T transver-
or intrastrand lesions can induce N7-guanine adducts. Inactivation of sions, C → A transversions, C → T
point mutations and large deletions. the tumour suppressor genes p16 transitions, and G → A transitions
However, if diepoxybutane alkylates and p15 may also be important in the (Singer et al., 1987; Cheng et al.,
an adenine at N6 in DNA, an exocy- development of 1,3-butadiene-in- 1991; Mroczkowska and Kuśmierek,
clic adenine adduct is formed pref- duced lymphomas (Zhuang et al., 1991; Singer et al., 1991; Basu et al.,
erentially to DNA–DNA cross-linked 2000). Mammary gland adenocarci- 1993). The same types of mutation
products (Antsypovich et al., 2007). nomas induced by 1,3-butadiene in have been observed in the TP53
1,3-Butadiene is genotoxic at mice frequently had mutations in the and RAS genes in vinyl chloride-in-
multiple tissue sites in mice and rats, p53, H-Ras, and β-catenin genes duced tumours. TP53 mutations
and its epoxide metabolites are mu- (Zhuang et al., 2002). Overall, these associated with exposure to vinyl
tagenic in a variety of in vitro sys- observations point to a genotoxic chloride (frequently A → T transver-
tems. Deletion mutations and base mechanism underlying the devel- sions) were found in angiosarcomas
substitution mutations induced by opment of 1,3-butadiene-induced in both humans and rats, and muta-
these alkylating agents are consis- cancers. tions in K-RAS were also associated
tent with their DNA adduct profiles with vinyl chloride-induced angio-
Vinyl chloride
and include G → A transition muta- sarcomas in humans (IARC, 2008).
tions, G → C transversions, A → T The carcinogenicity of vinyl chloride Polymorphisms in XRCC1, a gene
transversions, and A → G transitions is probably caused by its highly re- that encodes an enzyme that repairs
(Lee et al., 2002). Other genotoxic active metabolite chloroethylene etheno DNA adducts, may account
12
a genotoxic mechanism of kidney of various parts of the long arm of interaction between the parent elec-
carcinogenesis is strong. The evi- chromosome 5 or 7, or complete trophile or one or more electrophilic
CHAPTER 1
PART 1
dence for the liver as a target tissue loss of these chromosomes, gain of metabolites and nucleophilic DNA,
for TCE, from cancer assays and tox- the entire chromosome 8, and an leading to point mutations and induc-
icity findings in laboratory animals, is increased frequency of transloca- tion of CA. These effects have been
strong. The evidence for non-geno- tions between chromosomes 8 and observed in humans, in animals, and
toxic and/or genotoxic mechanisms 21 in peripheral lymphocytes of ex- in in vitro systems. In addition, pro-
of liver carcinogenesis is moderate. posed workers (Smith et al., 1998; duction of reactive oxygen species,
The available data suggest multiple Zhang et al., 1999, 2002). Benzene inhibition of DNA synthesis or repair,
non-genotoxic mechanisms and the and its quinone metabolites are in- and cytotoxicity/cell proliferation
potential for genotoxic mechanisms hibitors of topoisomerase II, leading could complement DNA modification
from the TCE metabolites dichloro- to increased frequencies of DNA to enhance DNA damage. Tumour
acetate and chloral hydrate. cleavage complexes and DNA dou- outcome can result from certain
ble-strand breaks; this effect can re- DNA adducts leading to mutations
Benzene
sult in the formation of chromosome and dysregulation initially described
Benzene induced CA, SCE, and MN translocations and inversions (Hutt with reference to proto-oncogenes
in bone marrow cells of exposed and Kalf, 1996; Lindsey et al., 2004, and tumour suppressor genes. For
mice, CA in bone marrow cells of 2005; Deweese and Osheroff, 2009). benzene, chromosomal transloca-
exposed rats, and CA and mutations Other potential pathways involved in tions, in combination with haemato-
in human cells in vitro. CA in human benzene-induced acute myeloid leu- toxicity or immunosuppression, are
peripheral lymphocytes have long kaemia include mutagenesis (pos- associated with increased risk of
been associated with occupational sibly through generation of reactive haematopoietic cancer in humans.
exposure to benzene (Forni, 1979; oxygen species), epigenetic changes The extent to which other process-
IARC, 1982; Eastmond, 1993; Zhang due to altered methylation status, de- es (inflammation, oxidative stress,
et al., 2002; Holecková et al., 2004). creased immunosurveillance (Cho, immunosuppression, epigenetic al-
As noted above, metabolism of ben- 2008; Li et al., 2009), haematotoxicity terations, and immortalization) might
zene produces several electrophilic and alterations in stem cell pool size contribute to the carcinogenicity of
agents (benzene oxide, in equilibrium (Rothman et al., 1997), and inhibition this class of chemicals in general is
with its tautomer oxepin, muconalde- of gap-junction intercellular commu- limited by the availability of few or no
hyde, benzoquinone, and benzene nication (Rivedal and Witz, 2005). published studies that address these
dihydrodiol epoxide) that can react Thus, multiple mechanisms are likely effects.
with DNA or proteins. DNA binding to be involved in benzene-induced
Polymorphisms and
and adduct formation may not be leukaemogenesis. Benzene produc-
susceptibility
the major steps in the development es multiple cytogenetic abnormalities
of benzene-induced leukaemias in human lymphocytes (Tough and Susceptibility to the carcinogenic
(Whysner et al., 2004). Although the Brown, 1965; Picciano, 1979; Smith effects of organic compounds may
mechanisms of benzene-induced and Zhang, 1998; Zhang et al., 2002) derive from acquired characteristics,
carcinogenesis and the potential and induces specific chromosomal such as altered expression of certain
relative roles of each of these me- changes associated with non-Hodg- enzymes, or from genetic factors,
tabolites are not fully known, there is kin lymphoma in human lympho- such as enzyme polymorphisms.
strong support for the involvement of cytes (Zhang et al., 2007). Induction Polymorphisms of enzymes involved
clastogenic and aneugenic effects, of DNA double-strand breaks and in the metabolism of organic com-
such as formation of CA, MN, and chromosomal rearrangements in pounds are likely to be responsible
DNA strand breaks. lymphoid cells in combination with for individual differences in activa-
Exposure to benzene has been immunosuppression by benzene tion and detoxification reactions that
associated with chromosomal might be the cause of lymphoma. control tissue levels of electrophilic
changes that are commonly ob- The carcinogenicity of the group intermediates. The enzymes that
served in acute myeloid leukaemia, of electrophilic chemicals dis- catalyse epoxide formation and elim-
including those comprising loss cussed above is likely to be due to ination are polymorphic in human
14
in connection with susceptibility to pigmentosum cells (human fibro- pancytopenia) may have increased
TCE toxicity and carcinogenicity. blasts) compared with repair-profi- susceptibility to leukaemia from
CHAPTER 1
PART 1
Polymorphisms in genes for organic cient cells; the location of mutations formaldehyde.
anion transporters (OAT1 and OAT3) was affected by repair proficiency A common polymorphism in
in the kidney may also influence the (Levy et al., 1992). the DNA repair gene XRCC1 is
rates of uptake and the extent of cellu- Polymorphisms in genes involved a biomarker of susceptibility to
lar accumulation of DCVG or DCVC. TP53-induced mutations in work-
in repair of DNA double-strand
With respect to life-stage susceptibil- ers exposed to vinyl chloride (Li
breaks (WRN [Werner syndrome],
ity, data are available to support the et al., 2003). In workers exposed to
TP53, BLM [Bloom syndrome],
influence of differences in exposure 1,3-butadiene, MN frequencies were
RAD51, and BRCA1) can modify
(e.g. transplacental transfer or ex- higher in peripheral lymphocytes of
susceptibility to benzene-induced
posure through breast milk in early individuals with polymorphisms in
life stages) or life stage-specific dif- haematotoxicity in exposed workers
XRCC1 compared with individuals
ferences in toxicokinetics. Lifestyle (Shen et al., 2006; Lan et al., 2009;
carrying the wild-type repair gene
factors (e.g. consumption of alcohol- Ren et al., 2009).
(Wang et al., 2010).
ic beverages) may also affect TCE Mice deficient in nucleotide exci-
In summary, genetic polymor-
metabolism, and nutrition or obesity sion repair were more susceptible
phisms and variability in expression
may affect internal concentrations of than wild-type mice to the mutagenic
of enzymes due to induction or inhi-
TCE and its metabolites. effects of 1,3-butadiene or its reac-
bition of constitutive enzyme levels
Genes involved in DNA repair act tive metabolites epoxybutene and di-
can have considerable impact on the
to maintain the integrity of the ge- epoxybutane (Wickliffe et al., 2007).
carcinogenic process. Determining
nome by removing lesions (i.e. ad- Chicken cells deficient in the
the existence and functional role of
ducts) that – if left unrepaired – could Fanconi anaemia complemen-
genetic polymorphisms in cancer eti-
result in mutations or chromosomal tation groups/breast cancer A
damage. Individuals with defects in ology is an active area of research in
(FANC/BRCA) pathway are hyper- molecular epidemiology.
genes that encode DNA repair en-
sensitive (with reduced survival) to
zymes are at elevated risk for cer-
formaldehyde at levels measured in
tain cancers (Poulsen et al., 1993).
human plasma (Ridpath et al., 2007).
Heterozygous carriers may also
This observation is consistent with
have increased susceptibility, be-
cause of suboptimal levels of repair. an essential role for this pathway
The reactive aflatoxin B1 me- in the repair of DNA–protein cross-
tabolite exo-8,9-epoxide induced links caused by formaldehyde, and
a higher mutation frequency in a suggests that patients with Fanconi
shuttle vector plasmid transfected anaemia (a genetic disorder that
into DNA repair-deficient xeroderma is characterized by progressive
16
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chapter 2.
Carcinogenicity in humans uation for these dyes was raised to can be attributed to 4-aminobiphe-
Group 1 based on this mechanistic nyl, o-toluidine, 2-naphthylamine, or
Exposure to 4-aminobiphenyl, o-tolu information, although at present the other aromatic amines. Hair dyes
idine, 2-naphthylamine, and benzi corresponding epidemiological data are an additional source of expo-
dine (Fig. 2.1) has been consisten- are considered to provide inade- sure to 4-aminobiphenyl and o-tolu-
tly associated with the induction quate evidence for the carcinogeni- idine (IARC, 2010, 2012a; Lizier and
of cancer of the urinary bladder in city of these dyes in humans (IARC, Boldrin Zanoni, 2012).
humans. This association is based 2010, 2012a). Exposure to phenacetin (Fig. 2.1),
upon occupational exposures, pri- Cigarette smoke contains 4-amino through its use as an analgesic,
marily of workers in the rubber and biphenyl, o-toluidine, and 2-naphthyl- causes cancer of the kidney and
dye industries (IARC, 2010, 2012a). amine, and tobacco smoking caus- ureter in humans (IARC, 2012c).
Similarly, occupational exposure to es cancer of the bladder in humans Chlornaphazine (Fig. 2.1), a chemo
4,4′-methylenebis(2-chloroaniline) (IARC, 1986, 2004, 2010, 2012a, b). therapeutic agent that has been used
(MOCA; Fig. 2.1), a curing agent for The contribution of 4-aminobiphenyl, for the treatment of Hodgkin lympho-
polyurethane pre-polymers, causes o-toluidine, and 2-naphthylamine ma and for the control of polycythae-
cancer of the bladder in humans, al- to the induction of smoking-related mia vera, causes cancer of the
though the epidemiological data are cancer of the bladder is confounded bladder in humans, presumably due
not as strong as those for the other by the presence of numerous other to metabolism to 2-naph thylamine
agents (IARC, 2010, 2012a). Certain carcinogens, including carcinogenic (IARC, 2012c). An additional source
azo dyes that are used in commercial aromatic amines, in tobacco smoke. of human exposure to o-toluidine
products, for example, Direct Black Cigarette smoking also causes oth- is from the anaesthetic prilocaine
38, Direct Blue 6, and Direct Brown er cancers (e.g. cancer of the lung, (Fig. 2.1) (IARC, 2010, 2012a).
95 (Fig. 2.2), are known to undergo oral cavity, and pancreas, and pos- Exposure to herbal remedies pre-
azo reduction in vivo to yield the car- sibly breast cancer), but at present pared from plant species of the ge-
cinogen benzidine. The overall eval- it is unclear whether these cancers nus Aristolochia has been causally
24
correlation between urinary acidity Fig. 2.2. Structures of benzidine-derived azo dyes.
CHAPTER 2
and the incidence of bladder cancer
PART 1
in smokers (Alguacil et al., 2011).
The major metabolic activation
pathway for aristolochic acid I and
aristolochic acid II involves nitro
reduction, followed by cyclization
to give N-hydroxyaristolactams,
which – in contrast to other
N-hydroxyarylamides – do not ap-
pear to require additional activa-
tion to react with DNA (Stiborová
et al., 2011, 2013). Nonetheless,
N-hydroxyaristolactams have been
shown to serve as substrates for
human sulfotransferases, particu-
larly sulfotransferase family cy-
tosolic 1B member 1 (SULT1B1),
forming highly reactive N-sulfoxy
derivatives (Sidorenko et al., 2014).
The major adducts resulting from
the N-hydroxyaristolactams are N2 -
substituted deoxyguanosines and N6 -
substituted deoxyadenosines (Fig.
2.4) (IARC, 2002, 2012c).
DNA adducts derived from aris-
Alterations in the TP53 higher-grade tumours (grades 2 or 3,
tolochic acids have been detected
tumour suppressor gene in i.e. moderately or poorly differentiat-
in renal tissue from patients who humans ed) and only at G:C base pairs.
had been exposed to aristolochic Mutant p53 protein has also been
acid-containing herbal products and Mutations in the TP53 tumour sup- detected in workers exposed oc-
from individuals who had consumed pressor gene have been found in cupationally to benzidine (Xiang et
wheat grains contaminated with approximately 50% of all bladder al., 2007). The occurrence and the
Aristolochia (IARC, 2002, 2012c; cancers in humans (Petitjean et al., amount of mutant protein were pos-
Chen et al., 2012; Jelaković et al., 2007), with G:C base substitution itively correlated with the level of
2012; Schmeiser et al., 2012, 2014; mutations occurring to a greater benzidine exposure and the extent
Yun et al., 2013, 2014). Typically, extent than A:T base substitution of neoplastic changes in exfoliated
the major lesion detected is an N - 6 mutations. urothelial cells.
deoxyadenosine adduct derived TP53 gene mutations have been Urothelial tumours arising from
from aristolochic acid I, accompa- detected in bladder cancer patients exposure to aristolochic acids have
nied by smaller amounts of a similar exposed occupationally to 4-amino been consistently shown to carry mu-
adduct derived from aristolochic acid biphenyl, 2-naphthylamine, and/or tations in the TP53 tumour suppres-
II and an N2 -deoxyguanosine adduct benzidine (Sørlie et al., 1998). The sor gene, of which the most common
derived from aristolochic acid I. mutations occurred exclusively in mutation is an A → T transversion
26
Fig. 2.4. Structures of DNA adducts derived from aristolochic acids through kidney have been reported to occur
N-hydroxyaristolactam intermediates. dR, deoxyribose. sporadically. Mice treated with mix-
CHAPTER 2
PART 1
tures of aristolochic acids I and II
develop tumours of the forestomach,
kidney, and lung. In rabbits, mixtures
of aristolochic acids I and II admin-
istered intraperitoneally are associat-
ed with tumours of the kidney, ureter,
and peritoneal cavity.
DNA adducts derived from aris-
tolochic acid I and aristolochic acid II
have been detected in target tissues
in mice (forestomach, kidney, and
lung), rats (forestomach and kidney),
and rabbits (kidney) (IARC, 2002,
2012c; Debelle et al., 2003; Gillerot
et al., 2003; Dong et al., 2006; Mei
et al., 2006; Shibutani et al., 2007;
Chan et al., 2008; Rosenquist et al.,
2010; Shibutani et al., 2010; Baudoux
et al., 2012; McDaniel et al., 2012;
Wang et al., 2012a; Yun et al., 2013,
2014). Typically, three DNA adducts
are detected: an N6 -deoxyadenosine
adduct derived from aristolochic acid
I, an N6 -deoxyadenosine adduct de-
rived from aristolochic acid II, and an
N2 -deoxyguanosine adduct derived
from aristolochic acid I.
carcinogens, and again the major C8-substituted deoxyguanosine ad Oncogene alterations in
DNA adducts detected in each in- ducts have also been detected in experimental animals
stance were consistent with forma- the bladder DNA of mice treated
tion of an N-hydroxyarylamine inter- with 4-aminobiphenyl (Poirier et al., Transversion mutations at codon 61
mediate (IARC, 2010). 1995). These adducts presumably of the H-Ras oncogene (CAA → AAA)
In mice, there appears to arise from hepatic N-hydroxylation have been observed in the livers of
be a balance between hepatic and possibly O-acetylation of mice treated with 4-aminobiphenyl
N-acetylation, which is considered N-hydroxy-4-aminobiphenyl in the (IARC, 2010, 2012a). G → T trans-
to be a detoxification step, and he- bladder epithelium. version mutations in the cII trans-
patic N-hydroxylation, which is con- The carcinogenicity of aristolochic gene have been detected in the liv-
sidered to be an activation step. acids has been assessed in rats and ers and bladders of transgenic mice
Should N-hydroxylation occur, the to a lesser extent in mice and rab- treated with 4-aminobiphenyl (Wang
N-hydroxyarylamines can be further bits, primarily by oral dosing (IARC, et al., 2012b; Yoon et al., 2012). The
activated by hepatic O-acetylation to 2002, 2012c). Aristolochic acid I and occurrence of these mutations at
yield O-acetoxyarylamines, which mixtures of aristolochic acids I and G:C base pairs is consistent with
can give rise to the DNA adducts II consistently induce tumours of the the observation that the major DNA
detected in liver tissue (IARC, 2010). forestomach in rats. Tumours of the adduct detected in target tissues
and lacZ transgenes of mice treated tumours of the urinary tract; tumours exposed humans. Similarly, muta-
with mixtures of aristolochic acids I also arise in other tissues, primarily tions of the H-Ras oncogene con-
the liver. sistent with the major DNA adducts
and II, and in the gpt transgene of
Aromatic amines and aristolo derived from aromatic amines and
mice treated with aristolochic acid I
aristolochic acids have been found
or aristolochic acid II (IARC, 2012c; chic acids that are IARC Group 1
in target tissues of experimental
McDaniel et al., 2012; Xing et al., carcinogens are metabolized by
animals.
2012). The occurrence of these mu- amine oxidation (in the case of ar-
tations at A:T base pairs is consistent omatic amines) or nitro reduction Disclaimer
with the observation that the major (in the case of aristolochic acids) to
DNA lesions detected in target tis- N-hydroxyarylamine metabolites in The views expressed in this chapter
sues after exposure to aristolochic both humans and experimental an- do not necessarily represent those
acids are N -substituted deoxyaden-
6 imals. These N-hydroxyarylamine of the United States Food and Drug
osine adducts. intermediates can react directly Administration.
28
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publications.iarc.fr/118. mouse. Drug Metab Dispos. 38(5):761–8.
PMID:12698237 http://dx.doi.org/10.1124/dmd.110.032201
PMID:20164109
30
CHAPTER 3
PART 1
part 1.
concordance between cancer in humans and in experimental
animals
chapter 3.
Arsenic and arsenic compounds as a contaminant of drinking-water adult offspring in C3H/HeNCr mice
together with various metals, spe- (IARC, 2004). The most prevalent (two studies) and CD1 mice (IARC,
cifically including beryllium and source of human exposure to ar- 2012). In addition, in a study of CD1
beryllium compounds, cadmium senic is now drinking-water, where mice with “whole-life” exposure to
and cadmium compounds, chromi- it is found primarily as the inorgan- multiple levels of sodium arsenite in
um(VI) compounds, and nickel and ic forms of arsenite and arsenate. drinking-water from 2 weeks before
nickel compounds, were re-evalu- Inorganic arsenic can be metabolized breeding (male and female mice),
ated in IARC Monographs Volume by most mammals to form trivalent during gestation and lactation (fe-
100C (IARC, 2012) as carcinogenic and pentavalent methylated metab- male mice), and after weaning until
to humans (Group 1). The most re- olites through specific methyltrans- age 2 years (offspring, both sexes),
cent earlier evaluations appeared ferases, with S-adenosylmethionine bronchiolo-alveolar carcinoma oc-
in Volume 84 (IARC, 2004) for ar-
as the methyl donor (IARC, 2004, curred in a dose-related fashion
senic, Volume 58 (IARC, 1993) for
2012). Questions remain about the in both male and female offspring
beryllium and cadmium, and Volume
relative contribution of the inorganic (Tokar et al., 2011). In CD1 mice, in
49 (IARC, 1990) for chromium and
and the methylated arsenic species utero exposure via maternal con-
nickel.
to the overall carcinogenic potential sumption of sodium arsenite in drink-
Arsenic and arsenic of exposure to arsenic. Arsenic and ing-water during gestation with or
compounds arsenic compounds in drinking-water without subsequent dimethylarsinic
are human carcinogens; there is suf- acid (DMA(V)) in drinking-water of
Carcinogenicity ficient evidence in humans for can- the offspring throughout adulthood
Early on, exposure to inorganic arse- cer of the lung, urinary bladder, and induced bronchiolo-alveolar carcino-
nic via drinking-water or oral use of skin, as well as limited evidence for ma in animals that received prenatal
arsenic-based drugs was considered cancer of the kidney, liver, and pros- arsenite alone, DMA(V) alone, or the
carcinogenic to the skin in humans, tate (IARC, 2004, 2012). combination of prenatal arsenite and
and exposure to inorganic arsenic In rodents, transplacental arsenic DMA(V) (Tokar et al., 2012a). In CD1
via inhalation in occupational set- exposure via maternal consumption mice, in utero exposure to arsenic via
tings was evaluated as carcinogenic of sodium arsenite in drinking-wa- maternal consumption of monometh-
to the lung in humans (IARC, 1973). ter during gestation induced bron- ylarsinous acid (MMA(III)) in drink-
Arsenic was most recently assessed chiolo-alveolar carcinoma in the ing-water produced bronchiolo-alveolar
32
exposure to inorganic arsenic or same tumour type induced in rats plification, altered DNA methylation
arsenic compounds (IARC, 2012). by chronic oral exposure to DMA(V) (epigenetic effects), or aneuploidy
CHAPTER 3
PART 1
Inorganic arsenic can cause lung (IARC, 2012). Some researchers may cause alterations in gene ex-
cancer in humans after inhalation or believe that the rat is a poor model pression that lead to genomic in-
ingestion, but there are no studies for studying arsenic toxicology in hu- stability and cellular transformation.
showing development of lung cancer mans, because the toxicokinetics of The metabolism of inorganic arsenic
in rodents after inhalation exposure arsenic are dramatically different as by methylation may contribute to its
(IARC, 1973, 2012). In fact, an ade- a result of sequestration of arsenic in epigenetic effects, because the ar-
quate inhalation study in rodents with the blood of rats (Carter et al., 2003; senic methylation pathway overlaps
inorganic arsenic has never been Aposhian et al., 2004). However, for with DNA methylation by consump-
performed, presumably because the DMA(V) and cancer of the urinary tion of S-adenosylmethionine as the
agent had already been declared a bladder, there is clear site concor- common methyl donor (Brocato and
human carcinogen and rodent re- dance between humans and rats. For Costa, 2013). However, it is notewor-
search resources were directed bladder tumours induced by DMA(V) thy that inorganic arsenic can cause
elsewhere. in the rat, the mechanism may in- malignant transformation in cells that
volve sustained cytotoxicity, pos- do not methylate the metalloid, indi-
Mechanisms of
sibly from oxidative stress (Kitchin cating that neither methylation nor a
carcinogenesis
and Conolly, 2010), followed by cell methylated metabolite are required
Although a unifying mechanis- proliferation and genomic instability. for a cell to acquire a malignant phe-
tic hypothesis for arsenic-induced Specific methylated forms of arsenic notype after exposure to inorganic
carcinogenesis may seem reason- may be involved in the sustained cy- arsenic (Kojima et al., 2009). Thus,
able, it is important to emphasize totoxicity (Cohen et al., 2007). cell-specific, complex, multifaceted
that given the multitude of toxic Inorganic arsenic and methyl- mechanisms are likely to be opera-
events at the subcellular level seen ated arsenic metabolites generally tive with arsenic (Kitchin and Conolly,
with inorganic arsenic and arsenic show weak activity as mutagens. 2010; Tokar et al., 2010).
compounds (e.g. oxidative stress, Low-dose exposure to inorganic ar- Another important issue with
altered DNA repair, altered DNA senic can increase the number of mechanistic implications is the
methylation, gene amplification, and mutations resulting from genomic strong evidence that cancer can
altered growth factors), it is likely that instability, perhaps through produc develop long after elevated arsenic
multiple mechanisms are operative tion of reactive oxygen species, exposure ends. For instance, a re-
in arsenic-induced carcinogenesis and cells that methylate inorganic cent study on a human population
(Kitchin and Conolly, 2010; Tokar arsenic show much more oxidative in Chile measured rates of cancer
et al., 2010; Hartwig, 2013). These DNA damage than cells that poorly of the bladder and lung in individ-
multiple mechanisms are probably methylate the metalloid during in vi uals who were highly exposed to
linked, at least in part, to the quali- tro malignant transformation (Kojima inorganic arsenic in drinking-water
ties of specific target tissue (e.g. high et al., 2009). MMA(III) may be one of during 1958–1970 but drank low-ar-
oxygen tension in the lung might fa- the most deleterious arsenic methyl- senic water thereafter. These sub-
vour oxidative stress, in contrast with ation products, although the number jects still showed very high risks of
the situation in the bladder) (Kitchin of tumour end-point studies is very cancer even 40 years after the high
and Conolly, 2010). The target tis- limited (only one study). The main exposures ended (Steinmaus et al.,
sue-specific toxicokinetics of arsenic cascade of mechanisms leading to 2013). Similarly, the mouse transpla-
are likely to be key and may dictate carcinogenesis for inorganic arsenic cental model demonstrated that brief
that multiple toxic events combine and arsenic compounds after expo- exposure to inorganic arsenic may
into a target-specific carcinogenic sure to low concentrations could in- result in tumours in adulthood (IARC,
mechanism (Kitchin and Conolly, clude the rapid induction of oxidative 2012). Given the time lag between
2010). DNA damage and inhibition of DNA arsenic exposure and development
In humans, arsenic causes tran- repair, followed by changes in DNA of cancer, the operative mechanisms
sitional cell carcinoma of the urinary methylation patterns, aneuploidy, would appear not to require concur-
bladder (IARC, 2012), which is the and gene amplification. Gene am- rent high tissue levels of arsenic.
34
and disrupted signal transduction 2012), and therefore the combination lated scarring (confluent fibrosis) and
processes have been observed after of data from male and female ani- chronic inflammatory changes indic-
CHAPTER 3
PART 1
exposure to cadmium; these factors mals may be problematic. Male rats ative of high tissue burdens of the
could potentially contribute to aber- chronically exposed by inhalation to test agent and local toxicity.
rant cell growth, but their role in cad- sodium dichromate developed lung Many studies have demonstrat-
mium-induced carcinogenesis is un- tumours in one study, although the ed carcinogenic activity for various
clear. Cadmium can induce reactive Working Group for that Monograph chromium(VI) compounds in ro-
oxygen species, but this would be an cautioned about small group sizes dents, such as production of soft
indirect effect and its precise role in in that study (IARC, 1990). Nasal tissue sarcomas after repository in-
cadmium-induced carcinogenesis papilloma occurred after chronic jections (IARC, 1990, 2012). Studies
is not completely defined. Specific inhalation of chromium trioxide in that produced injection-site tumours
mechanisms of lung carcinogenesis female mice in one study (IARC, have provided some evidence of the
after exposure to cadmium have not 1990). Various compounds of chro- carcinogenic potential of chromium
been elucidated fully. As with the oth- mium(VI), including calcium chro- (VI), but there is no concordance
er inorganic human carcinogens, the mate, strontium chromate, and zinc with any specific target site in hu-
mechanisms of cadmium-induced chromate, produced local squamous mans. Sodium dichromate dihydrate
carcinogenesis are probably multi- cell carcinoma in rats when the test in drinking-water caused adeno-
faceted (Beyersmann and Hartwig, agent was first mixed with cholester- carcinoma of the small intestine in
2008; Brocato and Costa, 2013; ol and then used to fill or coat stain- mice and squamous cell carcinoma
Koedrith et al., 2013). less steel wire baskets that were of the oral mucosa and tongue in
subsequently surgically implanted rats (National Toxicology Program,
Chromium(VI) compounds via tracheotomy into the bronchus 2008), but these tissues are not
(IARC, 1990). The coated basket considered cancer target sites in hu-
Carcinogenicity
acts as a point of release for the mans. Given the response and the
There is sufficient evidence in hu- test agent. Implantation of a basket rarity of these tumours in rodents
mans for the carcinogenicity of chro- containing cholesterol alone caused and the potential for oral exposure of
mium(VI) compounds, which cause notable squamous metaplasia (7% humans to chromium(VI), these sites
cancer of the lung (IARC, 1990, of controls) and bronchial inflamma- deserve additional focus in epidemi-
2012). Most of the epidemiological tion (89% of controls), indicating that ological studies.
data come from occupational set- chronic, not agent-related, irritation is The lung is a target site for the
tings that would involve inhalation as involved with this model even without carcinogenic effects of chromi
the primary route of exposure. Also, a test agent. Although the tumours um(VI) compounds in humans
positive associations have been ob- induced by this technique of expo- (IARC, 1990, 2012). From inhalation
served between exposure to chro- sure via implantation of a wire basket studies in rats and mice, there is
mium(VI) compounds and cancer of were histologically defined as bron- sufficient evidence that chromi-
the nose and nasal sinuses (IARC, chiolar squamous cell carcinoma, um(VI) induces lung tumours, al-
2012). In rodents, there is sufficient their relevance to human lung can- though all the available studies are
evidence for the carcinogenicity of cer induced by inhalation of chromi- considered to have some limita-
chromium(VI) compounds (IARC, um(VI), or in fact by any other agent, tions (IARC, 1990). Lung tumours
1990, 2012). Calcium chromate in- has not been rigorously validated. produced by surgically implanting
duced lung tumours (adenomas) in Repeated weekly intratracheal instil- stainless steel wire baskets con-
mice, but only when data from male lations of calcium chromate or sodi- taining chromium(VI) compounds
and female groups were combined um dichromate in male and female in cholesterol into the bronchus
(Nettesheim et al., 1971). The sex rats produced bronchiolo-alveolar of rats, like injection-site tumours,
of a test animal is considered by carcinoma and squamous cell carci- probably reflect carcinogenic activ-
IARC as a quantitative aspect of a noma in one study (Steinhoff et al., ity, but the relevance of this expo-
tumour end-point study that poten- 1986). The authors noted that the sure technique in modelling tumours
tially affects the outcome in terms of chromium(VI)-induced tumours co- produced in humans by inhalation of
chemically induced tumours (IARC, existed with extensive treatment-re- chromium(VI) compounds requires
36
Mechanisms of carcinogens, it is likely that multiple, for the metals that are human car-
carcinogenesis cinogens (i.e. beryllium, cadmium,
CHAPTER 3
potentially interdependent, complex
PART 1
mechanisms are operative in nick- chromium(VI), and nickel) (IARC,
The nickel ion Ni(II) is considered to
el-induced carcinogenesis. 2012). However, this scenario is not
be the ultimate carcinogenic species likely to be entirely true for the met-
in nickel-induced carcinogenesis Comparative mechanisms alloid arsenic and its compounds. Of
(Beyersmann and Hartwig, 2008; of the inorganic human all the inorganic human carcinogens,
IARC, 2012). Water-soluble and carcinogens inorganic arsenic alone can undergo
poorly water-soluble nickel com- conjugative biotransformation with-
pounds both enter the cell and reach Among arsenic compounds and met- in the host. Methylation of inorganic
the nucleus, although the soluble als that are human carcinogens, only arsenic generally produces mon-
compounds do this by ion channels chromium(VI) seems to have the omethylarsenic (MMA) forms and
and transporters, whereas the poorly ability to interact with DNA directly, then dimethylarsenic forms, but this
soluble compounds are taken up by at least when it undergoes intracel- process is not complete in most peo-
phagocytosis. After phagocytosis, lular reduction, and to act as a direct ple (Melak et al., 2014). Incomplete
genotoxin. Chromium(VI) does show methylation can result in the forma-
particulate nickel compounds grad-
human-to-rodent target site con- tion of very toxic, monomethylated
ually release nickel ions, making
arsenic metabolites, like MMA(III).
them available for interaction with cordance with respect to the lung,
Recent data in humans indicate
key biomolecules. An increased lev- although up-to-date inhalation stud-
that an increased MMA level, as a
el of nickel in the nucleus is evident ies in rodents would greatly aid in
percentage of total urinary arsenic,
after exposure to water-soluble or defining the mechanisms of chromi-
strongly correlates with cancer of
insoluble nickel compounds. Nickel um(VI)-induced carcinogenesis (see
the lung and bladder in a population
compounds are weakly mutagenic above; Proctor et al., 2014). With the in northern Chile exposed to envi-
in mammalian cells but induce DNA inorganic human carcinogens other ronmental inorganic arsenic (Melak
damage, chromosomal aberrations, than chromium(VI), direct induction et al., 2014). This indicates that arse-
and micronuclei in vitro and in vivo. of DNA damage is not a key mechan- nic metabolites generated by incom-
Both water-soluble and insoluble ism. All the metals that are human plete methylation are associated with
nickel compounds induce malignant carcinogens seem to be able to increased carcinogenic risk after ex-
cell transformation in vitro. However, cause oxidative stress (Beyersmann posure to inorganic arsenic.
delayed mutagenicity and chromo- and Hartwig, 2008; Hartwig, 2013), Stimulation of inflammation is also
somal instability have been observed mostly by indirect means. This may common among the group of inor-
long after treatment of cells with nick- ganic human carcinogens. The role
contribute to their carcinogenic po-
of inflammation in carcinogenesis
el. Nickel compounds induce epige- tential because the resulting oxi-
may be secondary, through provi-
netic changes, including alteration in dative species could attack DNA.
sion of oxidants or radical species
DNA methylation patterns and mod- Arsenic, cadmium, chromium, and
produced by oxidation.
ification of histones (Brocato and nickel can have epigenetic effects on Definitive mechanisms have not
Costa, 2013). An inflammatory com- DNA that alter critical gene expres- been established for any inorganic
ponent is also thought to contribute sion and promote the acquisition of human carcinogen. These agents
to nickel-induced carcinogenesis. a malignant phenotype (Brocato and are best considered to be multi-
Direct effects of nickel on DNA are Costa, 2013). faceted, interrelated, and complex
probably limited, but oxidative stress With respect to carcinogenesis carcinogens. For the inorganic car-
and oxidative DNA damage have induced by inorganic chemicals, it cinogens with multiple target sites,
been found after nickel exposure. is generally accepted that the ionic there is a strong possibility that the
As with the other inorganic human species is the most active species mechanism is target site-specific.
38
CHAPTER 4
PART 1
part 1.
concordance between cancer in humans and in experimental
animals
chapter 4.
Smokeless tobacco
and its constituents
Stephen S. Hecht
Introduction appropriate here than the term “con- the risk of head and neck squamous
cordance”, which connotes a one-to- cell carcinoma (including cancers
Smokeless tobacco is defined one agreement, with no conflicting of the oral cavity, larynx, and phar-
as follows in Volume 89 of the data. ynx) (Zhou et al., 2013). This section
IARC Monographs (IARC, 2007): considers coherence between these
“Smokeless tobacco is used with Coherence: carcinogenicity conclusions and studies of the car-
out burning the product, and can be of smokeless tobacco in cinogenicity of smokeless tobacco in
used orally or nasally. Oral smoke humans versus experimental experimental animals.
less tobacco products are placed animals The use of smokeless tobacco by
in the mouth, against the cheek or
humans is a voluntary practice en-
behind the lip and sucked (dipped) Evaluations of smokeless tobac-
gaged in by hundreds of millions of
or chewed. Tobacco pastes or pow- co use by the IARC Monographs
people worldwide. There are great
ders are used in a similar manner concluded that this practice is car-
variations in use of smokeless to-
and applied to the gums or teeth. cinogenic to humans (Group 1),
bacco: in Sweden, fine-cut tobac-
Fine tobacco mixtures are usually causing cancers of the oral cavity,
co, called snus, is placed between
inhaled and absorbed in the nasal oesophagus, and pancreas (IARC, the upper lip and teeth; in North
passages.” 1985, 2007, 2012). A meta-analysis America, fine-cut tobacco, frequent-
This chapter considers carcino
of epidemiological data also con- ly in teabag-like sachets, is placed
genicity studies, data on constitu-
cluded that use of smokeless tobac- between the cheek and gums; and
ents, and mechanistic investigations
co significantly increased the risk of in South-East Asia and other parts
on smokeless tobacco, to evaluate
these cancers (Boffetta et al., 2008). of the world, there are vast arrays
overall coherence between observa-
A recent population-based case– of different practices (IARC, 2007).
tions in humans and in experimental
animals. Because of the differences control study, which was carried out Processed and fermented tobacco
between human use of smokeless in New England, USA, and was not of varying types and blends are the
tobacco and the exposure condi- included in the above-mentioned common ingredients in all of these
tions in studies in experimental an- evaluations, demonstrated a statisti- practices. Nicotine, perhaps along
imals, the term “coherence”, which cally significant association between with other tobacco alkaloids and con-
means logical consistency, is more ever use of smokeless tobacco and stituents, is the addictive substance
O N O OH N O
S' N N
2 N N CH3 CH3 N N
N O N O N O N O
N N N N N N
(S) -NN N (R)- NN N N NK N NA L N AB N AT
40
of total NNN in smokeless tobac- death from oesophageal tumours with Syrian golden hamsters and
co and cigarette tobacco (Balbo before oral cavity tumours could be mice are generally less coherent
CHAPTER 4
PART 1
et al., 2013; Stepanov et al., 2013). observed. with the epidemiology of smokeless
(S)-NNN was administered in the Based on consumption of half a tobacco use than are the studies in
drinking-water (15 ppm) to a group tin (17 g) per day of a popular smoke rats (IARC, 2007).
of 24 male Fischer 344 (F-344) rats. less tobacco product (Hecht et al., Swabbing the oral cavity and lips
Two other groups of rats were given 2008a) containing about 3 µg per of rats with a mixture of NNN and
either (R)-NNN (15 ppm) or race- gram of NNN (Hecht et al., 2011) NNK for 131 weeks produced 9 oral
mic NNN (30 ppm). The rats in the and an extraction efficiency of 60% cavity tumours in 8 of 30 rats, which
groups treated with (S)-NNN or race- (Hecht et al., 2008b), human expo- was statistically significant, but the
mic NNN began losing weight after sure would be about 34 µg per day of result was not nearly as strong as
1 year of treatment and had died or NNN, or 20 µg per day of (S)-NNN; in that noted earlier, in part because
were humanely killed by 17 months. 30 years of use, this would amount to the dose of racemic NNN in the
All rats treated with (S)-NNN had tu- about 220 mg (3 mg/kg body weight) swabbing study was about 40% of
mours of the oral cavity. A total of 91 of (S)-NNN. This compares to a dose that described for the drinking-water
such tumours were observed in 20 of 150 mg (375 mg/kg body weight) study mentioned above (Hecht et al.,
rats that were necropsied, including of (S)-NNN in the drinking-water 1986). NNK by itself did not induce
tumours of the tongue, larynx, phar- study described above. It is unclear oral cavity tumours when swabbed
ynx, oral mucosa, and soft palate. whether a body weight correction is in the oral cavity of rats or hamsters
Some of the oral cavity tumours were relevant, considering that smoke (Hecht, 1998a). An interesting and
large. The rats treated with (S)-NNN less tobacco is concentrated in the unexplored observation in the swab-
also had 122 oesophageal tumours. oral cavity and is frequently held at bing study was that an extract of fine-
In contrast, (R)-NNN was only weak- one site. cut moist snuff of the type used orally
ly tumorigenic. A highly significant Whereas administration of NNN inhibited the oral cavity carcinogeni-
carcinogenic response similar to that in the drinking-water to F-344 rats city of NNN and NNK.
resulting from exposure to (S)-NNN produces tumours of the oral cavity Although the carcinogenicity
was also observed in the rats treated and the oesophagus, subcutaneous studies of NNN administered oral-
with racemic NNN. The induction of injection of NNN causes mainly tu- ly to rats are in many respects re-
tumours of the oral mucosa, tongue, mours of the nasal mucosa, with ma- markably consistent with the results
larynx, and pharynx as well as oe- lignant tumours arising predominant- of epidemiological studies of can-
sophageal tumours in all rats treat- ly in the olfactory epithelium (Hecht, cers of the oral cavity and the oe-
ed with (S)-NNN or racemic NNN is 1998a). Treatment of mink with NNN sophagus in humans, they did not
remarkably consistent with the epi- by subcutaneous injection also pro- produce any pancreatic tumours.
demiological studies of smokeless duced malignant nasal tumours In another example of coherence,
tobacco use summarized above. (Koppang et al., 1992; Koppang et NNK and its metabolite 4-(methyl-
Although this was the first study to al., 1997; IARC, 2007). nitrosamino)-1-(3-pyridyl)-1-butanol
investigate the carcinogenicity of Carcinogenicity studies of NNN (NNAL) both produced significantly
(S)-NNN, previous studies of race- with Syrian golden hamsters have increased incidences of exocrine
mic NNN administered in the drink- involved subcutaneous injection pancreatic tumours when admin-
ing-water to rats uniformly produced of NNN or swabbing of the cheek istered in the drinking-water to male
high yields of oesophageal tumours, pouch. Tumours of the trachea and F-344 rats at doses of 1 ppm (NNK)
and oral cavity tumours were occa- nasal cavity were observed upon or 5 ppm (NNAL) (Rivenson et al.,
sionally observed (Hecht, 1998a; subcutaneous injection; the cheek 1988). It should be noted, however,
IARC, 2007). The doses of NNN pouch was generally unresponsive that the lung was clearly the main
given in the earlier studies probably (Hecht, 1998a). Treatment of various target organ for NNK and NNAL
either were too low to observe a high strains of mice with NNN by oral or in these studies – with significant
incidence of oral cavity tumours in intraperitoneal administration has increases in lung cancer for both
addition to oesophageal tumours, resulted mainly in pulmonary adeno- agents (P < 0.01) – whereas the re-
or were so high that they caused mas (Hecht, 1998a). Thus, studies sults of epidemiological studies on
42
by NNN (Hecht, 1998a; IARC, 2007). by smokeless tobacco itself, both in Conclusions
It is not known which cytochrome laboratory animals and in humans
CHAPTER 4
PART 1
P450 enzyme is responsible for (IARC, 2007). The few studies that There is considerable coherence
have been reported either used between established target tissues
NNN 2′-hydroxylation in the oral
non-specific techniques or did not for the carcinogenicity of smokeless
cavity and oesophagus in rats, or in
tobacco in humans – the oral cavity,
humans. Two human cytochrome find consistent effects of smokeless
oesophagus, and pancreas – and
P450 enzymes that catalyse (S)- tobacco on DNA adduct formation.
target tissues in rats treated orally
NNN metabolism by 5′-hydroxyla- Similarly, there is at present no con-
with NNN or NNK, which are constit-
tion – cytochrome P450 2A6 and vincing published evidence that use
uents of all smokeless tobacco prod-
2A13 enzymes – do not catalyse the of smokeless tobacco produces
ucts and are present in commonly
DNA adducts in the oral cavity, oe-
2′-hydroxylation (Wong et al., 2005). used products at concentrations
sophagus, or pancreas in humans. higher than those of other strong car-
This raises some questions about
This represents a significant gap in cinogens. There is also coherence
the enzymology of (S)-NNN meta-
a mechanistically coherent pathway between the mechanisms by which
bolic activation in humans. Further, in
to cancer upon smokeless tobacco NNN and NNK induce cancer in rats,
studies of NNN metabolism in patas
use as observed in epidemiological via DNA adducts and their conse-
monkeys, the major pathway appears
studies. quent effects, and observations in
to be 5′-hydroxylation (Upadhyaya et
Nevertheless, many studies in humans. There is less coherence
al., 2002). More research is needed
human users of smokeless tobac- between carcinogenicity and mecha-
to determine whether these obser- nistic aspects of smokeless tobacco
co – but fewer in laboratory ani-
vations reflect a lack of coherence exposure per se in laboratory ani-
mals – demonstrate genetic effects
between rats and humans or simply that are consistent with the conse- mals and humans, in part because of
a lack of relevant data. quences of DNA adduct formation. operational difficulties in carrying out
As noted above, the formation of carcinogenicity studies, and perhaps
Higher frequencies of micronuclei in
DNA adducts is critical in the car- because the right questions have
buccal cells of smokeless tobacco
cinogenic process induced by the not been addressed with respect to
users have been reported in multiple
mechanisms.
agents discussed here. In contrast to studies (Proia et al., 2006). Mutations
the plethora of information available in important growth control genes, Acknowledgement
on DNA adduct formation in labora- such as TP53 and RAS, from oral
tory animals by smokeless tobac- cavity tumours of smokeless tobacco This research on tobacco-specific
co constituents – most commonly users have also been observed fre- nitrosamines is supported by grant
NNN and NNK – there is a paucity quently and are likely to be the result CA-81301 from the United States
of studies on DNA adduct formation of DNA damage (IARC, 2007). National Cancer Institute.
44
Stolerman IP, Jarvis MJ (1995). The Wong HL, Murphy SE, Hecht SS (2005). Zhang S, Wang M, Villalta PW, Lindgren BR,
scientific case that nicotine is addictive. Cytochrome P450 2A-catalyzed metabolic Upadhyaya P, Lao Y, et al. (2009b). Analysis of
CHAPTER 4
Psychopharmacology (Berl). 117(1):2–10, activation of structurally similar carcinogenic pyridyloxobutyl and pyridylhydroxybutyl DNA
PART 1
discussion 14–20. http://dx.doi.org/10.1007/ nitrosamines: N′-nitrosonornicotine enantiomers, adducts in extrahepatic tissues of F344 rats
BF02245088 PMID:7724697 N-nitrosopiperidine, and N-nitrosopyrrolidine. treated chronically with 4-(methylnitrosamino)-
Chem Res Toxicol. 18(1):61–9. http://dx.doi. 1-(3-pyridyl)-1-butanone and enantiomers of
Upadhyaya P, Zimmerman CL, Hecht SS org/10.1021/tx0497696 PMID:15651850 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol.
(2002). Metabolism and pharmacokinetics Chem Res Toxicol. 22(5):926–36. http://dx.doi.
of N′-nitrosonornicotine in the patas Zhang S, Wang M, Villalta PW, Lindgren org/10.1021/tx900015d PMID:19358518
monkey. Drug Metab Dispos. 30(10):1115–22. BR, Lao Y, Hecht SS (2009a). Quantitation
ht tp://dx.doi.org/10.1124/dmd.30.10.1115 of pyridyloxobutyl DNA adducts in nasal and Zhou J, Michaud DS, Langevin SM, McClean
PMID:12228188 oral mucosa of rats treated chronically with MD, Eliot M, Kelsey KT (2013). Smokeless
enantiomers of N′-nitrosonornicotine. Chem tobacco and risk of head and neck cancer:
Res Toxicol. 22(5):949–56. http://dx.doi. evidence from a case-control study in New
org/10.1021/tx900040j PMID:19405515 England. Int J Cancer. 132(8):1911–7. http://
dx.doi.org/10.1002/ijc.27839 PMID:22987222
chapter 5.
Tobacco smoke
and its constituents
Stephen S. Hecht and David M. DeMarini
This chapter addresses the con- Coherence: carcinogenicity the induction of lung tumours, both
cordance in studies of carcinogen- of tobacco smoke in humans benign and malignant, by cigarette
icity and mechanisms between versus experimental animals smoke.
experimental animals and humans Although these studies have
Volume 100E and previous IARC established animal models for the
for tobacco smoke and its constit-
Monographs and certain reviews on study of tobacco smoke carcino-
uents. Volume 100E of the IARC
tobacco smoke have summarized genesis and, in aggregate, support
Monographs updated the literature the literature on animal studies of the the epidemiological findings that
on tobacco smoke and the evalua- carcinogenicity of tobacco smoke smoking is a cause of cancers of the
tions of its carcinogenicity (IARC, (IARC, 1986, 2004, 2012b; Hecht, lung and larynx in humans, specif-
2012b). It concluded that there was 2005). These studies demonstrated ic problems associated with animal
sufficient evidence that tobacco that cigarette smoke can induce tu- studies of tobacco smoke expo-
smoking causes multiple types of mours of the lung and nasal cavity in sure have been recognized. Many
cancer in humans, including (to var- mice and rats and tumours of the lar- of these issues result from the fact
ying extents) cancers of the lung, ynx in hamsters. Some recent stud- that most laboratory animals are ob-
oral cavity, pharynx, oesophagus, ies not included in the evaluations ligate nose breathers and, thus, do
in Volume 100E have consistently not inhale tobacco smoke voluntari-
stomach, colorectum, liver, pancre-
established the carcinogenicity of ly and habitually in the same way in
as, nasal cavity and paranasal si-
cigarette smoke to the lung in the which humans smoke tobacco prod-
nuses, larynx, uterine cervix, ovary
A/J mouse, where it produces ade- ucts (Wynder and Hoffman, 1967).
(mucinous), urinary bladder, kidney,
noma and adenocarcinoma, as well Constant whole-body exposure of
ureter, and bone marrow (myeloid as causing emphysema (Stinn et al., rodents to cigarette smoke, often at
leukaemia). 2010, 2013). The A/J mouse, which relatively high concentrations, pro-
is highly susceptible to lung tumour duces avoidance reactions, stress,
development, appears to present weight loss, and other indicators of
a relatively reproducible system for toxicity that are widely different from
48
studies with formaldehyde and ac- lead to the eventual development of and cause DNA replication errors
etaldehyde produced nasal tumours lung cancer (IARC, 2004; DHHS, that may lead to mutations. If these
CHAPTER 5
PART 1
(IARC, 1985, 2006, 2012a). 2010, 2014). This scheme is for lung mutations occur in important regions
Tobacco smoke contains com- cancer because it is for this disease of critical growth control genes, such
pounds that are carcinogenic to that the most data are available. as the oncogene KRAS or the tu-
the colorectum in rats, most nota- The central pathway of Fig. 5.1 mour suppressor gene TP53, cellular
bly certain heterocyclic aromatic in particular shows great coherence growth processes become severely
amines (IARC, 2004, 2012b; Hecht, with established genotoxic mecha- dysregulated, resulting in uncon-
2012). With respect to induction nisms by which many carcinogens, trolled cell proliferation and cancer.
of liver cancer by tobacco smoke, including most of the more than 70 There are convincing data from
there is coherence with furan and established carcinogens in cigarette studies of smokers and lung cancer
N-nitrosodimethylamine, which are smoke, drive the process of cancer patients that illustrate coherence of
liver carcinogens in rats (Peto et al., induction. Thus, exhaustive mecha- these observations in humans with
1991; NTP, 1993), whereas NNK nistic studies carried out both in vitro the results observed in the plethora
and its major metabolite 4-(methyl- and in laboratory animals since the of mechanistic studies noted above.
nitrosamino)-1-(3-pyridyl)-1-butanol middle of the 20th century and con- Carcinogen uptake by smokers has
(NNAL) induce pancreatic cancer in tinuing today provide solid evidence been unequivocally demonstrated
rats (Hecht, 1998). that most carcinogens, either direct- by biomarker studies that compare
Collectively, there is considerable ly or after metabolism catalysed by levels of carcinogens and their me-
concordance between established multiple cytochrome P450 enzymes, tabolites in the urine of smokers
sites of tobacco smoke carcinogen- react with nucleophilic sites in DNA and non-smokers (Hecht et al.,
icity in humans and target tissues to form covalent binding products 2010). These studies leave no doubt
in experimental animals of individ- called DNA adducts. that exposure to multiple carcino-
ual carcinogens present in tobacco There are cellular repair systems gens, including tobacco-specific ni-
smoke.
that have evolved to repair these trosamines, PAHs, aromatic amines,
DNA adducts and restore the nor- and various volatile compounds in-
Concordance: overall
mechanism of cancer mal structure of DNA. These repair cluding benzene and 1,3-butadiene,
induction in humans versus systems are crucial because cer- is significantly higher for smokers
laboratory studies tain rare DNA repair-deficiency syn- than for non-smokers.
dromes, such as xeroderma pigmen- These and related studies also
Fig. 5.1 presents a widely accepted tosum, lead to a high susceptibility to show that virtually all of these car-
mechanistic framework describing cancer development. Thus, DNA ad- cinogens are metabolized by cy-
the events that occur in smokers and ducts, if left unrepaired, can persist tochrome P450 enzymes, resulting
Fig. 5.1. Mechanistic framework describing events involved in lung carcinogenesis in smokers. Adapted with
permission from DHHS (2010).
50
contribute to the overall carcinogen- Disclaimer the contents reflect the views of the
ic effect (IARC, 2012b; Milara and agency, nor does mention of trade
CHAPTER 5
We thank J.A. Ross and C.E. Wood for
PART 1
Cortijo, 2012; Momi et al., 2014). names or commercial products con-
their helpful comments on this manu- stitute endorsement or recommen-
In summary, cigarette smoking
script. This article was reviewed by the dation for use.
represents a potent combination of
National Health and Environmental
biological effects associated with
Effects Research Laboratory, United
carcinogenesis, coherent with land-
States Environmental Protection
mark publications dating back more
Agency and approved for publica-
than 60 years (Hecht and Szabo,
tion. Approval does not signify that
2014).
References
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MG, Stepanov I, Wang M, et al. (2013). (S)-N′- GL, Hunter C, Bignell G, et al. (2007). Patterns tobacco carcinogenesis research: from
nitrosonornicotine, a constituent of smokeless of somatic mutation in human cancer genomes. mechanisms to early detection and prevention
tobacco, is a powerful oral cavity carcinogen Nature. 446(7132):153 – 8. http://dx.doi. of lung cancer. Cancer Prev Res (Phila).
in rats. Carcinogenesis. 34(9):2178–83. org/10.1038/nature05610 PMID:17344846 7(1):1–8. http://dx.doi.org/10.1158/1940-6207.
ht t p: //d x .d o i.o r g /10.10 9 3 /c a r c i n / b g t16 2 CAPR-13-0371 PMID:24403288
PMID:23671129 Hecht SS (1998). Biochemistry, biology,
and carcinogenicity of tobacco-specific Hecht SS, Yuan J-M, Hatsukami D (2010).
Castelao JE, Yuan JM, Skipper PL, N-nitrosamines. Chem Res Toxicol. 11(6):559– Applying tobacco carcinogen and toxicant
Tannenbaum SR, Gago-Dominguez M, 603. http://dx.doi.org/10.1021/t x980005y biomarkers in product regulation and cancer
Crowder JS, et al. (2001). Gender- and PMID:9625726 prevention. Chem Res Toxicol. 23(6):1001–8.
smoking-related bladder cancer risk. J Natl h t t p : / / d x . d o i . o r g / 1 0 .1 0 2 1 / t x 1 0 0 0 5 6 m
Cancer Inst. 93(7):538–45. http://dx.doi. Hecht SS (2005). Carcinogenicity studies of PMID:20408564
org/10.1093/jnci/93.7.538 PMID:11287448 inhaled cigarette smoke in laboratory animals:
old and new. Carcinogenesis. 26(9):1488–92. Hutt JA, Vuillemenot BR, Barr EB, Grimes
Chen RJ, Chang LW, Lin P, Wang YJ (2011). ht t p: //d x .d o i.o r g /10.10 9 3 /c a r c i n / b g i14 8 MJ, Hahn FF, Hobbs CH, et al. (2005). Life-
Epigenetic effects and molecular mechanisms PMID:15930027 span inhalation exposure to mainstream
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DHHS (2010). How tobacco smoke causes Wolters Kluwer/Lippincott Williams & Wilkins;
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PMID:18948947
52
CHAPTER 6
PART 1
part 1.
concordance between cancer in humans and in experimental
animals
chapter 6.
(Hijiya et al., 2007; Hodgson et al., (Hemminki et al., 2008). Anticancer Of the anticancer agents included in
2007; Maule et al., 2007; Hemminki agents are also used in some other Volume 100A, the current selection
et al., 2008; Swerdlow et al., 2011). cases, such as for certain autoim- does not include busulfan, 1-(2-chlo-
Although these studies present valu- mune diseases, but even if a single roethyl) -3 -(4-methylcyclohexyl) -
able data on many exposure-relat- anticancer agent is given, other med- 1-nitrosourea (methyl-CCNU), treo-
ed aspects, relevant treatments are ication and the inherent cancer risk sulfan, and some mixtures of anti-
seldom based on single agents or of some autoimmune conditions may cancer agents for which evidence is
single modalities, and individual car- limit the applicability of the results. sufficient in humans but evidence is
cinogens can rarely be singled out. In this chapter, data on antican- limited or lacking in animals.
Nevertheless, striking new data from cer agents from Volume 100A of
these studies show increased risks the IARC Monographs are used to Therapeutic applications and
of almost all site-specific cancers make qualitative comparisons be- trends in use
that emerge during the follow-up tween cancers induced in humans
The four anticancer agents dis-
period. Such data challenge the “ca- and in experimental animals, with
cussed here were first used in clin-
nonical” site-specificity of carcino- reference to the possible underlying
ical practice in the 1960s, but since
genesis. In their review of human mechanisms. Furthermore, quanti-
then the clinical indications have
carcinogens, Cogliano et al. indicate tative comparisons of carcinogens
been narrowed and their therapeutic
that no agents classified as carci- with respect to potency in humans
use has declined, with the possible
nogenic to humans (Group 1) are and in experimental animals are
exception of cyclophosphamide.
identified as causing prostate can- discussed. This review is limited to
Cyclophosphamide may be used
cer (Cogliano et al., 2011). However, anticancer agents for which the evi- alone for the treatment of several
some evidence is available. The risk dence of carcinogenicity was consid- types of cancer, but most often it is
of prostate cancer is significantly in- ered to be sufficient both in humans administered in combination with
creased in survivors of non-Hodgkin and in experimental animals: cyclo- other drugs. Diseases for which cy-
lymphoma after chemotherapy, for phosphamide, chlorambucil, mel- clophosphamide is the recognized
those diagnosed at age 40–49 years phalan, and thiotepa (IARC, 2012). treatment include breast cancer,
54
Table 6.2. Values of TD50 (the chronic dose rate estimated to reduce the proportion of tumour-free animals by 50%)
for anticancer agents in rodents
CHAPTER 6
PART 1
Agent TD50 (mg/kg bw/day)
Source: Adapted with permission from Kaldor et al. (1988), copyright 1988, with permission from Elsevier.
are equally potent as carcinogens, for primary ovarian cancer (Kaldor per 10 years for the second study re-
whereas cyclophosphamide is weak- et al., 1990). The potency accord- sulted in potency values of 0.02 and
er by approximately an order of mag- ing to Kaldor et al. was calculated 0.1, respectively (Table 6.3). Thus,
nitude. After treatment of rats with from the cumulative baseline inci- the potency of cyclophosphamide
cyclophosphamide, bladder cancer dence of leukaemia in Sweden of determined in relation to bladder
was detected with a TD50 of 21 mg/kg 0.2 per 10 years, multiplied by the cancer was lower than its potency in
bw/day, i.e. an order of magnitude relative risk given in the relevant pa- the haematopoietic system. A similar
lower than the value for all tumours per; the product was then divided outcome was evident in the rodent
combined (Gold et al., 1987). by the median doses cited for the studies (Table 6.2).
The measure of potency used low dose and the high dose (Kaldor
Mechanisms of action
by Kaldor et al. was the 10-year et al., 1988). The low and high doses
cumulative incidence of leukaemia differed widely, and the calculated
Cyclophosphamide is activated
(a percentage) divided by the total potency values were clearly higher
through a cytochrome P450-
administered dose in grams; thus, a for the low dose than for the high
mediated reaction to yield phos-
large number indicates high poten- dose. Thiotepa and melphalan were
phoramide mustard and acrolein,
cy (Kaldor et al., 1988). These data the most potent drugs, followed by both of which can bind to DNA.
are shown in Table 6.3. Information chlorambucil and the much weaker Phosphoramide mustard undergoes
was lacking for thiotepa, but of the cyclophosphamide. The potency of rapid dephosphoramidation, which in
remaining compounds melphalan cyclophosphamide to induce bladder neutral in vitro conditions proceeds
was the most potent, with values cancer was also calculated, accord- with a half-life of 8 minutes, result-
of 18.7 and 3.3 from two separate ing to the data from two studies; in ing in the formation of nornitrogen
studies. Chlorambucil showed an the first study, bladder cancer was mustard (Hemminki, 1985). Because
intermediate potency, which was an diagnosed in women after treatment most of the metabolic activation of
order of magnitude higher than that for ovarian cancer (Kaldor et al., cyclophosphamide takes place in the
of cyclophosphamide. 1995), and in the second study, blad- liver, it seems likely that a consider-
More recent data were added to der cancer was diagnosed in sur- able proportion of DNA binding in
Table 6.3 from studies in which the vivors of non-Hodgkin lymphoma peripheral tissues is in fact mediated
anticancer agent was the principal (Travis et al., 1995). The use of a by nornitrogen mustard (Hemminki,
drug used and no radiotherapy was cumulative baseline incidence of 1985). As summarized in Volume
applied. Kaldor et al. published a bladder cancer in women of 0.4 per 100A of the IARC Monographs, cy-
multinational study of secondary leu- 10 years for the data of the first study clophosphamide has several end-
kaemias in women after treatment and a sex-adjusted incidence of 0.9 points indicative of genotoxic effects
56
in humans, including DNA damage as Conclusions not more research activity to follow
measured by the comet assay, muta- up other patient groups who receive
CHAPTER 6
PART 1
tions at the HPRT locus, and sister For the anticancer drugs cyclophos- anticancer agents, such as patients
chromatid exchange. Historically, cy- phamide, chlorambucil, melphalan, with autoimmune diseases. The cur-
clophosphamide has been included and thiotepa, the data summarized in rent potency data for four anticancer
this chapter show that the target sites drugs suggest that the TD50 values
in several genetic structure–activity
for which there is sufficient evidence for rats and mice are reasonably
studies (Vogel et al., 1996, 1998).
of carcinogenicity are generally sim- homogeneous and consistent. As a
Chlorambucil and melphalan are
ilar in rodents and humans, particu- carcinogen, cyclophosphamide was
direct-acting derivatives of nitrogen
larly for bladder cancer induced by the least potent and thiotepa was
mustard, and thiotepa is a direct-act- the most potent agent in any of the
cyclophosphamide.
ing trifunctional derivative of aziri- rodent models analysed. In humans,
Anticancer agents allow unique
dine. These compounds bind to DNA cyclophosphamide was the least
comparisons of carcinogenic poten-
and give a positive response in a potent and thiotepa and melphalan
cy among species, because the dos-
wide spectrum of assays for genomic were the most potent compounds to
es administered to humans and an-
injury, including tests for cytogenetic induce secondary cancers.
imals are known. Cancer treatment
damage, specifically as indicated by has become increasingly multimod- Acknowledgements
chromosomal aberrations and sis- al and involves the use of multiple
ter chromatid exchange in patients. drugs; this makes it difficult to single This research was supported by the
These drugs have also been in- out individual agents. Also, survival Deutsche Krebshilfe, the Swedish
cluded in several genetic structure– rates have risen and the probabili- Council for Working Life and Social
activity studies (Vogel et al., 1996, ty of detecting second tumours has Research, and the EU FP7 grant
1998). increased. It is unclear why there is number 260715.
Hemminki K, Lenner P, Sundquist J, Moolgavkar S, Krewski D, Zeise L, Cardis Vogel EW, Nivard MJ, Ballering LA, Bartsch
Bermejo JL (2008). Risk of subsequent E, Moller H, editors (1999). Quantitative H, Barbin A, Nair J, et al. (1996). DNA
solid tumors after non-Hodgkin’s lymphoma: estimation and prediction of human cancer damage and repair in mutagenesis and
effect of diagnostic age and time since risks. Lyon, France: International Agency carcinogenesis: implications of structure-
diagnosis. J Clin Oncol. 26(11):1850–7. for Research on Cancer (IARC Scientific activity relationships for cross-species
http://dx.doi.org/10.1200/JCO.2007.14.6068 Publications, No. 131). extrapolation. Mutat Res. 353(1–2):177–
PMID:18347006 Pierce DA, Vaeth M (2003). Age-time patterns 218. http://dx.doi.org/10.1016/0027-
of cancer to be anticipated from exposure to 5107(96)00032-2 PMID:8692191
Hijiya N, Hudson MM, Lensing S, Zacher M,
Onciu M, Behm FG, et al. (2007). Cumulative general mutagens. Biostatistics. 4(2):231–48.
incidence of secondary neoplasms as a first http://dx.doi.org/10.1093/biostatistics/4.2.231
event after childhood acute lymphoblastic PMID:12925519
leukemia. JAMA. 297(11):1207–15. http:// Preston DL, Pierce DA, Shimizu Y, Cullings
d x . d o i . o r g / 1 0 .1 0 0 1 / j a m a . 2 9 7.11.12 0 7 HM, Fujita S, Funamoto S, et al. (2004). Effect
PMID:17374815 of recent changes in atomic bomb survivor
Hodgson DC, Gilbert ES, Dores GM, Schonfeld dosimetry on cancer mortality risk estimates.
SJ, Lynch CF, Storm H, et al. (2007). Long- Radiat Res. 162(4):377–89. http://dx.doi.
term solid cancer risk among 5-year survivors org/10.1667/RR3232 PMID:15447045
of Hodgkin’s lymphoma. J Clin Oncol.
25(12):1489–97. http://dx.doi.org/10.1200/
JCO.2006.09.0936 PMID:17372278
58
CHAPTER 7
PART 1
part 1.
concordance between cancer in humans and in experimental
animals
chapter 7.
Polycyclic aromatic
hydrocarbons and associated
occupational exposures Charles William Jameson
Properties of PAHs this makes them more readily uptake or degradation, which means
available for biological uptake and that their persistence in the environ-
Most polycyclic aromatic hydrocar- degradation (Mackay and Callcott, ment is increased (Johnsen et al.,
bons (PAHs) with potential biolog- 1998; Choi et al., 2010). Furthermore, 2005; Haritash and Kaushik, 2009).
ical activity have been determined two- to four-ring PAHs volatilize The properties that influence the
to have a molecular structure that sufficiently to appear in the atmo- biological activity of PAHs include
ranges in size from two to six fused sphere predominantly in gaseous their vapour pressure, their adsorp-
aromatic rings (IARC, 2010). The form, although the physical state of tion on surfaces of solid carrier par-
physicochemical properties of four-ring PAHs can depend on tem- ticles, their absorption into liquid
these PAHs that are critical to their perature (Atkinson and Arey, 1994; carriers, their lipid–water partition
biological activity vary greatly, be- Srogi, 2007). coefficient in tissues, and their limits
cause their molecular weights cover In contrast, PAHs with five or of solubility in the lipid and aqueous
a vast range. more rings have low solubility in wa- phases of tissues. These properties
Aqueous solubility of PAHs de- ter and low volatility. They therefore are linked with the metabolic activa-
creases approximately logarith- occur predominantly in solid form, tion of PAHs, as well as their deposi-
mically with increasing molecular bound to particulates in polluted air, tion and disposition.
mass (Johnsen et al., 2005). Two- soil, or sediment (Choi et al., 2010). PAHs share a similar mecha-
ring PAHs, and, to a lesser extent, In the solid state, these compounds nism of carcinogenic action in both
three-ring PAHs, dissolve in water; are less accessible for biological humans and experimental animals.
60
Table 7.1. Group 1 agents associated with dermal exposures to polycyclic aromatic hydrocarbons (PAHs) that cause
squamous cell carcinoma of the skin in humans and in rodents
CHAPTER 7
PART 1
Agent Target organ
metabolically activate benzo[a]py- mechanistic evidence from studies potential chemical interactions and
rene to benzo[a]pyrene diol epox- in exposed humans and in experi- the presence of other carcinogenic
ides that form DNA adducts. The mentally exposed animals, and from substances.
anti-benzo[a]pyrene-7,8-diol-9,10- in vitro studies in human and animal Certain occupations associated
oxide–deoxyguanosine adduct has with high exposure to PAHs have
tissues and cells, provides biologi-
been measured in populations (e.g. been classified by IARC as carci-
cal plausibility to support the overall
coke-oven workers and chimney nogenic to humans (Group 1); these
sweeps) exposed to PAH mixtures classification of benzo[a]pyrene as
include coal gasification, coke pro-
that contain benzo[a]pyrene. The carcinogenic to humans (Group 1) duction, coal-tar distillation, chimney
reactive anti-benzo[a]pyrene-7,8-di- (IARC, 2010, 2012). sweeping, paving and roofing with
ol-9,10-oxide induces mutations in coal-tar pitch, and work involving
rodent and human cells. Mutations Studies of cancer in humans mineral oils, shale-oil production,
(G → T transversions) in the K-ras and aluminium production. In most
proto-oncogene in lung tumours from There are no epidemiological stud-
cases the classification is based on
mice treated with benzo[a]pyrene are ies on human exposure to individu- epidemiological studies of increased
associated with anti-benzo[a]pyrene- al PAHs, because these chemicals cancer incidence without reference
7,8-diol-9,10-oxide–deoxyguanosine never occur in isolation in the envi- to supporting evidence from bio-
adducts. Similar mutations in the ronment but are present as compo- assays in experimental animals.
KRAS proto-oncogene and muta- The roles of individual PAHs in the
nents of complex chemical mixtures.
tions in the tumour suppressor gene genesis of cancer observed in these
PAHs are very widespread environ-
TP53 were found in lung tumours occupations could not be defined
mental contaminants, because they
from non-smokers exposed to PAH- (IARC, 2010).
rich products of coal combustion that are formed during incomplete com-
are known to contain benzo[a]pyrene bustion of materials such as coal, Tumour site concordance
(as well as many other PAHs). In an oil, gas, wood, or waste, or during
in vitro study, the codons in TP53 pyrolysis of other organic materials, There are six IARC Group 1 agents
that are most frequently mutated in such as tobacco. Data on the carci- that cause non-melanoma tumours
lung cancer in humans were shown nogenicity of PAHs to humans are of the skin (Rice, 2005). Five of
to be targets for DNA adduct forma- these are related to occupations
available primarily from studies in
tion and mutation induced by ben- where PAH exposures are high and
occupational settings where workers
zo[a]pyrene. The strong and exten- are believed to be the causative
sive experimental evidence for the are exposed to mixtures containing agents (Table 7.1). There is a precise
carcinogenicity of benzo[a]pyrene PAHs. It is difficult to ascertain the correlation between carcinogeni-
in many animal species, support- carcinogenicity of the component city to human skin and carcinogen-
ed by the consistent and coherent PAHs in these mixtures, because of icity to mouse skin for these five
PAH-associated exposures when by an appropriate route (Table 7.2). abolically active cell types include
the complex mixtures isolated from Both mice and rats developed lung pulmonary macrophages as well as
the occupational environment are tumours after inhalation of coal-tar epithelial cells.
applied topically. vapours from coke ovens. Soot ex- Benzo[a]pyrene is the only PAH
In 1775, Pott made the pioneering tracts caused lung tumours in rats that has been classified by IARC as
observation that cancer of the scro- after intratracheal instillation. There carcinogenic to humans (Group 1).
tum in chimney sweeps was an occu- appears to be a good correlation be-
As indicated above, the basis for
pational disease resulting from direct tween lung cancer in humans and in
this classification is the extensive
contact with soot (Pott, 1775). All five rodents for these two mixtures when
knowledge of the mechanism of car-
established PAH-based chemical studied by an appropriate route in
cinogenic action of benzo[a]pyrene
carcinogens for human skin to which mice and rats. All these complex
exposures occur by direct dermal mixtures have genotoxic activity, in humans and experimental ani-
contact are complex mixtures: coal which is recognized to underlie their mals. None of the many remaining
tar, coal-tar pitch, untreated and carcinogenic activity in the lung. In PAHs shown to be carcinogens in
mildly treated mineral oils, shale oils, summary, many of the individual animals have been classified as an
and soots. Because these mixtures PAHs in these complex mixtures that IARC Group 1 carcinogen, most like-
contain PAHs, all have a genotoxic have been classified by IARC as ei- ly because much less mechanistic
component to their mode of action in ther probably carcinogenic or possi- information is available for these
rodents. Most of the individual PAHs bly carcinogenic to humans are also agents than for benzo[a]pyrene.
classified by IARC as either probably genotoxic and have been shown to These other PAHs are classified as
carcinogenic to humans (Group 2A) cause lung tumours in rodents when either probably carcinogenic to hu-
or possibly carcinogenic to humans administered by an appropriate route mans (Group 2A) or possibly carci-
(Group 2B) (listed above) are geno- (IARC, 2010).
nogenic to humans (Group 2B). Most
toxic and have been shown to cause The various tissue compartments
marked human occupational expo-
skin cancer and/or be initiators of of the respiratory tract are meta-
sure to these compounds involves
skin cancer in rodents (IARC, 1983, bolically active towards exogenous
complex mixtures that contain more
2010). chemicals in both humans and ex-
Soots and vapours from coke pro- perimental animals and are clear- than one of these PAHs and that of-
duction, aluminium production, and ly capable of transforming many ten contain other, non-PAH carcin-
related industries also cause lung metabolism-dependent chemicals, ogens. Therefore, the carcinogenic
cancer in humans, but only extracts including carcinogenic PAHs, to activity of these mixtures cannot
of soot and vapours from coke pro- their chemically reactive metabo- confidently be ascribed to any one of
duction have been tested in rodents lites (Rice, 2005). In the lung, met- their individual components.
62
References
CHAPTER 7
PART 1
Atkinson R, Arey J (1994). Atmospheric IARC (2010). Some non-heterocyclic Mackay D, Callcott D (1998). Partitioning
chemistry of gas-phase polycyclic aromatic polycyclic aromatic hydrocarbons and and physical chemical properties of PAHs.
hydrocarbons: formation of atmospheric some related exposures. IARC Monogr In: Neilson A, editor. PAHs and related
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PMID:6586639
chapter 8.
Benzene and
haematological cancers
Bernard D. Goldstein and Martyn T. Smith
Introduction disorders in humans, as distinct from logical evidence also strongly sup-
AML. Whereas epidemiological evi- ports this notion (Bassig et al., 2015;
Haematological cancers present an dence establishes that benzene is a Linet et al., 2015).
example of seeming discordance cause of human AML (IARC, 1987),
between epidemiological data and
long-term studies in experimental Studies in experimental
animal data, which is apparently re- animals
animals exposed to benzene gener-
solved by mechanistic information.
Known causes of haematological ally have not indicated an increased In 1974, IARC concluded that studies
cancers in humans are ionizing ra- risk of AML. In contrast, increased in experimental animals did not show
diation, chemotherapeutic agents, incidence of lymphoma has been evidence of carcinogenesis from
infectious agents such as human readily evident in such studies, but exposure to benzene (IARC, 1974).
immunodeficiency virus (HIV), and the corresponding epidemiological Subsequently, results from two long-
occupational exposures to chemical evidence can be debated. However, term studies of experimental animals
agents such as formaldehyde and
recent mechanistic data, as well as exposed to benzene that did report
benzene. These agents are recog-
information that has led to a reclas- cancer were published by a research
nized as causes of acute myeloid
leukaemia (AML), and all have been sification of haematological neo- group at New York University (NYU)
implicated in the causation of other plasms, are consistent with benzene in the USA (Snyder et al., 1980, cit-
forms of haematological cancers. being recognized as a cause of hu- ed in IARC, 1982), who exposed
This chapter focuses on the issue man lymphoproliferative disorders C57BL/6J and AKR/J mice to ben-
of whether benzene can be consid- (Smith et al., 2007, Goldstein, 2010; zene by inhalation, and by Maltoni
ered to cause lymphoproliferative Smith, 2010). Recent epidemio- et al. (1989) in Bologna, Italy, who
65
Part 1 • Chapter 8. Benzene and haematological cancers
exposed Sprague-Dawley rats by munity long before cohort-based NHL and other lymphoprolifera-
gavage. Both studies reported an epidemiological studies provided tive disorders (Bassig et al., 2015;
increased incidence of lymphoma unequivocal evidence. Despite sev- Linet et al., 2015).
as well as a variety of other tumours. eral studies evaluating AML in shoe
There are now at least seven stud- Changing diagnostic criteria
workers in Italy (Vigliani and Saita,
ies, including long-term animal bio- for haematological disorders
1964) and leather workers in Turkey
assays by the United States National
Toxicology Program and by others, (Aksoy, 1989), the relationship be- The classification of haematologi-
showing an increased incidence tween benzene and AML required cal disorders continues to evolve,
of lymphomas of various types a conventional cohort study in a including relatively recent modifica-
(Huff et al., 1989; Farris et al., 1993; well-defined worker population tions that have major implications
Huff, 2007; National Toxicology (Infante et al., 1977) before causality for studying and understanding
Program, 2007; Kawasaki et al., was fully accepted. causality. These reclassifications are
2009). Numerous epidemiological stud- largely based on advances in under-
In contrast, evidence that AML re- standing the pathological and molec-
ies evaluating the relationship be-
sults from exposure to benzene has ular basis for haematological diseas-
tween exposure to benzene and
been difficult to obtain in experimen- es, and on the development of assays
different forms of lymphoma have
tal animals, and has generally been
that permit differentiation among the
lacking in the same studies that read- yielded inconsistent results. Some
various haematological cell types.
ily showed an increase in the inci- studies suggest a relationship (e.g.
Myeloid leukaemias are no longer
dence of lymphatic cancers. In other Arnetz et al., 1991; Hayes et al.,
divided simply into AML and chron-
NYU studies, 3 of 40 CD1 mice were 1997; Fabbro-Peray et al., 2001;
ic myeloid leukaemia (CML). The
found to have myeloproliferative dis- Kristensen et al., 2008; Wong et al.,
French–American–British classifi-
orders, and 1 of 40 Sprague-Dawley 2010), whereas others do not (e.g.
rats was found to have AML; the re- cation has eight distinct subtypes of
Raabe et al., 1998; Divine et al., AML (Bennett et al., 1989). The more
sults are notable only because these
1999; Bloemen et al., 2004). recent World Health Organization
disorders are rare in both species
Recent meta-analyses suggest an (WHO) classification makes greater
(Goldstein et al., 1982). The NYU
group also noted an 8-fold increase association of exposure to benzene use of cytogenetic findings to sub-
in the number of early precursor cells with NHL, multiple myeloma, chron- classify AML (Swerdlow et al., 2008).
in the bone marrow of CD1 mice ex- ic lymphocytic leukaemia (CLL), and Myelodysplasia has also been sub-
posed to benzene (Snyder et al., acute lymphoblastic leukaemia (ALL) divided into various types, enabling
1981). An increase in the number of (Infante, 2006; Smith et al., 2007; recognition of the different pathways
haematopoietic progenitor cells was Steinmaus et al., 2008; Vlaanderen and rates of transformation to AML
also noted by Cronkite et al. (1989), et al., 2011). However, at the Working (Bennett et al., 1989; Swerdlow et al.,
who also observed AML in CBA/Ca 2008).
Group meeting for Volume 100F
mice exposed to benzene. More re- Similarly, the newer approaches
of the IARC Monographs, the epi-
cent inhalation studies by Kawasaki to classifying NHL have divided this
et al. (2009) found an increase in demiological evidence relating ex-
entity into more than 40 subtypes,
the incidence of AML in leukae- posure to benzene to NHL or mul-
while at the same time moving pre-
mia-prone C3H/He mice exposed tiple myeloma was not deemed to
viously separate diseases into this
to benzene, particularly if they were establish causality. As discussed
general classification. NHL now
Trp53-deficient. Thymic lymphomas below, recent changes in diagnostic
includes CLL, ALL, and multiple
and non-Hodgkin lymphoma (NHL) criteria complicate epidemiological
myeloma, as well as the multitude
were also noted. evaluation of lymphoproliferative dis- of lymphocytic disorders that were
orders, as does the recognition that formerly included within the NHL
Epidemiological studies
the criteria will continue to evolve. diagnostic rubric (Swerdlow et al.,
The causal relationship between Recently published epidemiological 2008). It should be noted that both
exposure to benzene and AML studies also conclude that expo- CLL and ALL are no longer stand-
was accepted by the medical com- sure to benzene is associated with alone diagnoses (Swerdlow et al.,
66
2008). This is not surprising, be- its effects through metabolism to one gens to give additional emphasis to
cause clinicians have long known or more haematotoxic metabolites. the role of mechanistic understand-
CHAPTER 8
PART 1
that there was little distinction in clin- Like other well-established causes ing. IARC now allows a chemical
ical course, prognosis, and response of AML, including ionizing radiation to be classified as carcinogenic to
to chemotherapy between CLL and and chemotherapeutic agents, ben- humans (Group 1) “when evidence
lymphomas with similar mature lym- zene has the ability to cause aplas- of carcinogenicity in humans is less
phocytes involving other organs tic anaemia at high doses and a than sufficient but there is sufficient
but not blood, or between ALL and pancytopenic effect at lower doses, evidence of carcinogenicity in exper-
more aggressive lymphomas with indicating toxicity to the pluripotent imental animals and strong evidence
similar primitive lymphocytes in- haematopoietic stem cell population in exposed humans that the agent
volving other organs but not blood. responsible for the production of red acts through a relevant mechanism
However, the ability to use molecular blood cells, white blood cells, and of carcinogenicity” (IARC, 2006).
markers to build on this clinical in- platelets. In the case of benzene and
sight permits reclassification. Lymphocytes are affected by ben- lymphoproliferative cancers, there
zene, as is evident from a decreased is clearly sufficient evidence in ex-
Evidence for an overlap lymphocyte count in exposed work- perimental animals and strong
between myeloid and evidence in humans of a relevant
ers (Goldstein, 1988; Rothman et al.,
lymphoid cancers in humans
1996), and from the severe loss of mechanism of carcinogenicity. This
function of lymphatic organs in ex- evidence includes the recognition
There are two lines of evidence
perimental animals as a result of that the stem cell known to be at
that myeloid and lymphoid haema-
tological cancers are closely relat- longer-term high-level exposure. risk for benzene-induced AML is
ed: (i) evidence that has led to the Particularly pertinent to the mech- also responsible for lymphoprolifer-
general acceptance that there is a anistic considerations with respect ation, the well-known vulnerability
common haematological stem cell, to whether benzene is a cause of of human lymphocytes to benzene
and (ii) clinical evidence based on lymphatic tumours is the finding in toxicity, and the demonstration of
the use of newer biological markers many studies of genotoxic effects in increased chromosomal abnormali-
that show the overlap between the circulating lymphocytes of exposed ties in the circulating lymphocytes of
two types, which were previously humans or experimental animals workers exposed to benzene. It also
considered to be separate. The clin- (Vigliani and Forni, 1969; Forni, includes the promiscuous DNA dam-
ical evidence includes recognition of 1979; Zhang et al., 1996, 2002, age caused by benzene metabolites
the following: perhaps 10% of new 2005, 2011; Navasumrit et al., 2005). and the observation of aberrations in
cases of acute leukaemia have both multiple chromosomes among work-
These effects are seen in bone mar-
lymphoblastic and myeloid char- ers who have been heavily exposed
row precursor cells and in circulat-
acteristics; leukaemia that occurs to benzene or who have haematolog-
ing lymphocytes and include overt
in individuals with Down syndrome ical cancers attributable to benzene.
chromosomal abnormalities, trans-
can be lymphoid or myeloid, as can These mechanistic findings bridging
locations, deletions, and aneuploidy
leukaemia resulting from chemo- lymphoproliferative and myelopro-
of several different chromosomes
therapy for cancer; and blast trans-
(Zhang et al., 2007, 2011, 2012). The liferative cancers appear to explain
formation of CML can be lymphoid
evidence is consistent with exposure the seeming lack of congruence
rather than the more usual myeloid
to benzene potentially affecting mul- between epidemiological data and
(Gassmann et al., 1997; Calabretta
tiple sites within the genetic material animal data for myeloid and lymphoid
and Perrotti, 2004; Lee et al., 2009;
of pluripotent stem cells. cancers observed with benzene, and
Xavier et al., 2009).
with other agents.
Mechanism of benzene- Conclusions
induced haematotoxicity
Both IARC and the United States
Benzene, which has been a known National Toxicology Program have
cause of human bone marrow toxic- in recent years changed their ap-
ity since the 19th century, produces proach to classification of carcino-
68
Navasumrit P, Chanvaivit S, Intarasunanont Steinmaus C, Smith AH, Jones RM, Smith MT Zhang L, Eastmond DA, Smith MT (2002).
P, Arayasiri M, Lauhareungpanya N, (2008). Meta-analysis of benzene exposure The nature of chromosomal aberrations
CHAPTER 8
Parnlob V, et al. (2005). Environmental and non-Hodgkin lymphoma: biases could detected in humans exposed to benzene.
PART 1
and occupational exposure to benzene in mask an important association. Occup Environ Crit Rev Toxicol. 32(1):1–42. http://
Thailand. Chem Biol Interact. 153-154:75–83. Med. 65(6):371–8. http://dx.doi.org/10.1136/ d x . d o i . o r g / 1 0 .1 0 8 0 / 2 0 0 2 4 0 9 1 0 6 41 6 5
http://dx.doi.org/10.1016/j.cbi.2005.03.010 oem.2007.036913 PMID:18417556 PMID:11846214
PMID:15935802
Swerdlow SH, Campo E, Harris N, Jaffe Zhang L, Lan Q, Guo W, Hubbard AE, Li G,
Raabe GK, Collingwood KW, Wong E, Pileri S, Stein HJ, et al. (2008). WHO Rappaport SM, et al. (2011). Chromosome-
O (1998). An updated mortality study classification of tumours of haematopoietic wide aneuploidy study (CWAS) in workers
of workers at a petroleum refinery and lymphoid tissues. Lyon, France: exposed to an established leukemogen,
in Beaumont, Texas. Am J Ind Med. International Agency for Research on Cancer. benzene. Carcinogenesis. 32(4):605–12.
33(1):61–81. http://dx.doi.org/10.1002/
Vigliani EC, Forni A (1969). Benzene, ht tp: //dx.doi.org /10.10 93 /c arc in / bgq28 6
(S I CI)10 97- 0 274 (19 9 8 01) 3 3:1< 61:: A I D -
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AJIM8>3.0.CO;2-Z PMID:9408530
Med. 11(3):148–9. PMID:5255337
Zhang L, Lan Q, Guo W, Li G, Yang W,
Rothman N, Smith MT, Hayes RB, Li GL,
Vigliani EC, Saita G (1964). Benzene and Hubbard AE, et al. (2005). Use of OctoChrome
Irons RD, Dosemeci M, et al. (1996). An
epidemiologic study of early biologic effects of leukemia. N Engl J Med. 271(17):872–6. http:// fluorescence in situ hybridization to
benzene in Chinese workers. Environ Health dx.doi.org/10.1056/NEJM196410222711703 detect specific aneuploidy among all 24
Perspect. 104(Suppl 6):1365–70. http://dx.doi. PMID:14185112 chromosomes in benzene-exposed workers.
org/10.1289/ehp.961041365 PMID:9118921 Chem Biol Interact. 153–154:117–22.
Vlaanderen J, Lan Q, Kromhout H, Rothman
http://dx.doi.org/10.1016/j.cbi.2005.03.016
Smith MT (2010). Advances in understanding N, Vermeulen R (2011). Occupational
PMID:15935807
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Annu Rev Public Health. 31(1):133– subtypes: a meta-analysis of cohort studies Zhang L, Lan Q, Ji Z, Li G, Shen M,
48. http://dx.doi.org/10.1146/annurev. incorporating three study quality dimensions. Vermeulen R, et al. (2012). Leukemia-related
publhealth.012809.103646 PMID:20070208 Environ Health Perspect. 119(2):159–67. chromosomal loss detected in hematopoietic
h t t p: //d x . d o i . o r g /10 .12 8 9 /e h p .10 0 2 318 progenitor cells of benzene-exposed workers.
Smith MT, Jones RM, Smith AH (2007). PMID:20880796 Leukemia. 26(12):2494–8. http://dx.doi.
Benzene exposure and risk of non- org/10.1038/leu.2012.143 PMID:22643707
Hodgkin lymphoma. Cancer Epidemiol Wong O, Harris F, Armstrong TW, Hua F
Biomarkers Prev. 16(3):385–91. http:// (2010). A hospital-based case-control study
Zhang L, Rothman N, Li G, Guo W, Yang W,
dx.doi.org/10.1158/1055-9965.EPI-06-1057 of non-Hodgkin lymphoid neoplasms in
Hubbard AE, et al. (2007). Aberrations in
PMID:17337645 Shanghai: analysis of environmental and
chromosomes associated with lymphoma and
occupational risk factors by subtypes of the
therapy-related leukemia in benzene-exposed
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chapter 9.
Among the biological agents re- because species specificity limits the causes lymphoproliferative diseas-
viewed in Volume 100B of the IARC feasibility of this approach for most of es in New World monkeys and in
Monographs (IARC, 2012) are sever- these viruses. One exception is hu- humanized SCID mice, the use of
al oncogenic viruses that are strictly man T-cell lymphotropic virus type 1 surrogate hosts has not proven very
species-specific, causing cancer in (HTLV-1): in addition to its ability to useful for defining tumour site con-
humans only. For this reason, the infect humans, this virus can infect cordance between humans and ex-
question about tumour site concor- several other species – including perimental animals.
dance between humans and experi- rabbits, rats, and monkeys – and it Animal models for human tumour
mental animals is not easy to answer does induce adult T-cell leukaemia/ viruses that make use of animal virus-
for these agents, because cancer bi- lymphoma (ATLL), albeit in monkeys es are scarce. In fact, although many
oassays in animals are often lacking, only. animal viruses that infect non-human
and hence a proper comparison be- For other human tumour virus- primate species are related to the hu-
tween data in humans and in experi- es, the use of humanized severe man tumour viruses, the incidence of
mental animals is not obvious. In this combined immunodeficiency (SCID) cancer is low in these species (as it
chapter, some aspects of this issue mice, in which the human target is in humans), which renders cancer
are discussed. cell for the virus is placed in a mu- studies costly and difficult. Moreover,
The use of animals as surrogate rine host, can provide a platform for animal models for tumour viruses in
hosts for the study of human tu- in vivo infection. However, except non-primate species often do not
mour viruses is often problematic, for Epstein–Barr virus (EBV), which accurately reflect the mechanism of
72
These data show that early in the MYC, LMP2A accelerates the de- ic neoplasms and a higher incidence
carcinogenic process, LMP1 acts as velopment of B-cell lymphomas in of HCCs. No hepatocellular adeno-
CHAPTER 9
PART 1
a tumour promoter after chemical ini- a transgenic mouse model (Bieging mas or HCCs were seen in non-in-
tiation, but it may also block expan- et al., 2009; Bultema et al., 2009). A fected woodchucks that received
sion or progression of benign lesions more recent study has also shown AFB1 (but pre-neoplastic hepatic foci
(Curran et al., 2001). that LMP1 and LMP2 can cooperate were seen), and no pre-neoplastic or
A further study on LMP1 trans- in the induction of epithelial squa- neoplastic lesions were found in un-
genic mice showed that they have mous cell carcinomas (SCCs) when treated controls. These results pro-
a higher incidence of lymphoma co-expressed under the control of a vide strong evidence of a synergistic
and that the progression to lympho- keratin 14 (K14) promoter in trans- hepatocarcinogenic effect of viral
ma correlates with higher expres- genic mouse models (Shair et al., infection and dietary AFB1 intake
sion levels of LMP1, compared with 2012). (Bannasch et al., 1995).
non-transgenic controls. Although Establishment of long-term latent Transgenic mice that contain the
LMP1 is expressed in all B lympho- infections with EBV was possible in BglIIA fragment of HBV under the
cytes of the transgenic mice, lym- a humanized mouse model that was transcriptional control of the mouse
phoma develops in a specific sub- challenged either with wild-type EBV albumin promoter overexpress the
set, the B-1a lymphocytes, which is or with a replication-defective virus. HBV large envelope polypeptide
a population predisposed to clonal B-cell lymphomas developed in both and accumulate toxic quantities of
expansion with age. The malignant cases, but at a higher frequency after hepatitis B surface antigen (HBsAg)
lymphocytes show constitutively infection with the wild-type virus, in- in their hepatocytes. As a result,
active Stat3 signalling, have de- dicating a potential role for lytic virus the mice develop severe, prolonged
creased levels of p27, and display infection in the development of ma- hepatocellular injury associated with
activated Akt and nuclear factor kap- lignancy (Ma et al., 2011). an inflammatory response, followed
pa-light-chain-enhancer of activated For EBV, the overall concordance by chronic hepatocellular regener-
B cells (NF-κB) pathways, properties between the animal models and hu- ation, transcriptional deregulation,
that are associated with promoting mans with respect to the types of tu- dysplasia, aneuploidy, hepatocellular
growth and survival of B lympho- mour and the identity and function of adenoma, and eventually HCC. The
cytes. The transgenic lymphomas the major oncogenes and oncogene incidence of HCC depends on the
mirror multiple aspects of EBV- products is high. frequency, severity, and age of onset
induced tumours; this suggests that of the liver cell injury, which itself de-
these properties of LMP1 are major Hepatitis B virus (HBV) pends on the intrahepatic concentra-
factors in cancer development (Shair tion of HBsAg and is influenced by
et al., 2007). Interactive viral–chemical hepato- genetic background and sex. Thus,
Transcripts of LMP2A can be ex- carcinogenesis was studied in wood- the excessive expression of a sin-
pressed in resting virus-carrying B chucks (Marmota monax) inoculated gle structural viral gene is sufficient
lymphocytes in healthy individuals as newborns with woodchuck hep- to cause malignant transformation
– the reservoir of persistently latent atitis virus, which is closely related in this model. Similar events may
EBV. In LMP2A transgenic mice, to the human HBV. Starting at age be responsible for the development
a block in surface immunoglobulin 12 months, the woodchucks were of HCC in humans after HBV infec-
rearrangement results in the gen- fed a diet containing aflatoxin B1 tion, irrespective of the mechanism
eration of B-cell receptor-negative (AFB1) (at a high dose for 4 months or mechanisms involved in the initial
cells, which normally would under- and then at a lower dose for lifetime). induction of liver cell injury (Chisari
go apoptosis. LMP2A transgenic B Carriers of woodchuck hepatitis vi- et al., 1989).
cells develop and survive without a rus with or without treatment with the Transgenic mice overexpressing
B-cell receptor. These data indicate carcinogen AFB1 developed a high the HBV large envelope polypeptide
that LMP2A imparts developmental incidence of pre-neoplastic hepatic suffer from hepatic injury as a re-
and survival signals to B cells in vivo foci, hepatocellular adenomas, and sult of accumulation of HBsAg (see
(Merchant et al., 2000). Furthermore, HCCs, but AFB1 treatment resulted in the previous study). When treated
when co-expressed with human a much earlier appearance of hepat- with the hepatocarcinogens AFB1
74
metabolic or genetic host suscepti- breakdown of mitochondrial out- This issue may be resolved with the
bility for HCV-associated HCC (Lerat er membranes. HCC developed in development of more physiological
CHAPTER 9
PART 1
et al., 2002). about 35% of Pparα+/+:HCVcp mice models that permit chronic and pro-
In a subsequent study by the by age 24 months, but no tumours ductive HCV replication. A recently
same group, the mechanisms un- were seen in the other genotypes. developed model holds promise in
derlying HCV-induced defects in These phenomena were closely this regard. Genetically engineered
lipid metabolism were studied in associated with sustained PPARα mice expressing two host restriction
transgenic mice that expressed the activation: in Pparα+/–:HCVcp mice, factors – human CD81 and occludin
full viral protein repertoire at lev- PPARα activation and the related – can be infected with HCV, and in
els corresponding to those seen changes did not occur despite the these mice sustained viraemia and
in natural human HCV infection. presence of a functional Pparα al- infectivity can be observed for more
Expression of the full-length HCV lele. Persistent activation of PPARα than 12 months after infection, with
open reading frame was associ- is essential for the pathogenesis of the expected fibrotic and cirrhotic
ated with hepatocellular steatosis, hepatic steatosis and HCC induced progression in the liver (Chen et al.,
impaired triglyceride secretion, and by HCV infection (Tanaka et al., 2014).
nuclear translocation of sterol reg- 2008).
ulatory element-binding protein 1c Kaposi sarcoma-associated
(SREBP1c), followed by increased Conclusions herpesvirus (KSHV)
transcription of lipogenic enzymes. Species specificity of KSHV
Stress markers in the endoplasmic In the absence of animal models
reticulum were expressed at similar that develop HCC in the context of After injection, KSHV can infect
levels in HCV transgenic mice and in an HCV infection, various groups non-human primates (Renne et al.,
non-transgenic controls. Transgenic have reported the use of transgenic 2004), NOD/SCID mice (Parsons
mice expressing the full-length HCV mouse models. Studies with mice et al., 2006), and humanized SCID
polyprotein have reduced plasma expressing HCV replicons, poly- mice (Dittmer et al., 1999; Foreman
triglyceride concentrations and de- proteins, or single HCV proteins as et al., 2001; Wu et al., 2006; Wang
velop hepatocellular steatosis in the transgenes, alone or in combination, et al., 2014). These infections do not
same way as do patients with HCV under the control of liver-specific result in the formation of tumours,
infection (Lerat et al., 2009). promoters have been described by but they confirm the viral tropism
several groups (Dorner et al., 2011, (with KSHV targeting B cells and en-
Effect of peroxisome 2013). There is good concordance dothelial cells) and drug susceptibili-
proliferator-activated
between the outcomes observed in ty (to ganciclovir) in vivo.
receptors
these mice and those in humans with In one report of KSHV infection
Peroxisome proliferator-activated HCV infection; however, questions in marmosets (Callithrix jacchus),
receptor alpha (PPARα) is a central remain about to what extent the re- viral replication was apparent in pe-
regulator of triglyceride homeosta- sults obtained with these experimen- ripheral blood mononuclear cells,
sis and a mediator of hepatocar- tal approaches reflect the patholog- and a Kaposi sarcoma-like lesion
cinogenesis in rodents. In a study to ical consequences of human HCV developed on one of the animals
determine the role of PPARα in HCV infection that contribute to HCC. (Chang et al., 2009). Viruses that
core protein-induced disease, dou- It remains a matter of consider- are homologous to KSHV exist in
ble transgenic mice were generated able debate whether HCV causes the bank vole (Myodes glareolus),
that carried Pparα (homozygous, HCC through a direct mechanism in as Murid herpesvirus 68 (MHV-68),
heterozygous, and null) and the which virally encoded genes contrib- and in virtually all non-human pri-
HCV core protein gene (HCVcp) as ute to carcinogenesis, or through an mates (Fleckenstein and Ensser,
transgenes. Severe steatosis was indirect mechanism, where the inju- 2007). The infection of macaques
observed only in Pparα+/+:HCVcp ry to the liver caused by HCV infec- (Macaca mulatta) with rhesus rhad-
mice, as a result of higher fat- tion and host immune responses to inovirus in the context of simian im-
ty acid uptake and decreased that infection, such as inflammation, munodeficiency virus (SIV) induces
mitochondrial β-oxidation due to contribute to the onset of cancer. B-cell lymphoma and endothelial cell
76
as placental growth factor, platelet- various cell lines. In particular, HPV transgenic mice treated with estro-
derived growth factor B, and induci- type 16 (HPV16) had transforming gen for 6 months developed high-
CHAPTER 9
PART 1
ble nitric oxide synthase by the vGP- potential in established rodent cells grade dysplasia and/or cervical can-
CR-expressing cells. Finally, contin- (Yasumoto et al., 1986), with the prin- cer, but K14-E6 mice only developed
ued vGPCR expression is essential cipal activity residing in the E7 onco- cervical cancer after treatment with
for progression of the Kaposi sarco- protein (Vousden et al., 1988). The estrogen for 9 months (Riley et al.,
ma-like phenotype, and downregu- E5 and E6 proteins of both HPV16 2003; Shai et al., 2007, 2008).
lation of vGPCR expression results and HPV18 also showed transform- An additional activity of HPV16 E7
in reduced expression of angiogenic ing potential in such assays (Pim that contributes to its oncogenicity
factors and regression of the lesions. et al., 1992). The E6 protein can in- is the ability to inactivate p21 (Shin
These findings implicate vGPCR as et al., 2009). In transgenic mice car-
activate p53 (Scheffner et al., 1990),
a key element in the pathogenesis rying a tetracycline-regulated HPV16
and as a result, E6 can abrogate
of Kaposi sarcoma (Jensen et al., E7 transgene, the continued expres-
cell-cycle arrest induced by a variety
2005).
of DNA-damaging agents, such as sion of E7 was found to be critical for
Further support for a role of vG-
actinomycin D. The normal response the maintenance not only of cervical
PCR in tumorigenesis has come
to DNA damage, i.e. inhibition of cancer but also of the dysplastic neo-
from studies with MHV-68. In mice,
DNA synthesis and increase in p53 plasia that is recognized as its pre-
this virus can replicate transiently
protein levels, did not occur after cursor lesion (Jabbar et al., 2009).
before entering a latent state, but
treatment with actinomycin D of ke- This dependence on continued ex-
no lymphoproliferative disorders
ratinocytes that had been immortal- pression of E7 was observed even in
arise in immunocompetent animals.
ized with HPV16 E6/E7 (Kessis et al., the context of constitutive expression
However, when a recombinant MHV-
1993). of HPV16 E6 (Jabbar et al., 2012).
68 in which the vGPCR is replaced
Like E7, the E6 protein of HPV
with the KSHV-derived vGPCR was
used to infect mice, angiogenic le-
Transgenic models for HPV- appears to contribute to cervical
associated cancers carcinogenesis through multiple ac-
sions formed that had features char-
acteristic of those seen in human tivities. This protein is known to de-
The first germline transgenic mouse grade p53 and other cellular targets
Kaposi sarcoma lesions. The differ-
model for HPV-associated cervical through its interaction with the ubiq-
ence in activity between the wild-
cancer was developed with a K14- uitin ligase E6AP. This enzyme was
type MHV-68 and the recombinant
HPV16 construct that contained the found to be critical for E6-mediated
MHV-68 was linked to differences in
activation: the KSHV-derived vGP- early genes of the virus under the oncogenesis in the cervix (Shai et al.,
CR was constitutively active, where- control of the K14 transcriptional 2010). E6 is known to bind to sever-
as the murine vGPCR in MHV-68 promoter, which directs the expres- al cellular proteins that contain PDZ
was not (Zhang et al., 2015). This sion of these genes to the stratified domains (common structural regions
study provides compelling evidence epithelium of the oral cavity and of 80–90 amino acids in proteins
for a direct role of vGPCR in the de- the lower female reproductive tract. involved in signalling). Transgenic
velopment of Kaposi sarcoma in a These mice did not develop cer- mice expressing a mutant form of
non-transgenic animal model. vical cancers spontaneously, but HPV16 E6 that is unable to bind to
For KSHV, the overall concor- treatment with estrogen, sufficient PDZ-domain proteins (Nguyen et al.,
dance between the animal mod- to induce continuous estrus, led to 2003) had a reduced susceptibility to
els and humans with respect to the a highly penetrant cervical cancer cervical cancer compared with mice
types of tumour and the identity and phenotype in the context of a pro- expressing the wild-type E6 protein
function of the major oncogenes and gressive disease much like that seen (Shai et al., 2007). It remains un-
oncogene products is high. in women, given that it was preceded clear which of the interactions with
by the onset of cervical intraepitheli- PDZ-domain proteins contribute to
Human papillomaviruses
al neoplasia (CIN) of grades 1–3. As E6-mediated carcinogenesis in vivo,
The cell-transforming capacity of hu- in women, the cancers preferential- and how E7 is involved in this pro-
man papillomavirus (HPV)-encoded ly arose in the transformation zone cess (Simonson et al., 2005; Shai
proteins has been demonstrated in (Arbeit et al., 1994, 1996). All K14-E7 et al., 2007).
78
susceptible to tumours compared Because HIV-1 is species-specif- and multiple other cellular proteins
with non-transgenic mice, and the ic, like the oncogenic herpesviruses (Gatignol, 2007). Tat also affects the
CHAPTER 9
PART 1
HPV20 E6/E7 transgenic mice had EBV and KSHV, there are no ideal course of HIV-1-associated disease
an increased incidence of malignant animal models for HIV-1-associated indirectly, because it is secreted by
tumours. Alterations in the expres- cancers. In contrast to what is ob- infected cells and can enter non-in-
sion of both p53 and p63 were noted served with infectious agents that fected cells (Gupta and Mitra, 2007).
in the transgenic mice exposed to are directly oncogenic, the HIV-1 ge- Evidence that Tat is involved in
UV radiation (Michel et al., 2006). nome is not present in cancer cells. oncogenesis includes its ability to
For HPV, the overall concordance Therefore, any interaction between induce apoptosis in neighbouring
between the animal models and hu- virus and host is indirect. Although non-infected cells when secreted
mans with respect to the types of tu- none of the HIV-1-encoded proteins from infected cells, thereby increas-
mour caused by mucosal HPV types has been unequivocally shown to be ing the susceptibility of bystander
and the identity and function of the directly oncogenic, some are associ- CD4-positive T cells to death in-
major oncogenes and oncogene ated with immunodeficiency, thereby duced by cross-linking (Alimonti
products is high. There are important indirectly promoting cancer develop- et al., 2003). This may contribute
context-dependent differences in the ment. In addition, there is evidence to the massive depletion of CD4-
function of the E6 oncoprotein, de- that some of the HIV-1-encoded pro- positive T cells by apoptosis, lead-
pending on the anatomical site. teins may promote cancer by other ing to the severe immunodeficien-
indirect mechanisms that are not cy seen in the acquired immune
Human immunodeficiency dependent on immunodeficiency. deficiency syndrome (AIDS). Tat
virus type 1 (HIV-1) There are also reports of transgenic has also been shown to stimulate
mouse models containing HIV provi- the growth of Kaposi sarcoma cells
Infectious agents can act as indirect (Aoki and Tosato, 2007). However,
ral transgenes. In some cases these
carcinogens by causing immunosup- when cells are removed from Kaposi
animals develop lymphoproliferative
pression. This has been shown for sarcoma lesions and expanded in
disorders, including B-cell lympho-
infection with HIV-1, which strongly vitro, they lose the KSHV genome,
mas, which show characteristics
increases the incidence of several and the question remains whether
similar to those of B-cell lymphomas
human cancers. Strikingly, the ma- the “Kaposi sarcoma” cells lacking
arising in patients with HIV infection
jority of cancers associated with HIV- KSHV used in most of these studies
(Curreli et al., 2013). Virus-encoded
1 have another known infectious eti- represent a valid model for Kaposi
proteins including Nef, gp120, p17,
ology, and HIV-1 infection increases sarcoma.
and Tat have all been implicated in
their incidence considerably. Among To investigate the role of Tat in
promoting B-cell hyperproliferation,
these cancers, those associated carcinogenesis, several studies have
although the strongest association in
with the herpesviruses KSHV and been carried out in vivo, in trans-
animals comes from work on the viral
EBV are most strongly enhanced genic mice. Transgenic mice carry-
Tat protein.
by immunosuppression. The same ing a recombinant DNA sequence
cancers are also enhanced by iat- Tat protein containing the early region of the
rogenic immunosuppression, as BK virus and the HIV-1 Tat gene
shown by their increased incidence The multifunctional Tat protein is the developed skin leiomyosarcomas,
in transplant recipients, which lends only HIV-1 protein for which there is squamous cell papillomas and carci-
additional support to the notion that experimental evidence of a potential nomas, adenocarcinomas of skin ad-
HIV-1 acts as a carcinogen mainly role in Kaposi sarcoma. Tat is an im- nexal glands, and B-cell lymphomas.
through this indirect effect. The most portant regulator of viral transcription; Although the incidence of HCC was
common cancers in individuals with it recruits cellular transcription fac- low, most animals showed liver cell
HIV-1 infection are Kaposi sarco- tors to the HIV-1 promoter, strongly dysplasia of variable degree. These
ma (caused by KSHV), lymphomas stimulates HIV-1 DNA transcription, mice were also affected by skin le-
(many of which are EBV-positive), and interacts with protein–kinase sions resembling the early stages
and cervical and anogenital carcino- complexes (Cdk9/cyclin T1, Cdk2/ of Kaposi sarcoma (see also Vogel
mas associated with HPV infection. cyclin E), protein phosphatases, et al., 1988). The Tat transgene was
80
a tumour suppressor gene (Hidaka Tgat, was identified. Expression and humans with respect to the
et al., 2008). There have been only of Tgat in NIH 3T3 cells resulted in types of tumour and the identity and
CHAPTER 9
PART 1
few reports of cellular oncogenes cellular transformation, indicated function of the major oncogenes and
in ATLL cells. When complementa- by anchorage-independent growth oncogene products is high.
ry DNA expression libraries derived in semi-solid medium, and tumour
from leukaemic cells of patients with formation in nude mice (Yoshizuka
ATLL were screened for the potential et al., 2004).
to transform NIH 3T3 mouse fibro- For HTLV-1, the overall concor-
blasts, a novel transforming gene, dance between the animal models
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84
part 2.
mechanisms of carcinogenesis
chapter 10.
Key characteristics of
carcinogens
Martyn T. Smith
CHAPTER 10
PART 2
Introduction which carcinogens produce cancer. differences, may explain the lack
The Workshop participants conclud- of concordance or coherence be-
The agents documented and list- ed that carcinogens commonly show tween tumour sites in humans and
ed as carcinogenic to humans one or more of 10 key characteristics experimental animals. Neither the
(Group 1) in Volume 100 of the IARC (Table 10.1). list given in Table 10.1 nor the set of
Monographs show several key char- To achieve wide dissemination modulating factors mentioned by the
acteristics that distinguish them as and assessment, these key char- Workshop participants is meant to
carcinogenic agents. Many appear to acteristics have been described in be exhaustive, but they were agreed
act via multiple mechanisms, caus- an open access journal publication upon as being established charac-
ing various biological changes in the (Smith et al., 2016) that also delin- teristics or modulating factors. It is
multistage process of carcinogene- eates their application, and hence hoped that they will assist future
sis. Others appear to act by a single IARC Monographs Working Groups
complements material presented
predominant mechanism. in evaluating additional potential
in this chapter and, to a broader
The participants in the IARC human carcinogens.
extent, this Scientific Publication.
Workshop on Tumour Site Concor- Here, these key characteristics are
Characteristic 1: Is
dance and Mechanisms of Carcino- defined, and reference is made to
electrophilic or can be
genesis, after considering previously subsequent chapters where these
metabolically activated to
published options for classification particular characteristic properties electrophiles
of carcinogens and related matters are extensively discussed.
(see Chapter 11, by Stewart, and The Workshop participants also Electrophiles are electron-seeking
Chapter 12, by DeMarini), exten- discussed several modulating fac- molecules that commonly form addi-
sively debated the mechanisms by tors that, along with mechanistic tion products, generally referred
86
Genomic instability is a well-rec- ed that their mode of action may in- Reactive oxygen species produce
ognized feature of many cancers volve disruption of epigenetic mech- at least 24 base modifications, as
(Bielas et al., 2006). Studies of cul- anisms. Because the evidence for a well as DNA–protein cross-links and
tured cells exposed to ionizing ra- truly causal role of epigenetic chang- other lesions (Berquist and Wilson,
diation have shown that instability es in cancer produced by Group 1 2012), all potentially leading to ge-
is a relatively late-occurring event agents was deemed to be limited in nomic instability. Oxidative damage
that appears several cell genera- Volume 100, for many agents their to DNA can lead to point mutations,
tions after irradiation and results impact on the epigenome was not deletions, insertions, or chromoso-
in a reduced ability to replicate the considered to be a secondary mech- mal translocations, which may cause
genotype faithfully (see Chapter 18, anism of carcinogenesis. However, activation of oncogenes and inacti-
by Hill and Ullrich). The events that it should be noted that most carcin- vation of tumour suppressor genes,
indicate genomic instability include ogens (even those considered for potentially leading to initiation of
chromosomal aberrations, gene mu- Volume 100 in 2008 and 2009) were carcinogenesis (Klaunig et al., 2011;
tations, microsatellite instability, and evaluated by IARC Working Groups Berquist and Wilson, 2012). Thus,
apoptosis. The instability phenotype before new data on their epigenetic agents that generate and promote
may play a major role in radiation-in- effects became available. Many re- oxygen radical-induced cellular inju-
CHAPTER 10
duced cancers and other forms of cent studies have demonstrated the ry may be carcinogenic.
PART 2
cancer by providing the cell and its impact of several Group 1 agents in-
progeny with a constantly elevated cluded in Volume 100 on epigenetic Characteristic 6: Induces
rate of any of the various genetic mechanisms (Koturbash et al., 2011; chronic inflammation
and epigenetic changes that may Ravegnini et al., 2015; Chappell
occur in multistage carcinogenesis et al., 2016). This rapidly evolving Chronic inflammation from persis-
(Aypar et al., 2011). area will generate new mechanistic tent infections, such as that caused
data on carcinogens in the next few by Helicobacter pylori as well as that
Characteristic 4: Induces years. produced by silica or asbestos fibres,
epigenetic alterations has been associated with several
Characteristic 5: Induces forms of cancer (see Chapter 17, by
The term “epigenetic” refers to all
oxidative stress Kane). Indeed, inflammation is an
stable changes in gene expression
“enabling characteristic” of cancer
and chromatin organization that are Many human and animal carcino- (Hanahan and Weinberg, 2011), and
independent of the DNA sequence gens are capable of influencing re- it has been hypothesized to contrib-
itself and that can be mitotically in- dox processes and redox balance ute to cancer initiation, promotion,
herited over cell divisions. Epigenetic within target cells (see Chapter 15, and progression (Trinchieri, 2012).
phenomena, including genomic im- by Bucher). An imbalance between Inflammation acts by both intrinsic
printing, X-chromosome inactivation, formation of reactive oxygen and/ and extrinsic pathways. Persistent
global reconfiguration of the DNA or nitrogen species and their detox- infection and chronic inflammation
methylome, and changes in chro-
ification is commonly referred to as disrupt local tissue homeostasis
matin compaction states and histone
oxidative stress. Reactive oxygen and alter cell signalling, leading to
modification patterns, occur during
species, which can arise from in- the recruitment and activation of in-
development and contribute to the
flammation, may contribute to geno- flammatory cells. These constitute
lineage-specific epigenome that is
mic instability and – along with other extrinsic pathways linking inflam-
maintained over the lifetime of an
free radical species – play key roles mation to cancer (Multhoff and
organism. Many of these same phe-
nomena are altered during carcino- in many of the processes identified Radons, 2012). In contrast, intrinsic
genesis (see Chapter 20, by Rice as being necessary for the conver- pathways driven by activation of pro-
and Herceg). sion of normal cells to cancer cells. to-oncogenes in pre-neoplastic and
A wide range of known and sus- Oxidative damage is considered a neoplastic cells recruit host-derived
pected carcinogens (including chem- major factor in the generation of mu- inflammatory cells that accelerate
ical, physical, and biological agents) tations in DNA, and more than 100 tumour promotion and progression
have been shown to deregulate the different oxidative DNA adducts have (Grivennikov et al., 2010). Strong
epigenome, and it has been suggest- been identified (Klaunig et al., 2011). links exist between inflammation and
88
invokes the predisposition for unre- of impaired nutrient supply. The ex- an impact on this complex process
paired DNA damage to lead to can- ponentially increasing number of ne- in multiple ways and can act through
cer-initiating mutations in replicating oplastic cells may quickly outstrip the multiple mechanisms of action to
cells. The second has attempted to supply capabilities of the existing tis- induce cancer and other adverse
identify sustained replication as a sue vasculature. Neo-angiogenesis, health outcomes. As an illustration
key mechanistic event, and the third in which new blood vessels grow of this point, the evidence has been
describes the ability of a transformed into a tumour, is key to providing this evaluated for which key characteris-
cell to escape normal growth control supply of nutrients. Thus, agents tics contribute to the carcinogenicity
and to continue replication. A com- that promote or inhibit angiogenesis, of benzene, an IARC Group 1 carcin-
ponent common to all three scenar- such as arsenic, will promote or de- ogen, in humans and in experimental
ios is the evasion of apoptosis or oth- lay tumour growth (Yang et al., 2014). animals. The results are shown in
er terminal programming, including Table 10.2, where the level of evi-
autophagy, in at least a proportion Multiple mechanisms of dence for a particular characteristic is
of the cell population (Ryter et al., action of human carcinogens classified on a scale with 2 = strong
2014). evidence, 1 = moderate evidence,
Sustained cellular proliferation The number of mechanisms by
CHAPTER 10
and 0 = weak evidence. For ben-
which chemicals are known to con-
PART 2
has been argued to be a factor in zene, there is strong evidence in my
increased cancer susceptibility. As tribute to carcinogenesis can be ex-
view that metabolic activation, geno-
summarized in the United States tensive if one includes all biochemi-
toxicity, and immunosuppression are
Environmental Protection Agency cal or molecular end-points, but the
established mechanisms of carcino-
guidance assessing risk of can- mechanisms can be grouped into a
genicity in both animals and humans
cer from early-life exposures (EPA, limited number of categories (geno-
(McHale et al., 2012). There is weak
2005), more frequent cell division toxicity, immunosuppression, etc.).
or no evidence that inflammation and
during development can result in Guyton et al. described 15 types of
immortalization play a role in the car-
enhanced fixation of mutations be- key events associated with carcino-
cinogenicity of benzene. However,
cause of the reduced time available genesis, which collectively represent
moderate evidence exists for the oth-
for repair of DNA lesions, while the majority of known carcinogen-
er five key characteristics or mecha-
clonal expansion of a mutated cell ic modes of action (Guyton et al.,
nisms in humans. This suggests that
produces a larger population of mu- 2009).
there is strong or moderate evidence
tant cells. For mature organisms, The IARC Workshop participants
that eight of the key characteristics of
sustained proliferation has also been initially identified 24 mechanistic
carcinogens contribute to the carci-
postulated to increase risk of cancer, end-points, with several subcatego-
nogenicity of benzene and that they
based on the same rationale. ries in each. This was considered too
are consistently observed, for the
The mechanism by which necro- many categories, and it was deter-
most part, both in humans and in ex-
sis may enable cancer induction is mined that several of them could be
perimental animals (Table 10.2).
also part of the description of the merged. The Workshop participants
hallmarks of cancer. In contrast to then concluded that carcinogens Factors modulating human
apoptosis and autophagy, necrotic commonly show one or more of the carcinogenesis
cell death releases pro-inflammatory 10 key characteristics described
signals into the surrounding tissue above (see Table 10.1). These Lack of concordance or coherence
microenvironment, resulting in re- represent the majority of known between tumour sites in humans
cruitment of inflammatory cells of the carcinogenic mechanisms of action. and experimental animals may be
immune system that can participate It is increasingly evident that mul- explained by several modulating
in tumour promotion through their tiple biological alterations or sets of factors that, along with mechanistic
influence on cancer cell proliferation different perturbations are neces- effects, cause discordance between
and invasiveness. sary to convert a normal cell into a the findings. For example, physiolog-
In addition to cell death caused transformed cell, and ultimately a ical differences exist between ani-
by direct toxicity of an agent, cells tumour (Hanahan and Weinberg, mals and humans, including the fact
within a tumour may die as a result 2011). Carcinogens appear to have that rodents are nose-only breathers,
2. Is genotoxic 2 2 2
7. Is immunosuppressive 2 2 2
9. Causes immortalization 0 0 0
whereas humans breathe through cal: they may absorb, distribute, me- the end products are not carcinogen-
both the nose and mouth. Rodents tabolize, and excrete a compound in ic. With regard to infectious agents,
do not retain their urine as humans ways that are different to those seen it is clear that a human infectious
and dogs do, perhaps explaining the in humans. There are many exam- agent, for example a human tumour
lack of carcinogenicity of aromatic ples of this kind. For instance, mice virus that is not infectious to other an-
amines to rodents (see Chapter 2, by hydrolyse 6-propylthiopurine to mer- imal species, will not produce carci-
Beland and Marques). captopurine, which has a potent car- nogenic effects in these species (see
Experimental animals may also cinogenic effect, whereas humans Chapter 9, by Lambert and Banks).
exhibit differences in the pharmaco- oxidize the drug at two positions in
kinetics or toxicokinetics of a chemi- the molecule without hydrolysis, and
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chapter 11.
Mechanisms of carcinogenesis:
from initiation and promotion
to the hallmarks
CHAPTER 11
PART 2
Bernard W. Stewart
Part 2 • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks 93
Table 11.1. A selection of proposals for the categorization of chemical carcinogensa
Hormone Exogenous
hormones
Immunosuppressant
Promoter
listings indicate those used in particular publications (e.g. Searle, 1984; Tomatis et al., 1990; Vainio et al., 1992; Vainio and Hietanen,
2003; Hsu and Stedeford, 2010) as ways of ordering data, as indicated by chapter headings in many cases, and are not necessarily
comprehensive. Categories shown in bold involve or include at least one Volume 100 (Group 1) agent.
there is no generally accepted mech- categorization of chemical carcin- “hallmark” or “hallmarks” have been
anistic basis for classifying chemi- ogens on the basis of the organ af- published. These papers typically
cal carcinogens (Loeb and Harris, fected (Warshawsky and Landolph, describe signal transduction path-
2008), beyond categorization ac- 2006). ways and their therapeutic implica-
cording to genotoxicity (Weisburger Currently, the most widely rec- tions. Although the characterization
and Williams, 1981). There is no ognized description of the nature of by Hanahan and Weinberg (2011)
single comprehensive basis for cat- cancer is that presented by Hanahan of the hallmarks of cancer did not
egorization; chemical carcinogens and Weinberg in two reviews – pub- refer to chemical carcinogens or
are sometimes ordered according lished more than a decade apart – causative agents in general, recent-
to the context in which information is that identify the “hallmarks” of can- ly the hallmarks have been used to
presented, with genotoxicity ordered cer (Hanahan and Weinberg, 2000, characterize chemical carcinogens
according to mutational signatures, 2011). These papers have been so (Kleinstreuer et al., 2013).
or agents categorized in relation to influential that others refer to “the These considerations give rise to
differing classes of receptors. There hallmarks” without further qualifica- two questions: (i) whether previous-
have been many proposals for the tion, for example in the title of a re- ly used mechanism-based descrip-
categorization of chemical carcin- cent perspective on tumour metabol- tions of chemical carcinogens may
ogens according to various crite- ism (Cantor and Sabatini, 2012). be recast in relation to the hallmarks;
ria. A selection of these is shown Since 2000, about 200 cancer re- and (ii) whether, and to what extent,
in Table 11.1; others include the search papers with a title including the hallmarks provide opportunities
94
to characterize agents apart from Morphological and genetic biological macromolecules had been
currently known carcinogens as changes variously demonstrated over dec-
contributing to the development of ades, carcinogen adducts in DNA
cancer. Both of these matters are Within 20 years of the publica- were crucial.
addressed in this chapter. tions cited above, the identification Alkylation of DNA by N-nitroso
of multistage carcinogenesis with compounds was shown by Magee
Multistage carcinogenesis particular carcinogens or other exog- and Farber (1962), with tumorigene-
enous agents had become irrelevant sis attributable to the pro-mutagenic
Exogenous agents
to an understanding of cancer de- O6 -methylguanine product, which
The widely accepted paradigm of velopment. Over the same decades, mispairs with thymine. In rats, acti-
carcinogenesis as involving a mul- the context in which carcinogenesis vation of H-Ras in mammary gland
tistage process is generally recog- was best understood changed from tumours induced by N-methyl-N′-
nized to have been developed from rodents to humans. Critical to this nitrosourea was correlated with
the two-stage model of carcino- transition was the identification of H-Ras mutation at codons 12, 13,
genesis in mouse skin (Berenblum multistage carcinogenesis with alter- and 61 (Sukumar et al., 1983).
CHAPTER 11
and Shubik, 1947), which typically ations in gene structure or expres- However, although this insight had
PART 2
involves a polycyclic aromatic hydro- sion rather than with the impact of been gained, it was clear that the eti-
carbon (PAH) and a phorbol ester exogenous agents. ology of some types of cancer, such
(identified as the active agent in the A key development was the as breast cancer in humans, did not
irritant croton oil). Because tumor- correlation by Vogelstein et al. (1988) primarily involve alkylating agents.
igenesis in animals is amenable to of morphological change during the Thus, in human cancer RAS activa-
histological examination at all stag- development of colon cancer in hu- tion is a relevant genetic change in
es, morphological criteria can be mans with particular genetic change. tumour tissue, without reference to
used to characterize the process. The concept was applicable to all exogenous agents (Bos et al., 1987).
With the production of malignant tu- tumour types. Thus, in a diagram il- Although the concept of multi-
mours as the end-point, two-stage or lustrating multistage carcinogenesis stage carcinogenesis was estab-
multistage carcinogenesis was read- with respect to human lung cancer, lished through the use of exogenous
ily described in various organ sites in Harris (1992) made no reference to agents that target particular organ
animals, including the liver and the any particular exogenous agents as sites in animals, by 1990 multistage
bladder (Slaga et al., 1978). mediating specific stages in tumori- carcinogenesis was primarily iden-
Thus, in relation to hepatocarcino- genesis, and showed the transitions tified with altered structure or ex-
genesis, agents such as phenobarbi- between stages as being mediated pression of genes associated with
tal, dichlorodiphenyltrichloroethane, by alterations in the structure or ex- cell proliferation, specifically as de-
polychlorinated biphenyls, butylated pression of oncogenes and tumour scribed in human tumours. However,
hydroxytoluene, and estradiol ben- suppressor genes. the focus of that research has not
zoate were identified as promoters Oncogenes and tumour suppres- involved the specification of genetic
(Dohi et al., 1996). The relevant sor genes mediate altered prolifera- change over time in a manner that
experimental observations, in addi- tive activity in a positive and nega- might account for the emergence of a
tion to indicating the possible risk to tive sense, respectively. Classically, metastatic cell population from with-
humans presented by the relevant increased proliferative activity due in normal tissue. Rather, the relevant
chemicals, also led to the contempo- to oncogene expression accounted research has involved the identifica-
rary understanding of the nature of for the transformation of NIH 3T3 tion of disordered signal transduction
malignancy itself. That understand- cells by DNA isolated from tumours pathways, with a view to developing
ing was based on the identification of and not by DNA from normal tissue targeted therapies. The archetype
particular abnormal cell populations, (Shih et al., 1981). Oncogene ac- of such research is that establish-
specifically including chemically in- tivation (e.g. mutation of Ras) has ing the transforming role of the ty-
duced hyperplastic nodules in rat liv- shown that although binding of many rosine kinase BCR-ABL in chronic
er (Farber, 1973). chemical carcinogens to diverse myeloid leukaemia, and its inhibition
Part 2 • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks 95
– to the great benefit of patients – by emerge early, whereas others – sus- • enabling replicative immortality;
the low-molecular-weight inhibitor tained angiogenesis, and tissue inva- and
STI-571 (imatinib) (Bilanges and sion and metastasis – are seen later. • activating invasion and metastasis.
Stokoe, 2007; Rosa et al., 2008). Although hallmarks such as sus- It is notable that, in almost every
tained angiogenesis and metasta- instance, the hallmark is not the
Molecular changes sis involve morphological change, name of a phenotype but refers to
Among a series of reviews marking all of the hallmarks were identified a dynamic process. Consistent with
the publication of the 100th volume with reference to changes in gene this perception, the authors wrote,
of the journal Cell, Hanahan and expression and not by reference to, “The hallmarks of cancer comprise
Weinberg (2000) delineated the very or necessarily in correlation with, six biological capabilities acquired
wide (even then) spectrum of stud- a change in morphology. Diversity during the multistep development
ies addressing the genetics of can- between tumour types and within a of human tumours. The hallmarks
cer by reference to phenotype. Six given tumour type was noted, and no constitute an organizing principle for
characteristics of how cancer cells reference was made to any particu- rationalizing the complexities of neo-
behave could be identified in rela- lar type of neoplasm for illustrative plastic disease.”
tion to particular genes or classes of purposes. In addition, a decade of progress
genes. The phenotypic characteris- In such a description of the mani- had enabled the specification of two
tics were: uncontrolled proliferative festation of essential alterations that “emerging hallmarks”:
activity (Hall, 1984), tumour growth
collectively characterize malignant • deregulating cellular energetics;
attributable to familial risk (Hussain
growth, there is no requirement to and
and Harris, 1998), survival of can-
identify exogenous agents as act- • evading immune destruction.
cer cells (Vaux et al., 1988), immor-
ing on normal or premalignant cells The enabling characteristic iden-
talization of cancer cells (Sedivy,
to cause the change. The focus is tified in 2000 as “genomic instabili-
1998), growth of blood vessels in
tumours (angiogenesis) (Cavallaro on the nature of tumours and how ty” was described in 2011 as “geno
and Christofori, 2000), and metastat- they may be distinguished from rele- mic instability and mutation”, and a
ic growth (Webb and Vande Woude, vant normal tissue. Finally, Hanahan second enabling characteristic was
2000). Accordingly, the hallmarks and Weinberg (2000) identified an identified as “tumour-promoting
of cancer were initially identified as enabling characteristic: genomic inflammation”. Superficially, such
follows: instability, which is equated with in- reference to mutation and to pro-
• self-sufficiency in growth signals; creased mutability evident during motion might be seen as implying, if
• insensitivity to anti-growth signals; the process of tumour progression not specifying, the roles that DNA-
(Loeb, 1994). damaging and proliferation-induc-
• evasion of apoptosis;
ing agents have in carcinogenesis.
• sustained angiogenesis; A decade on: “the next However, this is not the case.
• limitless replicative potential; and generation”
In this context, “mutation” refers
• tissue invasion and metastasis. to an acceleration of the accumu-
In 2011, Hanahan and Weinberg
The 2000 “hallmarks” review was lation of mutations, due to, among
provided a new assessment of the
concerned primarily with the charac- other things, defects in the DNA
hallmarks (Hanahan and Weinberg,
terization of the genes and associat- maintenance machinery (Kinzler
2011). They commented, “The past
ed signal transduction pathways that and Vogelstein, 1997). As a result,
decade has witnessed remarkable mutation occurs more readily, ir-
mediate these respective activities
in malignant cells and tumours. In progress towards understanding the respective of whether it is mediat-
that paper, hypothetical patterns of mechanistic underpinnings of each ed by exogenous or endogenous
multistage carcinogenesis were illus- hallmark.” One indication of progress agents. Accordingly, DNA adducts,
trated by a linear arrangement of the is that the original hallmarks were strand breakage, and related phe-
pictograms for the hallmarks, without rebadged as follows: nomena are not to be identified with
reference to any morphological crite- • sustaining proliferative signalling; this enabling characteristic and do
ria. From that diagram, it can be in- • evading growth suppressors; not account for, or are not proper-
ferred that some hallmarks – such as • resisting cell death; ly identified with, a particular hall-
self-sufficiency in growth signals – • inducing angiogenesis; mark. Mutation, in the context of
96
carcinogenesis, identifies a mecha- “genotoxic” indicated, among other include bacterial, mammalian, and
nism whereby a chemical carcinogen things, that the covalent binding of other cells, with weight being given
may cause the emergence of any of a carcinogen adduct to DNA, when to the extent to which the test system
the hallmarks, and almost certainly evident, might account for carcino- has been “validated”, as summa-
of several of them, or perhaps of all genesis. Thus, Weisburger and rized by sensitivity and specificity in
of them. The enabling characteristic Williams (1981) categorized carcin- relation to known carcinogens and
“genomic instability and mutation” ogens primarily on the basis of ge- non-carcinogens. In vivo indicators
renders such outcomes more likely notoxicity. Research over the sub- of genotoxicity include, among oth-
(Wang et al., 2012), rather than refer- sequent 30 years did not alter that ers, (i) metabolism of a chemical to
ring to the mechanism through which approach (Hsu and Stedeford, 2010). produce reactive, typically electro-
the change occurs. The multiplicity of agents and the philic, intermediates, which are the
The identification of “tumour-pro- relatively limited understanding of source of adducts bound to DNA and
moting inflammation” as the second their respective mechanisms of ac- other macromolecules, and (ii) ev-
enabling characteristic recognizes tion have precluded the adoption of a idence of subsequent DNA repair
that inflammation causes the emer- scheme for categorizing carcinogens
and/or mutation.
gence of several of the hallmarks, beyond the consideration of geno-
CHAPTER 11
This description of indicators of
including sustaining proliferative sig- toxicity. Arguably, until the present
PART 2
genotoxicity also summarizes the
nalling and inducing angiogenesis. In IARC Scientific Publication, the most
their discussion of this enabling char- relevant mechanism of chemical
authoritative assessment on how
acteristic, Hanahan and Weinberg carcinogenesis as currently under-
carcinogens act was the 35-page
(2011) were concerned primarily with stood (Cohen and Arnold, 2011).
consensus report in the publica-
cellular infiltration by cells of both Thus, carcinogen metabolism and
tion Mechanisms of Carcinogenesis
the innate and the adaptive arms of DNA repair processes have been
in Risk Identification (Vainio et al.,
the immune response. They made used to identify candidate genes
1992); this was the agreed position
scant, if any, reference to exogenous for lung cancer susceptibility stud-
of a Working Group of more than 40
agents provoking an inflammatory ies (Yokota et al., 2010). Compared
scientists in 1991. The consensus re-
response. with the relatively modest number of
port did not centre on a scheme for
From a broad perspective, refer- genes that account for the absorp-
classifying carcinogens according to
ence to the multistep development tion, metabolism, and elimination of a
their mechanism of action.
of human tumours provides a way carcinogen, together with the repair
Across decades, commentaries
to consider the particular impact of of corresponding DNA adducts, the
on chemical carcinogens (Van
carcinogens and other exogenous hallmarks (Hanahan and Weinberg,
Duuren, 1980; Pitot, 1990; Xue and
agents that may contribute to can- 2011) enable the specification of
Warshawsky, 2006; Cohen and
cer development. However, in iden- tens – if not hundreds – of genes
Arnold, 2011) have not been based
tifying the hallmarks, Hanahan and whose expression contributes to the
on any generally agreed categori-
Weinberg did not pursue this matter.
zation according to mechanism of malignant phenotype.
action. Rather, the common theme At the single-gene level, mutation
Identifying mechanisms of
carcinogenesis has been the enumeration of bio- of TP53, specified with reference to
logical parameters that may deter- particular transitions and transver-
As mentioned above, chemical car- mine whether tumours develop in sions, is attributable to miscoding,
cinogens have been categorized response to carcinogens in general. which in turn is a consequence of
primarily with reference to whether DNA adduct formation from rele-
Genotoxicity: progress and
they exhibit genotoxicity. This mech- vant carcinogens, including those in
problems
anistic distinction began with many tobacco smoke (Soussi, 2011). The
then-known carcinogens being iden- Multiple indicators of genotoxicity data provide evidence of particular
tified as mutagens in vitro by use of have been recognized and catego- exposures, but it remains unclear
particular bacterial strains and after rized as involving data generated how tumorigenesis is enhanced
metabolic activation (the Ames test) either in vitro or in vivo (Montesano by such mutation, beyond the
(McCann et al., 1975). The term et al., 1976). In vitro test systems consideration that a functional p53
Part 2 • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks 97
Table 11.2. Chemicals cited by Ashby (1992) and Eastmond (2012) as examples of compounds with equivocal
genotoxicity
3-Amino-4-ethoxyacetanilide Bromate
3-Amino-9-ethylcarbazole.HCl Captan
1,2-Dibromo-3-chloropropane 1,3-Dichloro-2-propanol
di-Menthol 1,4-Dioxane
5-Nitroacenaphthene Hydroquinone
4-Nitro-o-phenylenediamine 2-Nitrotoluene
1,2-Propylene
Sulfallate
protein induces apoptosis, cell-cy- 10 times that in lung tumours from not evident from genomic analysis
cle arrest, and senescence, and never-smokers (Govindan et al., (Muzny et al., 2012). In short, the role
that these processes are compro- 2012). of mutation as contributing to cancer
mised after TP53 mutation (Bieging However, analysis of lung cancer development may be elucidated with-
and Attardi, 2012). The hallmarks genomics does not require immedi- out reference to any genotoxic agent,
offer a broadened perspective as ate reference to smokers and nev- even when the role of such an agent
to signalling pathways that may be er-smokers to present relevant data has been otherwise established.
affected by mutation of TP53 or any (Liu et al., 2012; Peifer et al., 2012). Distinguishing genotoxic
tumour suppressor gene. Moreover, the recognition of tobac- from non-genotoxic
In the first such determination co-induced genomic injury does not carcinogens
made, genotoxic injury by tobac- necessarily extend to other sites; for
Even though molecular process-
co smoke in one individual case of example, on the basis of individual
es associated with genotoxicity are
lung cancer accounted for 22 910 genomic analysis, it is not possible
being defined in steadily greater
somatic base substitutions, of which to differentiate between cases of
detail, it is not always possible to
134 were in coding sequences pancreatic cancer in smokers and in immediately discriminate between
(Pleasance et al., 2010). The role never-smokers (Wei et al., 2012). individual chemicals on the basis
of tobacco smoke as a determinant More generally, although mutation of whether particular substances
of the genomic landscape of lung of TP53 is highly relevant to colorec- should be categorized as genotox-
cancer has been confirmed, with an tal cancer, the impact of exogenous ic. Difficulties are evident when rel-
average mutation frequency in lung influences or causal factors on the evant chemicals are considered on
tumours from smokers of more than development of this tumour type is a case-by-case basis. More than
98
Table 11.3. Examples of categories of non-genotoxic carcinogens as variously proposed over more than three
decadesa
Weisburger and Weisburger (1989) Marquardt (1999) Hernández et al. Benigni et al. (2013)
Williams (1981) (2009)
CHAPTER 11
hypolipidaemic proliferators and inflammation
carcinogens inducers
PART 2
Phthalate ester Solid bodies or Cytotoxic agents and Hormonal imbalance
plasticizers particles immunosuppressants inducers
Gap-junction inhibitors
a Typically, the listings have been provided by the respective authors for illustrative purposes, without necessarily specifying an intent
to be comprehensive.
20 years ago, Ashby (1992) reported • the agent’s metabolism and Non-genotoxicity: multiple
on “practical examples of instances toxicokinetics; mechanisms and pathways
in which the term genotoxic is both • structural similarities to recognized
Regardless of any difficulty with par-
needed and capable of having differ- mutagenic carcinogens;
ent meanings”. Two decades later, ticular agents as discussed in the
• the origin of or mechanisms under-
Eastmond (2012) provided insight by previous section, the conceptual ba-
lying the observed effects; and
summarizing data for another set of sis of genotoxicity is unequivocally
• in vivo data, particularly in the
chemicals, different from those dis- focused on a particular pathway to
target organ.
cussed by Ashby (Table 11.2). malignant transformation. No such
Eastmond (2012) illustrated each
Hence, there are some chemicals single focus is available for non-
of these points with two or more
that are not readily categorized in re- genotoxic carcinogens, as illustrat-
examples.
lation to genotoxicity because, for ex- ed by the designation “epigenetic”,
Specifying genotoxicity is com- which, although previously applied
ample, they produce positive results
plex, as becomes evident when to these agents (Weisburger and
when assessed by use of in vitro
all available mechanistic data are Williams, 1981; Benigni et al., 2013),
genotoxicity tests but after their ad-
identified, as occurs, for example, can no longer be unequivocally used
ministration to intact animals, they do
in IARC Monographs evaluations. In in this context.
not cause structural DNA damage or
other manifestations of genotoxicity. some instances, the totality of avail- Epigenetic processes are relevant
As described by Eastmond (2012), able mechanistic data may indicate to both genotoxic and non-genotoxic
apparently contradictory findings that the categorization of a carcino- agents (Pogribny et al., 2008), and
can be reconciled when, for differ- gen as genotoxic is equivocal. There epigenetic change may be deter-
ent individual chemicals, account is does not appear to be a context in mined by mutation (You and Jones,
taken of: which awareness of the hallmarks 2012). From a different perspective,
• the chemical properties of the would provide an improved basis for when discussing non-genotoxic car-
agent, its metabolites, and/or its identifying genotoxic carcinogens cinogens, Meza et al. (2010) iden-
degradation products; specifically. tified tobacco smoke and radon in
Part 2 • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks 99
this context. Despite such ambigu- of cell differentiation and cycling, equally recognized (Schetter et al.,
ity, 45 non-genotoxic carcinogens hormonal and nutritional homeosta- 2010). Cell proliferation in this con-
were recognized in 2009 among sis, coordination of cellular stress text does not pertain to proliferation
371 agents classified by IARC in responses (including inflammation after toxic injury by genotoxic agents.
Group 1, Group 2A (probably carci- and apoptosis), immune responses, Proliferative activity induced by ge-
nogenic to humans), and Group 2B and ageing. Therefore, it is difficult nomic injury may be considered in
(possibly carcinogenic to humans) to identify AhR-mediated processes relation to the pluripotent stem cells
(Hernández et al., 2009). with a specific hallmark. (Cohen and Arnold, 2011), further in-
Grouping agents on the basis of a The adoption of a mechanistic ap- dicating how a characteristic – such
default criterion – i.e. that the agent proach to categorize non-genotoxic as the hallmark “sustaining prolifer-
is not genotoxic – implies uncertain- carcinogens leads to incongruities ative signalling” – cannot readily be
ty. The scope of uncertainty can be if definitive and exclusive specifica- assigned or restricted to a particular
seen from differences between re- tions are sought. Thus, TCDD may category of carcinogens.
ports indicating categories of agents be readily identified as a promoter
that are reasonably considered (Ray and Swanson, 2009) while also Public health decision-
to be non-genotoxic carcinogens; being recognized as a complete car- making: the definitive
Table 11.3 shows selected examples cinogen on the basis of bioassay and consideration
from 1981 to 2013. epidemiological data (Baan et al.,
Parameters used to identify 2009). Similarly, although PAHs can This IARC Scientific Publication is
non-genotoxic carcinogens include be identified with the genotoxicity of, based on evaluations made in Volume
either the nature of the agent or for example, tobacco smoke, Puga 100 of the IARC Monographs. Two
some indicator of a putative mecha- et al. (2009) noted that exposure to broad issues are addressed: (i) the
nism of action. The terminology is far toxic PAHs raises several toxic and extent to which the occurrence and
from definitive. Thus, while the term carcinogenic responses in experi- anatomical site of agent-attributable
“promoter” may be used to identify a mental animals and humans, medi- cancer in humans may be correlat-
non-carcinogen that contributes to ated for the most part by AhR. Such ed with the occurrence and, where
tumour development, tumour promo- apparent paradoxes indicate that relevant, organ site of tumours in
tion may be identified with the action although mechanistic categorization animals treated with the same agent;
of many non-genotoxic carcinogens of many genotoxic carcinogens is and (ii) whether known mechanisms
(Schulte-Hermann et al., 1999). definitive and exclusive, the same of action of the carcinogenic agents
in question, considered together
The role of receptors has long process applied to non-genotoxic
with current knowledge of cancer
been recognized as key to the car- agents may lead to outcomes de-
etiology, reveal options for catego-
cinogenicity of many non-genotoxic termined by context. The relevant
rizing carcinogens, so as to better
agents (Lucier, 1992) and under- agents cannot be identified with a
indicate the risk posed to humans by
pins current commentaries (Klaunig, single path to malignancy.
exposure.
2010). Relevant receptors include The role of cell proliferation in re-
These two considerations are inti-
the aryl hydrocarbon receptor (AhR), lation to non-genotoxic agents also
mately related. Thus, the occurrence
the peroxisome proliferator-activated depends on the context (Preston-
or absence of tumours in rodents
receptor (PPAR), and various hor- Martin et al., 1990; Marquardt,
treated with particular agents may
mone receptors. 1999). With respect to chemicals, the
be wholly dependent on biological
Arguably, AhR is recognized original focus was on mitogens, in- mechanisms operating, or not oper-
mainly as mediating the carcino- cluding peroxisome-proliferating car- ating, in particular species. Until now,
genicity of 2,3,7,8-tetrachlorodiben- cinogens (Butterworth et al., 1992). mechanistic assessment of carcino-
zo-para-dioxin (TCDD). However, This approach now identifies inflam- gens has not established a compre-
as specified by Matsumura et al. mation as contributing to cancer de- hensive basis for determining wheth-
(2009), apart from mediating toxic velopment, and auto-inflammatory er particular agents are capable of
effects of some pollutants, AhR is disease and the impact of various causing cancer in humans. This situ-
involved in development, regulation cancer-causing infectious agents are ation confirms that evaluations of the
100
IARC Monographs are appropriate available data are ordered according correlates with the enabling charac-
for hazard identification, as distinct to these end-points, it is evident that teristic “genomic instability and mu-
from any simple categorization of for many agents, simple categoriza- tation”. The end-points “alterations in
relevant agents. The fact that agents tion according to a single mechanism telomere length” and “immortaliza-
may be classified into Groups does is not possible or appropriate. tion” address the hallmark “enabling
not alter the need to make evalua- An important consideration is the replicative immortality”.
tions on a case-by-case basis. discrepancy between the extents It would appear that the hallmark
The determination of whether a “evading growth suppressors” cor-
to which end-points have been as-
chemical induces cancer through
sessed. DNA damage and gene responds to end-points identified by
a genotoxic mechanism frequently
mutations have been studied most cell-cycle effects taken together with
plays an important role in evaluating
extensively, and agents for which a subset within the end-point “gene
the risks associated with low expo-
there is unequivocal evidence of ge- mutations”: the subset of mutation of
sures (Eastmond, 2012). For low
notoxicity across in vitro and in vivo tumour suppressor genes as distin-
levels of exposure to non-genotoxic
systems have rarely been studied in guished from mutation of oncogenes
carcinogens, there is expected to
relation to, for example, epigenetic or other genes. The default position
be a dose–response threshold for
CHAPTER 11
the carcinogenic effects; this does alterations. Epigenetic alterations would then be to identify “sustaining
PART 2
not apply to genotoxic carcinogens have been described for estrogenic proliferative signalling” – arguably
(Klaunig, 2010). Low-dose models of hormones (Imamura, 2011), arse- the premier hallmark – with the re-
liver cancer induction in fish by geno nic (Jensen et al., 2008), and nickel maining end-points. However, ref-
toxic carcinogens indicate further (Costa et al., 2005), although each erence to those end-points leads to
levels of complexity (Williams, 2012), of these agents had also been char- the recognition that end-points such
and ongoing controversy about acterized as causing DNA damage. as “epigenetic alterations” are the
non-monotonic responses means Evidence of immunosuppression means through which many, if not all,
that such issues remain pertinent may have been considered as a sin- of the hallmarks may emerge.
(Fagin, 2012). Mechanisms that un- gular mechanism of carcinogenesis, Finally, “deregulating cellular en-
derpin, for example, dose–response but while azathioprine can be char- ergetics” remains as the hallmark
curves may become amenable to ge- acterized as immunosuppressive, not addressed through the char-
nomic and related analyses. acteristics identified, because this
this agent also causes DNA damage.
Having been adopted as de- parameter has not been recognized
Systematic appraisal
scribed, the 10 key characteristics in systematic efforts to character-
of mechanisms of
warrant review with reference to the ize mechanisms of carcinogenesis.
carcinogenesis
hallmarks as cataloguing a broad Overall, no particular insight ap-
Information about mechanisms of biological basis for malignancy pears to be gained by attempting to
carcinogenesis for the Group 1 (Hanahan and Weinberg, 2011). One relate the 10 key characteristics with
agents in the IARC Monographs hallmark, “activating invasion and specific hallmarks.
is summarized in this Scientific metastasis”, is not recognized as a
Tobacco smoke, cancer of the
Publication with initial reference to mechanistic end-point because few,
lung, and the hallmarks
24 mechanistic end-points, which if any, agents are identified primarily
were then merged into 10 key with metastatic growth, given that no Generalizing across tumour types,
characteristics (see Chapter 10, by such hazard needs to be established genomic and comparable analyses
Smith). These end-points – which over and above carcinogenicity. are concerned little, if at all, with ex-
include DNA damage, changes in Some hallmarks are singularly iden- ogenous agents that mediate malig-
gene expression, receptor-mediated tified as mechanistic end-points or nant transformation. Paradoxically,
effects, and inhibition of gap junc- enabling characteristics, i.e. those the first tumour genome document-
tional intercellular communication – corresponding to chronic inflam- ed was described with a total focus
have been adopted on the basis of mation, immune effects, cell death, on mutations attributable to tobac-
their wide use to investigate mech- and angiogenic effects. Arguably, co smoke (Pleasance et al., 2010).
anisms of carcinogenesis. Once the the end-point “DNA repair alteration” Although genomic analysis revealed
Part 2 • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks 101
Fig. 11.1. Hallmarks of lung adenocarcinoma. Left: The prevalence of mutation or somatic copy number alterations
of genes mapping to cancer hallmarks defined by Hanahan and Weinberg (2011) based on tumour specimens
from a cohort of 183 patients of whom more than 85% had a history of smoking. Top right: Genes comprising
the mutated genes in the hallmark “sustaining proliferative signalling” are shown. Bottom right: A proposed new
hallmark of “epigenetic or RNA deregulation” is shown, depicted as above. Genes shown in grey are candidate
lung adenocarcinoma genes identified in the study of Imielinski et al. (2012) that may additionally contribute to the
hallmark. Reprinted from Imielinski et al. (2012), copyright 2012, with permission from Elsevier.
102
an average mutation frequency in Possible inferences from oncogene activation was achieved
lung tumours from smokers of more hallmark-based studies by genetic manipulation or after ex-
than 10 times that in lung tumours posure to an alkylating N-nitroso
from never-smokers (Govindan et al., Any malignancy is expected to ex- compound (Westcott et al., 2015).
2012), the genomic pattern of squa- hibit the hallmarks, whether it arises Hence, genomic analysis may reveal
mous cell lung cancer, established spontaneously or upon exposure to a distinct patterns of tumour-associ-
from 178 patients of whom 96% had carcinogen. Insight into mechanisms ated changes that are dependent
of carcinogenesis is gained by the on etiology and relevant to the full
a history of smoking, was presented
demonstration of biological change, scope of tumour-associated signal
with no overt reference to tobacco
which may be aligned with a hallmark transduction as identified by the
use (Hammerman et al., 2012).
(He et al., 2014). The public health hallmarks.
The genomic profile of lung ade-
implications of such a discovery may Apart from any mechanistic cate-
nocarcinoma, involving a cohort of
apply to agents not recognized as gorization of carcinogens in relation
patients of whom more than 85%
carcinogenic but shown to be pro- to particular hallmarks, the hallmarks
had a history of smoking, was pre-
moters and/or inducers of inflamma- do provide a basis for innovation.
sented with reference to the hall- tion or angiogenesis. Nicotine is an Genes identified from the perspec-
marks, documenting the prevalence
CHAPTER 11
example of such an agent (Cardinale tive of each hallmark provide a ba-
PART 2
of the enabling characteristic “geno- et al., 2012; Schaal and Chellappan,
sis on which to analyse both known
mic instability and mutation” in 25 ad- 2014). In addition to its contribution
carcinogens and agents of unknown
enoma genes adopted as indicators to a better understanding of tobacco
status in that regard. An indication
(Imielinski et al., 2012). The findings smoke carcinogenesis, this informa-
of agents worthy of attention may
were not presented with reference tion about the properties of nicotine
well be achieved by adding hall-
to smoking status but indicated is relevant to appropriate regulation
mark-related targets in the context of
markedly different fractions of mu- of electronic cigarettes (also known
high-throughput screening assays,
tation (Fig. 11.1), including 42% with as electronic nicotine delivery sys-
as described by Kavlock and col-
respect to “genomic instability and tems) (Dutra and Glantz, 2014).
leagues (Kleinstreuer et al., 2013).
mutation”. This result indicates the Nicotine may contribute to cancer
The outcome may be the recognition
requirement to distinguish between development, for example by stimu-
of new classes of toxins that contrib-
gene mutation being relevant to eti- lating angiogenesis, in a manner not
ute to increased risk of cancer.
ology, whether or not it is caused by likely to result in the compound being
an exogenous agent, and frequency designated a carcinogen.
Summary
of mutation being an indicator of ge- During the past 50 years, the
nomic instability and thus a charac- understanding and use of the term Cancer was once described with ref-
“carcinogenesis” has changed from erence to causative agents, and mul-
teristic of malignancy. Also of note,
that involving a necessary reference tistage development of tumours was
only 6% of tumours had alterations
to one or more exogenous carcin- characterized through the impact of
assigned to all six original hallmarks.
ogens to that involving intracellu- particular chemicals. Subsequently,
Mutation of genes that mediate
lar processes leading to malignant multistage development of cancer
particular hallmarks and are at-
transformation, with no necessary was identified with morphological
tributable to, among other agents,
or implied reference to exogenous change being correlated with altered
N-nitroso derivatives of nicotine and
agents. This understanding has genetic makeup. The more recent
related compounds, and PAHs, is to description of eight hallmarks of ma-
recently included the description of
be expected. However, beyond lung random mutations arising from DNA lignancy is based not on morpholo-
cancer, there are only few references replication in normal non-cancerous gy or on the impact of carcinogens
to genomic analyses that enable indi- stem cells as accounting for sporadic but on changes in gene expression,
vidual tumours attributable to smok- disease (Tomasetti and Vogelstein, sometimes mediated by mutation,
ing to be distinguished from others. 2015). However, another recent and on selection for growth.
Thus, genomic analysis did not re- development is the identification In parallel to this evolution of our
veal likely tobacco causation for par- of different mutational landscapes understanding of cancer, no gener-
ticular pancreatic cancers (Biankin between classes of K-ras-driven ally recognized mechanism-based
et al., 2012). tumours, depending on whether scheme for classifying carcinogens
Part 2 • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks 103
has evolved beyond categorization variously resulting in emergence signal transduction pathways as-
of chemical carcinogens accord- of the hallmarks, with the relevant sociated with particular hallmarks
ing to genotoxicity. When appropri- processes being facilitated by ge- may provide new understanding of
ately studied, both genotoxic and nomic instability and inflammation. agent-related carcinogenesis.
non-genotoxic agents may medi- Enhancing –omics-based screening
ate genetic and epigenetic change, procedures to specifically include
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106
part 2.
mechanisms of carcinogenesis
chapter 12.
CHAPTER 12
PART 2
The process of mutagenesis be called DNA-damaging agents. of a molecule between a pair of
Instead, it is the cell that produces bases. Again, DNA damage is itself
The process of agent-induced mu- the mutation – either through faulty not a mutation and generally does
tagenesis consists of three parts: the DNA repair of the mutagen-induced not alter the linear sequence of nu-
induction of DNA damage, the sen- or spontaneous DNA damage, or cleotides. A mutation is defined as a
sing of the DNA damage by the cell by replicating past the unrepaired change in the sequence or number
(the DNA damage response), and DNA damage, thereby introducing a of nucleotides in the DNA.
the processing of the DNA damage replication error (Shaughnessy and When DNA damage occurs, the
by the cell, which may or may not DeMarini, 2009). cell detects it by means of the DNA
result in a mutation. A key under- A description of the process of damage response system and de-
lying concept is that mutagenesis is mutagenesis begins with the induc- termines how it will be processed;
a cellular process, frequently invol- tion of DNA damage by an endoge- the DNA damage response includes
ving DNA replication. Another key nous or exogenous event. Examples DNA repair and apoptosis path-
concept is that there is a distinct dif- of DNA damage are DNA adducts ways, which are described in detail
ference between DNA damage and (i.e. a molecule bound covalently to by Ciccia and Elledge (2010). The
mutation. Thus, mutagens, despite DNA) and single- or double-strand DNA damage response can mediate
what their name suggests, generally breaks (i.e. breakage of the phos- the repair of the damage, attempt to
do not produce mutations; instead, phodiester backbone). Other types repair the damage but instead pro-
mutagens produce DNA damage, of DNA damage are oxidized or frag- cess it into a mutation, or direct the
and they might more appropriately mented bases and the intercalation cell to undergo apoptosis. Another
108
after mammalian metabolism was Indeed, a comprehensive analysis present at high frequencies in tu-
provided by Legator and Malling showed that more than 90% of the mours, DNA sequencing methods
(1971) with the host-mediated assay. IARC Group 1 chemical carcinogens were introduced in 1977 (Pettersson
Ames et al. (1972) introduced the are genotoxic (Waters et al., 1999). et al., 2009), which provided the tech-
use of the plate incorporation assay The current genetic toxicity test nical means to directly determine the
in Salmonella and demonstrated that battery is based on this relationship presence and types of mutations in
DNA-reactive metabolites of known between mutagenesis and carcino- any gene or chromosome.
carcinogens were direct-acting mu- genesis. Consequently, mutagenic- DNA sequencing of mutations
tagens. The connection between ity assays continue to be used as induced in selected genes by a lim-
mutagenesis and carcinogenesis a potential screen for carcinogens, ited number of mutagenic carcino-
was extended when Ames et al. and the results are used for regula- gens in microbes in the 1980s and in
(1973) combined a rat liver homoge- tory purposes throughout the world mammalian cells and tumours in the
nate centrifuged at 9000g (S9 frac- (Eastmond et al., 2009). For exam- 1990s began to show that any par-
tion) plus cofactors prepared as de- ple, a positive result in the Salmonella ticular mutagen produced an array
scribed by Garner et al. (1972) with mutagenicity assay indicates a 70% of mutations and that these varied
Salmonella and a variety of rodent among the genes and cells exam-
CHAPTER 12
probability that the test chemical is
PART 2
carcinogens then considered to be a rodent carcinogen (Zeiger, 1998). ined. A variety of mutagens produce
non-mutagenic in the plate incorpo- When a randomly selected set of similar mutation spectra, and the
ration assay and showed that these 100 organic compounds was tested predominant base substitution that
carcinogens were, in fact, muta- in the Salmonella mutagenicity as- an agent induces in one system
genic. Additional refinements of the say, about 20% of them were posi- is generally the same one that the
Salmonella tester strains and the tive (Zeiger and Margolin, 2000). agent produces predominantly in all
conduct of multiple testing studies, Thus, out of an estimated 80 000 other systems across the phyloge-
involving not only Salmonella but such compounds in commercial use, netic scale, from bacteria to humans
also other test systems (Tennant 16 000 (20%) may be positive for (DeMarini, 1998, 2000). Thus, in
et al., 1987), resulted in the current mutagenicity in the Salmonella mu- terms of the predominant base sub-
recognition that many carcinogens, tagenicity assay, and 11 200 (70%) stitution produced by agents, there is
by themselves or after metabolic of those may be potential rodent concordance across species in that
activation, are mutagens, and that carcinogens. the DNA damage induced by a par-
mutagenesis is a critical feature of ticular agent is processed similarly
carcinogenesis. Mutations in tumours by a wide range of species.
Despite the recognized impor- With regard to mutations in tu-
tance of mutagenicity as a part of Soon after the discovery of the mours, generally elucidated without
cancer induction and progression, by correct number of human chromo- reference to any exogenous caus-
the 1990s it appeared that many ro- somes (46) by Tjio and Levan in ative agent, the technology in use
dent and human carcinogens were, 1956 (Gartler, 2006; Harper, 2006), from the 1980s until the early 2000s
in fact, not clearly mutagenic or ge- cytogenetic studies began to show permitted the determination of mu-
notoxic. Some operate through re- that tumours (specifically leukaemic tations in only a few cancer-related
ceptor binding, which can result in an cells) had higher frequencies of chro- genes, such as TP53 and KRAS.
alteration in gene expression, often mosomal aberrations than did nor- The first gene mutation in a human
leading to increased cell replication. mal cells (Nowell and Hungerford, tumour was determined in 1982
However, an analysis of a set of so- 1960). A decade later, the develop- (Reddy et al., 1982), and by the end
called non-genotoxic carcinogens ment of quinacrine fluorescence and of the 20th century, there was clear
found that most of them were, in fact, Giemsa staining enabled the first evidence that some tumours had
genotoxic (inducing DNA damage discovery that a specific chromoso- mutations in certain oncogenes and
and/or mutation) when tested ade- mal aberration was associated with tumour suppressor genes that could
quately for both gene, chromosomal, a specific type of leukaemia (Rowley, be associated with the types of mu-
or genomic (aneuploidy) damage 1973). As evidence accumulated tations produced by the carcinogen
and mutation (Jackson et al., 1993). that chromosomal aberrations were associated with the induction of the
110
normal human skin contains a epigenetic changes per se are not disease and (ii) an agent that causes
patchwork of thousands of evolving mutations because the sequence of cancer induces alterations in gene
clones, with more than one quarter nucleotides has not been changed, function (by mutation) and/or gene
of such cells having cancer-causing as evidenced above, mutation may expression (by epigenetic changes),
mutations. be the basis for some epigenetic either by direct interaction with DNA
Although there is now also over- events. or chromatin or by indirect mecha-
whelming evidence for the essential nisms, such as through generation
role of epigenetic changes in the car- Models of agent-induced of reactive oxygen species, inflam-
cinogenic process (Grønbaek et al., carcinogenesis mation, and/or receptor-mediated
2007; Baylin and Jones, 2011) and interactions. These considerations
Data generated in recent years have
for the fact that many carcinogens suggest that carcinogens must be ge-
led to a reconsideration of the dichot-
can induce such changes (Ceccaroli notoxic in the broadest sense of the
et al., 2015; Nicolaidou and Koufaris, omy between so-called non-geno- term, i.e. they damage DNA or alter
2015), as discussed below there is toxic versus genotoxic carcinogens its expression either directly or indi-
emerging information that mutation (Waters et al., 1999) and indicate rectly, leading to a change in function
itself might underlie some, if not that some epigenetic events may or expression of genes. Such chang-
CHAPTER 12
have a mutational basis (You and
PART 2
most, of these epigenetic changes. es in the appropriate genes with pro-
There are three primary epigenet- Jones, 2012). In addition, chronic motion through cell replication and
ic mechanisms by which cells regu- inflammation, which is associated selective pressure can then lead to
late gene expression: methylation of with increased cancer risk (Colotta a tumour. For colorectal tumours
DNA (Hsiao et al., 2009), modifica- et al., 2009), causes DNA damage this concept has been characterized
tions of histones (Ellis et al., 2009), (etheno-base lesions and other exo- as the “Big Bang” model for tumour
and binding of microRNAs and other cyclic DNA adducts) that appears to growth, in which tumours start early
non-coding RNAs to the genome or be the basis for the increased risk, on producing mixed subclones that
to other RNAs (Garzon et al., 2009). as demonstrated by the fact that re- are not subject to stringent selection,
However, studies have shown that pair of the damage by base excision thus explaining the heterogeneity of
mutations in genes involved in these repair enzymes (alkyl glycosylases) tumours (Sottoriva et al., 2015).
three processes may be the basis for reduces the risk of cancer (Calvo This greater appreciation for how
many of the epigenetic events me- et al., 2012). Indeed, an analysis of a chemical, physical, and biological
diated by these mechanisms (You dozen human studies found strong- agents may induce cancer leads to
and Jones, 2012). For example, mu- ly increased risks of cancer among a model for agent-induced carcino-
tations in specific chromatin-modi- individuals with high levels of DNA genesis that integrates portions of
fying genes appear to occur in spe- adducts relative to those with low lev- the classic initiation–promotion mod-
cific cancers, such as in JARID1C els, and the cancer risks were even el with elements of the hallmarks of
in renal cancer, in SMARCA4/BRG1 higher for the group with high adduct cancer. Such a model would envi-
in lung cancer, and in ARID1A in levels when other risk factors, such sion a carcinogenic agent establish-
ovarian cancer (Jones et al., 2010). as infection and inflammation, were ing the process by either genetic or
Also, mutations in the DNA meth- taken into account (Poirier, 2012). As epigenetic mechanisms that cause
yltransferase genes DNMT1 and noted in Chapter 19, by Caldwell et changes in gene function and ex-
DNMT3A are found in colorectal al., host susceptibility factors mod- pression, resulting in the plethora of
cancer or acute myeloid leukaemia, ulate all of these events and are a characteristics of cancer cells, i.e.
the histone lysine methyltransferas- critical element in the overall cancer the hallmarks of cancer: mutations
es or demethylases HK4, H3K9, and risk. in key oncogenes, altered gene ex-
H3IK27 are mutated in kidney can- Within the context of both the ini- pression, changes in cell signalling,
cer and colon cancer, and the his- tiation–promotion model of carcino- altered cell growth, evasion of ap-
tone acetyltransferases H3K18 and genesis and the “hallmarks” of can- optosis, sustained angiogenesis,
H3K27 are mutated in acute lymph- cer (Hanahan and Weinberg, 2011), increased genomic instability, and
oblastic leukaemia (Peltomäki, 2012; these data have led to the view that eventual metastasis. Much of this
Ryan and Bernstein, 2012). Although (i) cancer is essentially a genetic can be modulated by various sus-
112
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CHAPTER 12
PART 2
chapter 13.
CHAPTER 13
PART 2
Introduction these agents – that can be used to 1986; Jayat and Ratinaud, 1993;
identify and organize mechanistic in- Stacey and Hitomi, 2008; Irish and
Mechanistic data have been in- formation related to cancer induction Doxie, 2014). Although for many of
cluded in Volume 100 of the IARC (see Chapter 10, by Smith; see also the human carcinogens Volume 100
Monographs, and they vary with the Smith et al., 2016). One of these 10 of the IARC Monographs contains
agent studied. These data are espe- mechanistic categories of data is a more descriptive data under this cat-
cially dependent on the type of study composite that includes information egory, primarily as changes in cell
and the contemporary understand- on the ability of a carcinogen to alter
proliferation, these changes are in-
ing of the state of the science at the cell proliferation, cell death, or nutri-
herently related to alterations in cell
time of publication of the study. ent supply.
signalling and/or cell-cycle control.
As an outcome of the two-part Alteration of cell proliferation is
Many challenges are associated
IARC Workshop on Tumour Site identified through assays that detect
with the use of data described for
Concordance and Mechanisms replicative DNA synthesis, 5-bro-
of Carcinogenesis, a mechanistic mo-2′-deoxyuridine (BrdU) labelling, alterations in cell proliferation, cell
database was assembled for the proliferating cell nuclear antigen death, or nutrient supply to examine
IARC Group 1 carcinogens (see (PCNA) labelling, and hyperplasia mechanistic and tumour site concor-
Chapter 22, by Krewski et al.). These or the occurrence of multinucleated dance between humans and experi-
agents were examined with regard to cells by light microscopy, and through mental animals. Several key mecha-
10 key characteristics – one or more analysis of some of these end-points nistic characteristics can result in or
of which are commonly exhibited by by use of flow cytometry (Gray et al., arise from changes in cell signalling
Part 2 • Chapter 13. Alterations in cell proliferation, cell death, or nutrient supply 117
(e.g. inflammation, genotoxicity, and This chapter focuses on issues as- ellers, growth factors, growth factor
epigenetic alterations) and can have sociated with the understanding and receptors, signal transducers, and
both genetic and epigenetic origins. interpretation of available data for apoptosis regulators (Narayanan
There are other levels of interde- this key mechanistic characteristic. et al., 2015). In response to mito-
pendence between the key mecha- gens, cell proliferation is triggered by
nistic characteristics. Inflammation, Genetic drivers of cell increased translocation into the nu-
excessive oxidative stress, and ge- proliferation and apoptosis: cleus of ERK 1 and 2 (ERK1/2), the
complex relationships and
nomic instability are related (see last proteins in the MAPK/ERK cas-
pleiotropic roles of cell
Chapter 17, by Kane). Mutagenesis cade. Activating mutations upstream
signalling molecules
may also underlie some epigenetic or within the ERK1/2 cascade are
events that change cell signalling. Cell signalling is a process whereby present in several human cancers,
For example, mutations in genes proteins or other chemical messen- but ERK1/2 activation also occurs in
involved in the methylation of DNA, gers activate receptors at the cell cancers without mutation of compo-
modification of histones, and bind- surface and then transmit signals nents of the cascade (Plotnikov et al.,
ing of microRNAs to the genome or inside the cell via membrane-to-nu- 2011).
to other RNAs may initiate epige- cleus pathways. In healthy adults, Ras, a small upstream guano-
netic changes (see Chapter 12, by cell proliferation, cell differentiation, sine-5′-triphosphate (GTP)-binding
DeMarini, and Chapter 20, by Rice and cell death determine the size protein in several signalling path-
and Herceg). of the proliferating cell population ways, has two isoforms, H-Ras and
Cell signalling pathways that reg- in soft tissues, for example surface K-Ras, with different potencies to
ulate cell proliferation are not inde- epithelia, mucosal lining cells of ex- activate the MAPK/ERK pathway;
pendent of those associated with cretory ducts, columnar epithelia the KRAS gene is more frequent-
other key mechanistic characteris- lining the gastrointestinal tract and ly mutated in human cancer, which
tics of IARC Group 1 carcinogens. uterus, transitional epithelium of the can result in constitutive activation
Many of the genes associated with urinary tract, and bone marrow and (McCubrey et al., 2007). H-Ras
cell proliferation are also linked with haematopoietic cells. These pro- has been implicated as contributing
apoptosis, inflammation, and several liferating cells replace dead cells to the cancer phenotype, through
pleiotropic responses. Dysregulation throughout life. Pathological effects evasion of anti-growth signalling,
in the mitogen-activated protein (e.g. injury resulting from hepato- angiogenesis, genetic instability,
kinase (MAPK) pathway affects cellular necrosis or partial hepatec- tissue invasion and metastasis, tu-
most, if not all, processes involved tomy) and physiological conditions mour-promoting inflammation, and
in cancer (Dhillon et al., 2007). The (e.g. estrogen-induced effects on the changes in the tumour microenviron-
extracellular signal-regulated kinase endometrium during the menstrual ment (Engström et al., 2015). K-Ras
(ERK) pathway of the MAPK family cycle) can involve stimulation of cell promotes metabolic reprogramming,
is most commonly associated with proliferation (Engström et al., 2015). activation of proliferative signalling
regulation of cell proliferation (Reuter The relationships between cell pathways, glycolysis, reduction of
et al., 2010). signalling molecules and pathways oxidative metabolism in the tricar-
The ability to use this character- that control cell proliferation and pro- boxylic acid cycle, and channelling of
istic to evaluate both mechanistic grammed cell death (apoptosis) are glucose intermediates into anabolic
and tumour site concordance is in- complex. Numerous enzymes and pathways, such as the hexosamine
fluenced by recent developments in cell signalling pathways are modulat- biosynthesis pathway.
cancer research, by the overarching ed during apoptosis, and dysfunction The tumour suppressor protein
issue of how carcinogens may ex- of cell death pathways is associated p63, which is activated by DNA dam-
press certain characteristics, and with initiation and progression of tum- age, cellular stress, and oncogenic
by the question as to the biological origenesis; the products of proto-on- signal transduction, has pleiotropic
basis of the differences between cogenes (genes that encode proteins anti-proliferative and metabolic ef-
species, strains, target organs, and that stimulate cell proliferation, inhibit fects that include metabolic cell-cy-
target cells in cell signalling and apoptosis, or do both) include tran- cle arrest (Robey et al., 2015).
cell-cycle control. scription factors, chromatin remod- Numerous pathways have been
118
identified to be involved in disruption trinucleotides that identify amino protein-coding genes, which are like-
of resistance to cell death, and p53 acids, and the regulatory code that ly to mediate species differences (Lin
has been described as implicated determines how DNA sequences di- et al., 2014).
in cell-cycle arrest, apoptosis, reg- rect gene expression are highly con- Human-to-mouse transgenic ex -
ulation of metabolism, DNA repair, served between species. However, periments demonstrate recapitu-
and every pathway linked to these species differ in the composition and lation of human gene regulation in
processes (Narayanan et al., 2015). the length of the DNA sequences mice, even in the case of human
Disruption of the MAPK cascades, that use this language in the regu- genes that lack murine orthologues.
which are central signalling pathways latory regions of their genes (Nitta However, for distinct biological path-
that regulate a wide variety of cellular et al., 2015). ways, the expression profiles of
processes, is associated with induc- The Mouse ENCODE (Encyclo- many mouse genes diverged from
tion and progression of various dis-
pedia of DNA Elements) Consortium those of human orthologues (Yue
eases, including not only cancer but
reported that the degree of conser- et al., 2014). A core set of candidate
also diabetes, autoimmune disease,
vation is high: the mouse genome is regulatory sequences were con-
and developmental abnormalities
similar to the human genome in size, served and display similar activity
(Plotnikov et al., 2011).
CHAPTER 13
structure, and sequence composi- profiles in humans and mice: expres-
The role of gene activation in
PART 2
tion, and more than 80% of mouse sion patterns for genes that encode
carcinogenesis is also complex and
genes have human orthologues. proteins in the nuclear and intracel-
evolving. Activation of protein kinase
The chromatin landscape in a cell lular organelle compartments, and
C, which acts as a catalyst for sever-
lineage is relatively stable in both genes involved in RNA processing,
al cellular functions that are related
humans and mice, transcription fac- nucleic acid metabolism, chromatin
to cancer (e.g. cell survival, prolif-
eration, apoptosis, and migration), tor networks are substantially more organization, and other intracellular
has been thought to enable tumour conserved, and both the human and processes. However, less interspe-
development. However, protein ki- mouse genomes are pervasively cies concordance was observed for
nase C isozymes have recently been transcribed (Vierstra et al., 2014; Yue genes involved with the extracellular
reported to be suppressed in human et al., 2014). The pattern of chromatin matrix, cellular adhesion, signalling
cancers, possibly through loss of states (defined by histone modifica- receptors, and immune responses
function that suppresses other on- tions) and the large-scale chromatin (Yue et al., 2014).
cogenic signals (Antal et al., 2015). domains are highly similar between Within orthologous mouse and hu-
The gene for an RNA-binding protein mice and humans, but there is a di- man cell types, there is conservation
that is highly active in blood cancers vergence in the regulatory landscape across species of the global fraction
(i.e. RNA-binding protein Musashi that confers plasticity both between of regulatory DNA sequences that
homolog 2) is not directly mutated cell types and between species (Yue encode recognition sites for each
in tumours, but its activation affects et al., 2014). transcription factor (Vierstra et al.,
the ability of RNA to be translated Organ-specific genes are more 2014). However, between humans
into proteins (Wang et al., 2015), and highly expressed than housekeep- and mice there is variation in regu-
consequently its role in cancer has ing genes (i.e. those present in all latory regions that govern individual
not been identified through mutation tissues), and the highest organ-spe- gene systems and the occupancy
or gene expression patterns. cific gene expression is observed in pattern of transcription factors, with
the testes, brain, liver, muscle (car- extensive cis-regulatory “rewiring”,
Genetic variability in cell
diac and/or skeletal), and kidney (Lin mediated by elements that recognize
signalling between species,
strains, and target organs et al., 2014). Comparisons of gene transcription factors. Although they
expression between human and mu- have a common language in regula-
Genetic variability between species rine tissues showed similarities in tion, active elements in one species
has been described in terms of their gene expression profiles at the tissue may be reassigned to a different
genomic content and the regulation and organ level. However, there were tissue in another species (Vierstra
and expression of their genes. Both greater similarities within each spe- et al., 2014). Thus, differences in the
the genetic code, which specifies cies for non-coding and conserved regulation of gene expression and
Part 2 • Chapter 13. Alterations in cell proliferation, cell death, or nutrient supply 119
cell signalling between species and mutations, one chemically induced i.e. it was lower in areas of active
tissues may affect mechanistic and and the other genetically engineered chromatin and transcription (Polak
tumour site concordance. transgenic, produced tumours with et al., 2015).
different gene expression patterns To create a comprehensive cat-
Variability in mutation targets alogue of genes responsible for the
(Westcott et al., 2015) and showed
and cell signalling across initiation and progression of cancer,
differences not only in tumour sus-
tissues and in tumours
ceptibility but also in model-de- 27 types of cancer were studied
pendent signalling pathways. (See through sequencing of matched tu-
Effects from activation of the MAPK/
mour and normal tissue samples as
ERK pathway, such as cell growth, Chapter 19, by Caldwell et al., for
part of the Cancer Genome Atlas and
prevention of apoptosis, and cell-cy- a discussion of host susceptibility
the International Cancer Genome
cle arrest, depend on the cell line- factors that influence tumour site
Consortium (Lawrence et al., 2013).
age; for example, activation of this concordance.)
However, as sample sizes increase,
pathway is associated with prolifera- As noted above, human tumours
the number of putative significant
tion and drug resistance in haemato- carry mutations in genes that en-
genes also increases and the risk of
poietic cells, but the activation is sup- code components of cell signalling
false positives resulting from tissue
pressed in some prostate cancer cell pathways associated with cell prolif-
lines (McCubrey et al., 2007). heterogeneity between cancer types
eration and cell death. High mutation in mutation type, distribution, and
The difficulty in predicting
frequencies have been associated frequency is highly variable. Across
cell-specific effects on cell signal-
with tumours induced by particular the 27 types of cancer, the median
ling is also illustrated by differences
carcinogens or mixtures of carcin- frequency of non-synonymous mu-
in certain biological responses be-
ogens, for example melanoma in- tations varied over more than three
tween histological subtypes of lung
duced by exposure to ultraviolet light orders of magnitude; half of the var-
cancer, i.e. adenocarcinoma versus
squamous cell carcinoma, in human and lung cancer induced by exposure iation in mutation frequency was as-
patients and in chemically induced to tobacco smoke (Lawrence et al., sociated with tissue type of origin.
lung cancer in mouse models. In 2013). Within cancer types, patient-specific
A/J mice treated with urethane to However, cancer is not a disease mutation frequencies also spanned
induce adenocarcinoma, or with of uniform origin, progression, or cell three orders of magnitude. This mu-
N-nitrosotris-(2-chloroethyl)urea to biology. Different types of cancer tational heterogeneity was strongly
induce squamous cell carcinoma, show variation in overall mutation correlated with DNA replication tim-
inhibition of vascular endothelial rate, predominant mutation type, ing and with transcriptional activity,
growth factor has the opposite ef- and distribution of mutations along i.e. it was higher in late-replicating
fect in these two tumour subtypes DNA regions and lower in highly
the genome. Epigenetic patterns
(increased apoptosis vs increased expressed genes. Higher mutation
of chromatin accessibility, histone
proliferation) (Larrayoz et al., 2014). frequencies occurring in late-rep-
modification, gene expression, and
In another example, gene ex- licating genes may be responsible
DNA replication timing are also cell
pression profiling was poor at dis- for potentially false-positive putative
lineage-specific (Polak et al., 2015).
tinguishing histological subtype and cancer genes, such as the olfacto-
A study of 173 cancer genomes from
cell type of origin for human breast ry receptor genes and some genes
eight different types of cancer, rep-
cancer, but a mouse model could cited in association with lung cancer
resenting a wide range of tissues of
demonstrate the correct genetic le- (Lawrence et al., 2013). Thus, the
origin, carcinogenic mechanisms, tissue of origin greatly affects mu-
sion and cell type to model human
disease, by confirming that the ori- and mutational signatures, showed tation patterns and is linked to DNA
gin of BRCA1 mutation-associated that chromatin features of the cell replication timing and tissue-specific
breast cancer is a luminal estrogen type of origin, and not of matched transcriptional activity.
receptor (ER)-negative mammary cancer cell lines, were the best pre- Genomic sequencing of estab-
epithelial progenitor (Molyneux and dictors of local frequency of somatic lished tumours to study their caus-
Smalley, 2011). However, different mutations. Mutation density was as- es has its limitations, because such
mouse models with the same K-ras sociated with epigenomic features, an approach is unable to study the
120
evolution of the clones, the accumu- 2013). Two distinct expression ar- It is difficult to identify associa-
lation of mutations in normal somatic rays of breast cancer cells, with al- tions that directly support a primary
cells, the variability among individ- most no genes – and thus no pro- metabolic link between environmen-
uals in driver mutation profiles, and tein changes – in common, can be tal exposures and cancer, for several
the variability among cancer genes equally useful for predicting clinical reasons: metabolic control does not
in clonal dynamics. In a study of 74 behaviour, and analyses with gene occur in a single step in a metabol-
cancer genes in sun-exposed skin, expression arrays may not provide a ic pathway; controlling factors differ
i.e. a polyclonal quilt of mutations between intact cells and in vitro cell-
true understanding of cancer biology
in key cancer genes consistent free systems; observed changes in
(Weinberg, 2014).
with damage from ultraviolet light, individual pathway elements do not
Sequencing of entire tumour ge-
multiple cancer genes were found always lead to changes in metabol-
nomes has yet to demonstrate de-
to be under strong positive selec- ic flux; and cancer cell phenotypes
finitively the number of somatic mu-
tion even in physiologically normal are neither fixed nor cancer-specific.
tations required to create a human
skin (Martincorena et al., 2015). The review also noted the function-
Positively selected mutations were tumour. A few conceptual insights
al interdependence of dysregulated
found in 18–32% of normal skin into cell and tissue behaviour have
CHAPTER 13
metabolism and other hallmarks of
resulted from elaborate maps of
PART 2
cells. The size of clonal expansions cancer, considering that, for exam-
varied across genes, and gene size interacting signalling components
ple, proliferating cancer cells have
was not necessarily correlated with and computer models of signalling
shared regulatory factors associ-
the potential of the somatic mutation (Weinberg, 2010). The paradigm
ated with the fundamental anabol-
to induce malignant transformation. of somatic evolution and multistep
ic and catabolic demands of the
Consistent with findings in tumours, tumorigenesis does not provide a
hallmark “sustaining proliferative
the mutation rate also varied along logical reason why oncogenesis
signalling” (Robey et al., 2015).
the genome, with higher rates found recapitulates ontogenesis (Huang Increased body mass index has
in less frequently expressed genes et al., 2009). been associated with increased risk
and in repressed chromatin. These
of cancer: obesogens – chemicals
findings were inconsistent with the Alterations in nutrient supply
that disrupt normal development
assumption that driver mutations oc-
and the balance of lipid metabol-
cur infrequently in long-lived cell line- Although dysregulated metabolism
ism – are able to cause permanent
ages and that those arising in cancer is one of the most common and
changes in metabolism that may ren-
are too small to be detected clinically recognizable features of cancer and
der the subject more susceptible to
(Martincorena et al., 2015). is associated with other phenotyp-
If a gene signature – a group of cancer later in life (see Chapter 19,
ic indicators, the results of a recent
genes with a characteristic com- by Caldwell et al.). Inflammation is
literature review attempting to link
bined expression pattern – is associ- associated with metabolic changes
cancer development and dysregulat-
ated with a prognosis, it is assumed and has been linked with several
ed metabolism suggested that there
to be likely to encode a biological chronic diseases, including cancer.
are major gaps in the understanding
signature driving carcinogenesis. Extracellular pro-inflammatory met-
of exposure-related carcinogenesis abolic signals are adenine nucleo-
However, this assumption has been
and metabolic reprogramming, for tides, succinate, oxidized nicotin-
questioned in view of findings that
example with respect to the specif- amide adenine dinucleotide (NAD+),
random changes in gene sets are
ic causal and temporal relationships and urate (McGettrick and O’Neill,
associated with prognosis and
that prognostic signatures in ER- between exposures, dysregulated 2013; Tannahill et al., 2013). The
negative breast cancer – associated metabolism, and the development gut microbiome has an important
with hypoxia and angiogenesis – of cancer and the associated phe- role in carbohydrate absorption and
are more similar to those in ovarian notypic hallmarks of cancer (Robey metabolism in humans and plays a
cancer than to those in ER-positive et al., 2015). This review did not con- significant part in inflammatory re-
breast cancer, which are driven by sider lifestyle-related exposures and sponses as well (see Chapter 19, by
proliferation pathways (Beck et al., IARC Group 1 carcinogens. Caldwell et al.).
Part 2 • Chapter 13. Alterations in cell proliferation, cell death, or nutrient supply 121
The transgenerational character modes of action, and the third de- out the need for either continued
of metabolic disturbances and ef- scribes the ability of a transformed exposure or sustained proliferation
fects on cell signalling is demonstrat- cell to escape normal cell-cycle con- during exposure (see Chapter 19, by
ed by studies of multigenerational trol and to continue replication. The Caldwell et al.). It has been noted for
undernutrition in rats (i.e. for 50 gen- interpretation of mechanistic data some time that enhanced cell divi-
erations). The undernourished rats for cell proliferation and cell death sion does not always predict carcino-
were predisposed to insulin resis- is dependent on the development genesis (Melnick et al., 1993). After
tance, had altered levels of several of appropriate animal models (see exposure to a carcinogen, the de-
metabolic regulators (e.g. circulating Chapter 19, by Caldwell et al.), and velopment of cancer in experimental
insulin, homocysteine, endotoxin, although cell proliferation has been animal models is influenced by the
leptin, adiponectin, vitamin B12, and used in descriptions of hypothesized circumstances under which expo-
folate), and had a higher susceptibili- modes of action (Wood et al., 2015), sure occurs (e.g. sustained vs tran-
ty to streptozotocin-induced diabetes it should be viewed in the context of sient) and by the presence or ab-
compared with properly fed control the newer understandings of cancer sence of inflammatory mediators or
rats. These changes were not re- mechanisms. DNA damage.
versed by feeding rats a normal diet For DNA damage to lead to a
in the two subsequent generations Liver cancer
mutation, DNA replication and cell
(Hardikar et al., 2015). division are typically required (see The complex interactions between
Studies on altered cell signalling Chapter 12, by DeMarini). As noted proliferation, mutation, and inflam-
have traditionally been performed in the United States Environmental matory cell signalling have been
on putative target cells of cancer, Protection Agency guidance assess- studied extensively for liver cancer.
but the contribution of the gut mi- ing the risk of cancer from early-life In humans, hepatocellular carcinoma
crobiome (i.e. the microbiota living exposures (EPA, 2005), more fre- (HCC) is markedly heterogeneous,
on and in humans) has only recently quent cell division during develop- both histomorphologically (Yeh et al.,
been investigated as a factor in can- ment can result in enhanced fixation 2007) and genetically, with a wide
cer susceptibility (see Chapter 19, of mutations because of the reduced diversity in gene expression patterns
by Caldwell et al.). The microbiome time available for repair of DNA le- (Chen et al., 2002). Histopathological
plays a role in the control of nutri- sions, and clonal expansion of a variability is also associated with ge-
ent supply (e.g. the gut microbiome mutated cell produces a larger pop- ographical region: slow-growing, dif-
is highly enriched in carbohydrate ulation of mutant cells. For adult or- ferentiated HCC nodules surrounded
metabolism genes, compared with ganisms, sustained cell proliferation by a fibrous capsule are common
the human genome overall; Bultman, has also been postulated to increase in this type of cancer in Japanese
2014), in metabolic pathways, and in risk of cancer, based on the same ra- patients, whereas a febrile form of
host susceptibility to metabolic dis-
tionale, and it has been proposed as HCC, characterized by leukocytosis,
ease (Suez et al., 2014).
a factor in increased cancer suscep- fever, and necrosis within a poorly
tibility. Sustained cell proliferation differentiated tumour, is common in
Cell proliferation as a
component or cause of is a feature of several hypothesized this cancer type among black peo-
cancer modes of action for cancer develop- ple in South Africa (Feitelson et al.,
ment, for example the induction of 2002).
There are at least three scenarios kidney cancer via alpha2u-globulin HCC signature genes vary con-
related to cancer and mechanisms of accumulation (EPA, 1991). siderably and depend on etiologi-
cancer induction in which alterations Although alterations in cellu- cal and accompanying pathological
in cellular replication and/or cell-cy- lar replication or cell-cycle control conditions, such as viral infection,
cle control have been described. The are important features of carcino- cirrhosis, inflammation, and fibrosis.
first invokes the predisposition of genesis, cell proliferation in and of The study of tumour formation in the
replicating cells with unrepaired DNA itself is not able to induce cancer. liver is also affected by continuous
damage to develop into cancer cells. Several carcinogenic substances changes in the transcriptome that
The second identifies sustained can cause cancer in humans after accompany hepatectomy and age
replication as a key event in various perinatal or prenatal exposure with- (Colak et al., 2010). A comparison of
122
conserved genes between rats and simple paradigm to explain the differ- cell signalling and is consistent with
humans (human orthologues) with ences in strain sensitivity, for exam- inflammation contributing to cancer
respect to early expression profiles ple between C3H/HeJ and C57BL/6J development. After exposure of ro-
of HCC signature genes showed mice, which show a difference of dents to trichloroethylene, hepato-
some conservation between species up to 40-fold in multiplicity of liv- cyte proliferation is confined to only
for components of the MAPK/ERK, er tumours (Hanigan et al., 1988; a small population of cells without
phosphoinositide 3-kinase (P13K)/ Maronpot, 2009). regenerative hyperplasia, sustained
Akt, and transforming growth factor The activation of oncogenic hepatocellular proliferation, and
beta (TGF-β) pathways (Colak et al., pathways appears to be more het- hepatocellular necrosis. Any tran-
2010). erogeneous in human HCC than in sient DNA synthesis, peroxisome
Development of liver cancer af- other types of cancer (El-Serag and proliferation, or cytotoxicity is not
ter exposure to carcinogens is more Rudolph, 2007). The high degree of correlated with trichloroethylene-in-
common in rodents, especially in heterogeneity in the ways in which duced liver carcinogenicity (EPA,
the mouse, than in humans. There cell signalling is disturbed before 2011). Thus, induction of liver cancer
are obvious differences between hepatocellular neoplasia may make by trichloroethylene is not a result of
rodents, non-human primates, and induction of liver cancer a useful sustained cell proliferation.
CHAPTER 13
PART 2
humans in background susceptibil- marker for changes that can lead to Exposure to one of the most
ity to hepatocarcinogenesis and, cancer elsewhere, depending on cel- studied carcinogens, 2,3,7,8-tetra-
as noted above, in the regulation of lular context and target (Vogelstein chlorodibenzo-para-dioxin (TCDD),
gene expression and cell signalling. and Kinzler, 2004). induces liver cancer in rodents, but
With respect to the ability to respond Thus, pathway concordance be- short-term effects do not include
to a mitogenic stimulus such as par- tween species may not always result induction of hepatocellular prolifer-
tial hepatectomy, the liver responds in site concordance for expression ation. Rather than simply inducing
differently and much more slowly in of cancer. The analysis of liver tu- cell proliferation, TCDD is thought
non-human primates and in humans mour site concordance is complicat- to cause cancer by altering the cel-
compared with rodents (Gaglio et al., ed by the heterogeneity of disease lular ability to proliferate, migrate,
2002). in humans, as well as by rodent undergo apoptosis, senesce, and
Global gene expression patterns susceptibility. terminally differentiate in a multistep
in HCCs from seven different mouse For induction of cancer in the liv- process focused on the accumula-
models were compared with those er in rodents, the nature of cell pro- tion of mutations and heritable epige-
in human HCCs from groups with liferation also determines the risk of netic changes (Safe, 2001; Marlowe
poorer survival and better survival. cancer (Caldwell et al., 2008). When and Puga, 2005; Ray and Swanson,
Expression patterns in HCCs from both necrosis and inflammation are 2009). In addition, the upregulation
Myc-Tgfa transgenic mice and in di- present, the resultant hepatocellular of drug-metabolizing enzymes by
ethylnitrosamine-induced HCCs in proliferation is fundamentally differ- TCDD may enhance the formation of
mice were most similar to those in ent from the transient proliferation highly reactive intermediates during
human HCCs from the group with caused by peroxisome proliferators metabolic activation and/or trans-
poorer survival, whereas the pat- or other primary mitogens. After formation of several key hormones
terns in HCCs from Myc, E2f1, and treatment with a mutagenic agent, (e.g. enzyme induction as a source
Myc-E2f1 transgenic mice were most transient proliferation induced by pri- of reactive oxygen species forma-
similar to those in human HCCs from mary mitogens has not been shown tion, which is linked to decoupling of
the group with better survival (Lee to lead to cancer induction, whereas the cytochrome P450 catalytic cy-
et al., 2004). partial hepatectomy or necrogenic cle) and result in DNA damage and
Many factors, such as diet, hor- treatments with carbon tetrachlo- mutations (IARC, 2012c).
mones, oncogene activation, methyl- ride have (Ledda-Columbano et al., Although liver data provide an
ation, imprinting, and cell prolifera- 1993; Gelderblom et al., 2001). example of the role of inflammatory
tion or apoptosis, are modulators of The mechanism by which necro- signals under some circumstances,
spontaneous and induced murine sis may enable cancer development inflammation in itself may not induce
hepatocarcinogenesis. There is no involves concurrent inflammatory cancer without other concurrent
Part 2 • Chapter 13. Alterations in cell proliferation, cell death, or nutrient supply 123
cofactors. For many of the agents ducts in portal spaces, Mdr2 knock- Several key mechanistic charac-
discussed in Volume 100C of the out mice rarely develop tumours of teristics of IARC Group 1 carcino-
IARC Monographs (IARC, 2012a), the bile duct (Nickoloff et al., 2005). gens induce traits of cancer cells de-
inflammation is a key characteristic The relationship between chron- scribed as the hallmarks of cancer,
of their effects (see Chapter 17, by ic inflammation and cancer is com- including effects on cell proliferation,
Kane). One of the most recognized plex: inflammation may have roles cell death, and nutritional status (see
examples of how inflammation con- in initial genetic mutations or epi- Chapter 11, by Stewart). The descrip-
tributes to neoplastic development is genetic changes that not only drive tion of the hallmarks attempts to bring
the induction of mucosa-associated cell transformation but also provide together a fundamental understand-
lymphoid tissue (MALT) lymphoma a microenvironment that enables ing of how cancer cells manifest a
and gastric adenocarcinoma asso- progression and metastasis and distinct phenotype. More recently, a
ciated with exposure to Helicobacter prevents immune responses against series of reviews in Carcinogenesis
pylori. The MALT proliferations of the tumour. Chronic inflammation reported the findings from an inter-
B-cell lymphoid follicles are the pre- favours accumulation of DNA dam- national team of cancer biologists
cursor of a low-grade lymphoma of age and chromosomal damage and toxicologists who participated
B cells. A large proportion (98%) of (see Chapter 12, by DeMarini, and in the Halifax Project (Harris, 2015).
patients with gastric MALT lympho- Chapter 17, by Kane). They reviewed the literature on each
ma are also infected with H. pylori; of the hallmarks of cancer to exam-
The hallmarks of cancer ine the carcinogenic potential of ex-
however, only a small percentage of
H. pylori-positive individuals devel- posure to low doses and mixtures
In their updated paper, Hanahan
op MALT lymphoma (Bassig et al., of chemicals. Relevant reviews for
and Weinberg (2011) noted that the
alterations in cell proliferation, cell
2012). Little is known about the pos- most fundamental trait of cancer
death, or nutrient supply included
sible role of environmental cofactors cells involves their ability to sustain
the potential of chemical mixtures to
in the predisposition to H. pylori-in- chronic proliferation. As part of the
enable sustained proliferative signal-
duced gastric lymphomagenesis. “hallmarks” of cancer, alterations in
ling (Engström et al., 2015), to confer
Other factors are certainly involved, cellular replication and/or cell-cy-
resistance to cell death (Narayanan
including susceptibility (IARC, cle control figure prominently in the
et al., 2015), and to induce metabol-
2012b). discussions of cell proliferation, in- ic reprogramming and dysregulated
flammation, and changes in cell sig-
Inflammation metabolism (Robey et al., 2015). A
nalling that are part of cancer cell related review that encompasses
Certain types of inflammatory pro- physiology. The authors noted that many aspects of cell signalling re-
cesses in skin, and possibly in other the precise identities and sources ported on environmental immune
tissues, may serve a tumour suppres- of the proliferative signals in general disruptors, inflammation, and risk
sor function. Some clinical conditions remain poorly understood, but that of cancer (Thompson et al., 2015).
show that inflammation is a critical mitogenic signalling in cancer cells The overlap in the descriptions of
component of tumour progression, is characterized and known in some- pathway disruption and functions of
for example reflux esophagitis be- what more detail. The mechanism by cell signalling molecules between
fore oesophageal cancer, or inflam- which necrosis enables cancer in- these papers is striking and is con-
matory bowel disease that precedes duction was also described in terms sistent with the discussion presented
colorectal cancer. However, a condi- of the release of pro-inflammatory above with regard to the complex re-
tion such as psoriasis is known as a signals by necrotic cells and the in- lationship and pleiotropic roles of cell
chronic cutaneous inflammatory dis- fluence of cytokines on proliferation signalling molecules involved in cell
ease that is seldom, if ever, accom- and invasiveness of cancer cells. proliferation and apoptosis.
panied by cancer. Similarly, despite Thus, tumour-promoting inflamma- The paradigms of cytotoxicity,
extensive inflammation, activation of tion was considered by Hanahan and cell proliferation, and initiation–pro-
nuclear factor kappa-light-chain-en- Weinberg (2011) to be an enabling motion as mechanisms of carcino-
hancer of activated B cells (NF-κB), characteristic for acquisition of core genesis have been superseded by a
and abundant proliferation of bile hallmark capabilities. more nuanced understanding of the
124
process of carcinogenesis (Hanahan The biological basis for how cell delayed cancer induction after expo-
and Weinberg, 2011). As stated signalling and cell-cycle control dif- sure to toxicants and the bystander
above, cell proliferation, inflamma- fer between species, organs, and effect of radiation on tumour devel-
tion, or cytotoxicity alone do not lead tumour cells, as well as the variabil- opment. With regard to cell signal-
to cancer, and they are interrelated ity in mutation targets, are also dis- ling, spontaneous or environmentally
through changes in cell signalling. cussed here. Determining the caus- induced epigenetic alterations are
The hallmarks of cancer describe es of cancer through examination of increasingly recognized as early mo-
gene expression profiles in tumours lecular events in cancer formation,
well the characteristics that are
is difficult, especially in terms of in- and these alterations may potential-
manifested after the development of
creased and sustained cell prolif- ly be more adverse than nucleotide
cancer. However, by the time of di-
eration, which is a characteristic of mutations, because their effects on
agnosis, tumour cells already carry
cancer itself. Alteration in nutrient regional chromatin structure can
large numbers of mutations and are
supply is a common and recogniza- spread out, thereby affecting multiple
also very heterogeneous in gene
ble feature of cancer, and is also not genetic loci (Weidman et al., 2007).
product profiles; the multiple cell di- independent of activities associated The key characteristics of the
visions and the consequent damage with increased cell proliferation or IARC Group 1 carcinogens have
CHAPTER 13
processing obscure the initial lesion,
PART 2
the hallmarks of cancer. some overlap with the hallmarks
rendering it difficult, if not impossi- Some of the information col- of cancer and perhaps can provide
ble, to make a distinction between lected in Volume 100 of the IARC insight into the “environment” that
causal and consequential events in Monographs was presented in the creates the neoplastic cell. The elu-
carcinogenesis. context of the older hypotheses for cidation and understanding of sus-
mechanisms of cancer induction. ceptibility factors may help determine
Conclusions The understanding of cancer mech- what parts of that environment are
anisms and the descriptive data already present in individuals, spe-
Among the 10 mechanistic charac- associated with them continues to cies, or target tissues where cancer
teristics more commonly observed evolve (see Chapter 11, by Stewart). develops as a result of exposure to
for IARC Group 1 carcinogens is a The discussion of mechanistic data environmental carcinogenic agents.
composite that includes information for ionizing radiation in Volume 100D This may also help in evaluating
on alteration of cell proliferation, of the IARC Monographs (IARC, mechanistic and tumour site concor-
cell death, and nutrient supply. This 2012d) and Chapter 12, by DeMarini, dance between species. However,
chapter examines many of the chal- provide more current discussions the mechanistic data provided on
lenges associated with the use of about the understanding of cancer agents identified as carcinogenic
this type of information to determine and the key mechanistic character- to humans need to be examined in
mechanistic and tumour site con- istics of IARC Group 1 carcinogens. the context of more recent informa-
cordance between humans and ex- With the present state of knowledge, tion on carcinogenesis. Cancer is a
carcinogenesis cannot be confident- heterogeneous disease, even with-
perimental animals, and discusses
ly attributed to an underlying purely in the same target site. Because,
how this mechanistic characteristic
genetic or purely epigenetic pro- among other considerations, some
shows interdependence with others,
cess. Mechanistically, it is probably a epigenetic events may have a mu-
such as genotoxicity and inflamma-
mixture of the two. tational basis, the dichotomy once
tion. Many of the indicators of chang-
Epigenetic alterations may identified between genotoxic and
es in cell proliferation or cell death
precede DNA sequence mutations, non-genotoxic carcinogens should
are non-specific for the induction with subsequent mutations occurring be reconsidered.
of cancer, and although they result not in a random fashion but in re- Enhanced cell proliferation and re-
primarily from effects on the MAPK/ sponse to specific types of epigenet- duced cell death are key mechanistic
ERK cell signalling pathway, they are ic changes induced by the environ- characteristics of IARC Group 1 car-
influenced by a large array of cell ment (Karpinets and Foy, 2005). This cinogens, are a hallmark of cancer,
signalling molecules with pleiotropic selection for enhanced growth has and are necessary for DNA damage
effects. been suggested to explain both the to be processed into a mutation.
Part 2 • Chapter 13. Alterations in cell proliferation, cell death, or nutrient supply 125
However, such changes alone are Acknowledgements Approval does not signify that the
not sufficient to induce cancer. A key contents reflect the views of the
The author thanks D.M. DeMarini,
mechanistic question emerges as to agency, nor does mention of trade
M.V. Evans, and S. Vulimiri for their
what events or cellular environment names or commercial products con-
helpful comments on this manuscript.
may precede or cause such chang- stitute endorsement or recommen-
es and may stimulate the formation Disclaimer dation for use.
and selection of DNA sequence mu-
tations and epigenetic changes that This article was reviewed and
induce a cell and its descendants to approved for publication by the
acquire the hallmarks of cancer, in- National Center for Environmental
cluding increased cell proliferation Assessment, United States En-
and evasion of apoptosis. vironmental Protection Agency.
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128
part 2.
mechanisms of carcinogenesis
chapter 14.
Receptor-mediated
mechanisms
Maarten C. Bosland
CHAPTER 14
PART 2
Introduction have genotoxic effects; polycyclic biphenyls (PCBs) can be metabo-
aromatic hydrocarbons (PAHs), such lized to reactive, DNA-damaging in-
Carcinogenic agents can cause as benzo[a]pyrene, are examples of termediates that may contribute to
cancer by inducing DNA damage this group. Yet other agents have can- their receptor-mediated carcinogen-
through various genotoxic mecha- cer-enhancing or tumour-promoting icity (Ludewig and Robertson, 2012;
nisms that result in mutations. Many effects through pathways involving Lauby-Secretan et al., 2013; IARC,
of the agents classified as carcino- receptors but also cause formation of 2016).
genic to humans (Group 1) by the reactive oxygen species or enhance The purpose of this chapter is
IARC Monographs are not directly or the bioactivation of pro-carcinogens to provide an overview of recep-
indirectly genotoxic but cause cancer to ultimate carcinogens, both of tor-mediated mechanisms thought
via mechanisms that, by themselves, which can potentially damage DNA to be involved in carcinogenesis,
do not generate or involve DNA dam- and result in mutations; 2,3,7,8-tetra- followed by a discussion reflecting
age. One non-genotoxic mechanism chlorodibenzo-para-dioxin (TCDD) is on the complexity of these mech-
involves receptor mediation (Pitot, an example of this group. anisms and how such mechanistic
1995). Thus, the distinction between information can be used for rational
Hormonally active agents that are genotoxic carcinogens and carcino- hazard identification of carcinogenic
associated with carcinogenic effects gens that act through receptor-me- agents. Receptor-mediated carcino-
typically act as ligands for nuclear diated mechanisms is often not genesis was often discussed in the
receptors and, in some cases, for black and white. Insight continues 1990s as a major mechanism of
receptors located at the cell surface. to evolve about the mechanisms by cancer induction by non-genotoxic
There are also agents that are con- which some carcinogens act through carcinogens (Pitot, 1995). However,
sidered to be carcinogenic through receptors. For example, there is now carcinogenesis research has since
receptor mediation but in addition evidence that certain polychlorinated moved beyond these receptors to the
130
carcinogenicity of an agent that Birnbaum et al., 1990; Fernandez- carcinogenic processes (Pitot, 1995;
acts via a direct receptor-mediated Salguero et al., 1995). Although Shawver et al., 1995).
mechanism. Effects that are gener- some of these studies evaluated 12-O-tetradecanoylphorbol-13-ac
ally considered to be associated with the involvement of AhR in effects of etate (TPA) may act as a tumour
carcinogenic activity of such agents TCDD that are mechanistically as- promoter through activation of mem-
include, but are not limited to, the sociated with carcinogenesis, this brane-located protein kinase C re-
following: enhancement of carcino- approach has not been applied to ceptors, activating downstream sig-
gen bioactivation; reduction of DNA determine whether AhR is necessary nalling pathways that contribute to
repair; induction of oxidative stress; for TCDD-induced tumour formation. the enhancing effects of TPA on for-
stimulation of cell proliferation, an- Studies with mice that overexpress or mation of skin tumours (Niedel et al.,
giogenesis, and invasive or migratory lack estrogen receptor alpha (ER-α) 1983; Nishizuka, 1984). However,
cell properties (including epithelial– have demonstrated that this receptor conclusive evidence for this mech-
mesenchymal transition); inhibition of is involved in many of the develop- anism is still lacking (Gschwendt
cellular apoptosis, senescence, and/ mental and carcinogenic effects of et al., 1995; Marks and Gschwendt,
or differentiation; evasion of immune neonatal treatment with diethylstil- 1995). Moreover, TPA is a complete
surveillance; and epigenetic effects bestrol in female animals (see below) carcinogen for the skin in mice when
CHAPTER 14
(Hanahan and Weinberg, 2011) (see (Couse et al., 1997, 2001; Couse and given at sufficiently high doses with
PART 2
Chapter 10, by Smith). Korach, 2004). a sufficiently long period of obser-
Finding any one such effect, or vation (Iversen and Iversen, 1979).
even a combination of several of Non-genomic receptor- The involvement of protein kinase C
these effects, as a result of exposure mediated mechanisms and in TPA-induced tumour promotion is
to an agent that binds to cellular re- carcinogenesis highly complex and is only partially
ceptors is not by itself sufficient evi- understood (Griner and Kazanietz,
Non-genomic regulation of gene 2007), and more recent research is
dence that the agent is a carcinogen,
expression and cellular function in- focused on downstream signalling
but such findings do generate suspi-
volves signal transduction pathways effects (Hsu et al., 2000; Lu et al.,
cion that the agent might cause can-
that are activated by a wide range 2007). TPA has also been shown to
cer. If such receptor binding is asso-
of receptor molecules located at the act through other receptor mecha-
ciated with the mechanism by which
plasma membrane. These receptor nisms (Marks and Gschwendt, 1995)
a recognized human carcinogen op-
modules are activated by an equal- and, when applied to the skin in
erates, the evidence for carcinogeni-
ly large number of ligands, ranging mice, to induce inflammation, which
city in humans may be sufficient. An
from locally produced autocrine and in itself can stimulate cell prolifera-
example of this is the recent upgrad-
paracrine growth factors to circulat- tion and generate reactive oxygen
ing by IARC of PCB 126 and PeCDF
ing cytokines and hormones. The species (Aldaz et al., 1985; Wei and
to Group 1 carcinogens, based on major groups of these receptors in- Frenkel, 1993).
the similarity of their binding to AhR clude tyrosine kinase receptors such Receptors for several steroid
(IARC, 2012a, 2016). as the epidermal growth factor (EGF) hormones are not only intracellular
Proof that a receptor-mediated receptor, serine/threonine kinase re- nuclear receptors (see below) but
mechanism is involved in carcino- ceptors such as the protein kinase C may also be present at the plasma
genesis in mammals would require receptor, G protein-coupled recep- membrane, where their activation
evidence that blocking the activation tors, and receptors for cytokines, by agonists causes rapid non-ge-
of a specific receptor, or genetic re- chemokines, and other ligands. nomic signal transduction-medi-
moval of the receptor or reduction They all catalyse phosphorylation ated effects. These non-classical
of its expression in mouse models, of downstream signalling molecules receptor-mediated effects have
interferes with tumour induction by upon ligand binding, some via activa- been shown to occur for the andro-
the carcinogen in question. The latter tion of G protein signalling, ultimately gen receptor (AR) (Bennett et al.,
approach was used to demonstrate resulting in regulation of expression 2010; Lang et al., 2013), the gluco-
that several of the toxic effects of of specific genes or sets of genes corticoid receptor (Matthews et al.,
TCDD are indeed mediated by AhR that control cellular function and 2008; Samarasinghe et al., 2012),
in vivo (Poland and Glover, 1980; behaviour and potentially influence the progesterone receptor (PR)
132
Fernandez-Salguero, 1998; Carlson A second form of ER was discovered 2011) and often have opposite activi-
and Perdew, 2002). However, some in 1996 and was named ER-β to dis- ty in breast, prostate, and colon can-
endogenous compounds that bind to tinguish it from the receptor previous- cer cells (Bardin et al., 2004; Roger
and activate AhR have been identi- ly cloned, ER-α (Kuiper et al., 1996). et al., 2008; Chen and Iverson, 2012;
fied, such as certain tryptophan de- Genomic activity of ER, also Nelson et al., 2014).
rivatives, but their physiological role termed nuclear-initiated steroid sig- There are several isoforms of
has not yet been firmly established nalling, is achieved through two ER-α and ER-β that result from alter-
(Denison and Nagy, 2003; Henry main mechanisms. The first involves native mRNA splicing (Moore et al.,
et al., 2006). The tryptophan metab- the direct binding of ER to its target 1998; Flouriot et al., 2000; Wang
olite kynurenine has been identified gene. Estrogen binding to its recep- et al., 2005). Of these variants, ER-
as an endogenous ligand of human tor in the cytosol triggers a series of α36 and ER-α46 are predominantly
AhR. After receptor binding, down- events, starting with loss of chaper- localized to the plasma membrane
stream effects are the suppression one molecules such as heat shock and cytoplasm, mediating mem-
of anticancer immune mechanisms protein 90 (Hsp90), and followed by brane-initiated rapid non-genomic
and the promotion of cancer cell migration of the receptor from the cy- signalling (Flouriot et al., 2000; Wang
survival and motility in human brain tosol into the nucleus. Dimerization et al., 2005). Of note, the so-called
CHAPTER 14
tumours (Opitz et al., 2011), but the
PART 2
of the receptor then induces a con- estrogen-related receptors show a
role of kynurenine in carcinogenesis formational change that allows sub- high degree of sequence homology
has not been established. To exert sequent binding of the receptor dimer with the ERs, but they are orphan re-
its effects, AhR heterodimerizes with to specific sequences of DNA known ceptors for which no ligand has been
a unique molecule, the AhR nuclear as estrogen response elements. The identified (Deblois and Giguère,
translocator (ARNT). DNA–receptor complex recruits oth- 2011, 2013). Although activation of
AhR, ER, and PR mediate ef- er proteins such as co-activators, the α-isoform of estrogen-related
fects of several agents that are which are responsible for the ini- receptors resulted in suppression
classified as IARC Group 1 human tiation of transcription of downstream of growth of xenografted human
carcinogens (IARC, 2012a, b) and DNA into mRNA, resulting in trans- breast cancer cells in nude mice
are discussed in more detail below. lation to proteins to produce chang- (Chisamore et al., 2009), there is no
Although AR has been implicated es in cellular function (Dickson and evidence that these nuclear recep-
in the causation of prostate cancer Stancel, 2000; Aranda and Pascual, tors are involved in estrogen-induced
in humans, this has not been firmly 2001). The second mechanism of carcinogenesis.
established, and there is only limited transcriptional regulation does not Two isoforms of PR have
evidence of the carcinogenicity of involve estrogen response elements been identified, PR-A and PR-B,
androgenic steroids in humans; they but is based on interaction of ER which are encoded by the same
are classified by IARC as probably with the transcription factors Fos and gene but controlled by different
carcinogenic to humans (Group 2A), Jun to bind to AP1 sites, or with Sp1 estrogen-regulated promoter re-
because there is sufficient evidence to bind to Sp1 sites (Nilsson et al., gions and different translation ini-
of their carcinogenicity in experimen- 2001). tiation events (Conneely et al., 1989;
tal animals (IARC, 1979, 1987). In The two basic forms of ER, ER-α Kastner et al., 1990; Kraus et al.,
rats, testosterone is a weak complete and ER-β, show some sequence 1993). These two receptor forms
carcinogen and a strong tumour homology and are widely distribut- play different roles in various tissues
promoter in the prostate (Bosland, ed in tissues of the body, including and cell types and may have oppo-
2014). target tissues of estrogen carcino- site molecular effects (Jacobsen
genicity, but they differ greatly in cell and Horwitz, 2012). Although PRs
Estrogen receptor (ER) and
type-specific abundance. In addition, are in many respects similar to ERs
progesterone receptor (PR)
although their basic molecular mech- in the way they initiate transcrip-
ER was discovered by Jensen anism of action is similar, they differ tion, dimerization may not always
(Jensen et al., 1968; Jensen and in specificity and binding affinity for be necessary, and PR monomers
DeSombre, 1973), and its gene was ligands (Matthews and Gustafsson, can bind to progesterone response
cloned in 1986 (Greene et al., 1986). 2003; Thomas and Gustafsson, element half-sites (Jacobsen et al.,
134
The breast cells that proliferate inantly expressed in luminal cells, the interplay of these molecularly
are not the cells that strongly express whereas PR expression is enriched diverse mechanisms is likely to be
ER or PR, suggesting that paracrine in the basal cell compartment, which highly complex and is still poorly
mechanisms, possibly involving may contain progenitors of luminal understood (Yager and Davidson,
breast stromal cells, play a major cells and possibly cancer progenitor 2006). In addition, the understanding
role. Breast density (i.e. the relative cells (Hilton et al., 2012). This obser- of how these receptors function is
proportion of the stromal component vation may have a bearing on the no- still evolving in many ways. For ex-
of the breast) has been found to be tion that there are four basic breast ample, it has become apparent that
associated with the rate of cell pro- cancer types (and possibly subtypes microRNAs regulate ER and PR ex-
liferation (Clarke et al., 1997; Russo of these) (Sorlie et al., 2001; Guiu pression and in turn are regulated by
et al., 1999; Harvey et al., 2008). et al., 2012; Elsawaf et al., 2013). these receptors as well (Adams et al.,
Although it is currently not known 2007; Maillot et al., 2009; Pandey
Thus, in vitro studies with benign
which of these four breast cancer and Picard, 2010; Cochrane et al.,
or malignant breast epithelial cells
types are associated with estrogen– 2012), but it is not known whether or
exposed to the sex hormones con-
progestin treatment, breast can- how these mechanisms are involved
tained in estrogen–progestin treat-
cer risk associated with hormonal in breast carcinogenesis.
CHAPTER 14
ments have limited significance,
menopausal therapy varied among Cancer of the endometrium and
PART 2
because they do not involve a stro-
different histological types of inva- ovary
mal component, although once they
sive and in situ breast cancer in the
are malignantly transformed, breast The reduction of risk of cancer of
Million Women Study (Reeves et al.,
cancer cells may become inde- the endometrium and ovary by use
2006). Of interest in this respect is
pendent of paracrine mediation and of combined oral contraceptives is
the observation that there may be
regulate their growth by autocrine well established, whereas menopau-
cross-talk between PR subtypes
mechanisms (Obr and Edwards, sal estrogen therapy unopposed by
and human epidermal growth factor
2012). receptor (HER)/ErbB receptors in progestins causes cancer of the en-
Also, cell culture-based studies HER-positive breast cancers (Lindet dometrium (IARC, 2012b). In the nor-
have yielded a somewhat confusing et al., 2012). mal premenopausal endometrium,
overall picture of how estrogen and Genotoxicity of estrogen metab- cell proliferation rates are high dur-
progestin treatments interact in af- olites potentially plays a role in the ing the follicular phase, when estra-
fecting cell proliferation. Progestins carcinogenicity of estrogen and es- diol levels peak, but they decline as
can inhibit estrogen-stimulated pro- trogen–progestin treatments (Yager progesterone levels rise in the luteal
liferation of breast cells (Seeger and Liehr, 1996; Cavalieri et al., phase (Whitehead et al., 1981; Key
et al., 2003a, b), but they also in- 2000; Yager and Davidson, 2006). In and Pike, 1988).
crease the ratio of apoptosis to prolif- addition, some estrogen metabolites It is well established that the
eration (Krämer et al., 2005; Seeger (the 4- and 16α-hydroxylated but longer a woman menstruates, the
et al., 2005). Dose and type of pro- not the 2-hydroxylated metabolites) higher the risk of cancer of the en-
gestin appear to be critical in deter- can also have cell proliferative ef- dometrium (Key and Pike, 1988;
mining the eventual effect (Seeger fects through poorly defined mecha- Karageorgi et al., 2010). This rela-
et al., 2003b, 2005). Despite their nisms that may involve ER mediation tionship is similar for cancers that
limitations, these in vitro studies have (Seeger et al., 2006). differ in the degree of genomic insta-
shown that ER- and PR-mediated Overall, there is little doubt that bility (Amankwah et al., 2013) and for
apoptosis must be considered as an ER- and PR-mediated mechanisms, both the common endometrioid form
important effect of combined estro- including stimulation of breast cell of endometrial cancer (type I) and
gen–progestin treatment, and they proliferation, are involved in the the less common type II endometri-
have provided evidence that growth carcinogenicity of estrogen–pro- al cancers (including serous, clear
factors can be determinants of these gestin treatments (Sutherland et al., cell, and mixed Müllerian tumours)
effects (Krämer et al., 2006). 1998; Anderson and Clarke, 2004). (Setiawan et al., 2013).
More recent observations in nor- However, other mechanisms are Estrogen therapy during men-
mal human breast tissue have pro- clearly also operational and are opause also increases endometri-
vided evidence that ER-α is predom- probably critically important as well; al cell proliferation, and this effect
136
ligand, TCDD (Denison et al., 2002; interact directly with phosphorylat- relevant that there are interspecies
Tsuchiya et al., 2003; Flaveny et al., ed retinoblastoma protein, leading and rat and mouse strain-specific
2009). to cell-cycle arrest, and with ER-α differences in AhR binding affinity for
Endogenous ligands for AhR and ER-β in various ways, resulting TCDD, as well as in functional AhR
have not been identified with cer- in repression of ER-mediated signal- polymorphisms, AhR abundance,
tainty, but it is likely that these exist ling and anti-estrogenic effects (Safe and cofactors required for AhR ac-
and that AhR has a physiological role et al., 1998; Safe and Wormke, 2003; tivity, which may all be critical to the
(Gonzalez and Fernandez-Salguero, Dietrich and Kaina, 2010; Denison carcinogenic process (Barrett, 1995;
1998; Carlson and Perdew, 2002; et al., 2011). Interestingly, ARNT by De Souza et al., 2009; Flaveny et al.,
Bock and Köhle, 2009). Certain en- itself can activate ER-α, and par- 2009).
dogenously formed tryptophan deriv- ticularly ER-β (Rüegg et al., 2008). The binding affinity of human AhR
atives that bind to and activate AhR AhR may activate cyclin A via JunD for dioxin is much weaker than that
have been identified, but their phys- and ATF2, thereby inhibiting contact found for AhR in some rodent spe-
iological role has not yet been firm- inhibition in vitro, which would be a cies (Ema et al., 1994; Ramadoss
ly established (Denison and Nagy, pro-carcinogenic effect (Weiss et al., and Perdew, 2004). Rodents have
2003; Henry et al., 2006; Perdew 2008; Dietrich and Kaina, 2010). a high degree of AhR sequence ho-
CHAPTER 14
PART 2
et al., 2015). Factors that can acti- The great diversity of genes reg- mology (Korkalainen et al., 2001), but
vate AhR in cultured liver cells have ulated by AhR and the many mech- there is less homology with human
been found in the serum of knockout anisms involved are remarkable and AhR (Ema et al., 1994; Flaveny et al.,
mice that lack AhR (McMillan and illustrate the considerable complexity 2008). There are also differences
Bradfield, 2007), but whether these in how AhR functions (Denison et al., between humans and rodents in the
are the elusive endogenous ligands 2011). This complexity is exacerbated response of hepatic gene expres-
is uncertain. because (i) ligand-dependent differ- sion to TCDD, but little difference
This cytosolic receptor, once ences have been observed in co-ac- in inducibility of CYP450 enzymes
bound to a ligand, translocates to tivator recruitment and in binding (Mandal, 2005).
the nucleus, loses various chaper- specificity of AhR towards sequence Mice that carry AhR variants
one molecules, such as Hsp90, and variants in xenobiotic response ele- with different dioxin-binding affini-
heterodimerizes with ARNT. The ments, (ii) cell type-specific co-acti- ties vary in their response towards
AhR–ARNT complex then binds to vators and co-repressors can mod- TCDD toxicity and PAH-induced
xenobiotic response elements, also ulate DNA binding specificity of the carcinogenesis (Garte and Sogawa,
termed dioxin response elements, AhR–ARNT complex, (iii) AhR and 1999; De Souza et al., 2009; Flaveny
in the promoter regions of the genes the AhR–ARNT complex may them- et al., 2010). Thus, there are differ-
it regulates, including those encod- selves act as co-activators for other ences between humans and rodents
ing CYP1A1, CYP1A2, CYP1B1, transcription factors, and (iv) exten- in AhR binding affinity that may
glutathione-S-transferase M, and sive cross-talk exists with important account for interspecies variation
nicotinamide adenine dinucleotide signalling pathways (Beischlag et al., in AhR-mediated carcinogenicity.
phosphate NAD(P)H:quinone ox- 2008; Denison et al., 2011). Toxicogenomic comparisons of hu-
idoreductase, all of which are in- It is not surprising that activation man, rat, and mouse cells or tissues
volved in metabolism of xenobiotics of AhR results in distinct species- exposed to TCDD indicate consider-
(Beischlag et al., 2008; Denison and tissue-specific changes in gene able interspecies differences in the
et al., 2011). Involvement of AhR in expression profiles and that these response to dioxin (Boverhof et al.,
immune regulation, the cell cycle, may be subject to temporal changes 2006; Black et al., 2012). Of note,
the function of mucosal barriers, and can be dependent on, as well there are AhR polymorphisms in hu-
and development has recently been as independent of, TCDD and diox- mans, some of which could conceiv-
identified (Hubbard et al., 2015). in-like compounds such as PCBs ably be associated with differences
In addition, AhR can interact with and dibenzofurans (Vezina et al., in toxic effects and cancer risk in re-
molecules other than ARNT and can 2004; Tijet et al., 2006; Kopec et al., sponse to exposure to TCDD (Garte
engage extensively in cross-talk with 2008, 2013; N’Jai et al., 2008; Dere and Sogawa, 1999; Hung et al.,
various signalling pathways. It can et al., 2011a, b). In this regard, it is 2013; Luo et al., 2013).
138
combinations of PCBs have not been Stemmann et al., 2009; Puga et al., et al., 1997; Oliver and Roberts,
studied but would be of interest, giv- 2009) and the transforming growth 2002). TCDD has been found to in-
en that, for example, PCB 153 signif- factor beta (TGF-β) (Gomez-Duran duce hepatocellular replicative DNA
icantly increased the carcinogenic et al., 2009) and nuclear factor kap- synthesis in vivo in some studies
potency of PCB 126 (NTP, 2006c). pa-light-chain-enhancer of activated (Lucier et al., 1991) but not in oth-
Overall, the mechanism of action of B cells (NF-κB) pathways (Tian et al., ers (Fox et al., 1993; Bauman et al.,
TCDD and dioxin-like compounds 1999; Vogel and Matsumura, 2009). 1995), and it inhibits growth of pri-
appears to be highly complex and to There is also evidence for cross-talk mary hepatocytes in vitro (Hushka
be dependent on ligand, dose, du- with the constitutive androstane re- and Greenlee, 1995). Lack of AhR in
ration of exposure, and sex, and it ceptor and one of its target genes in knockout mice resulted in increased
is only partly understood (Silkworth mice, Cyp2b10 (Patel et al., 2007), hepatocellular apoptosis (Zaher
et al., 2008; Budinsky et al., 2014). and with cyclin G2 (Ahmed et al., et al., 1998), but TCDD treatment
Oxidative stress and oxidative 2012). of rats that express AhR also re-
DNA damage have long been recog- The extensive cross-talk with sulted in increased apoptosis in the
nized as important factors in carcino- ER signalling mentioned above ex- liver during hepatocarcinogenesis
genesis (Klaunig et al., 2011) (see plains the anti-estrogenic properties (Stinchcombe et al., 1995). In human
CHAPTER 14
PART 2
Chapter 15, by Bucher). Oxidative of TCDD (Safe and Wormke, 2003; skin cells in vitro, TCDD caused in-
stress has been demonstrated to Denison et al., 2011). There is evi- hibition of cellular senescence, pre-
occur after in vivo and in vitro expo- dence that this AhR–ER cross-talk sumably via AhR, which may explain
sure to AhR ligands including TCDD, can occur at different levels of AhR in part the tumour-promoting activi-
PCB 126, and PeCDF (Yoshida involvement in the regulation or ty of TCDD in initiated skin in mice
and Ogawa, 2000; Hennig et al., dysregulation of gene expression, (Ray and Swanson, 2009). However,
2002). Upregulation of CYP1A1 and including non-classical modes with whether this mechanism occurs in
CYP1B1 by activated AhR increases AhR–ARNT or just AhR acting as vivo and in the liver is not known.
the chance of production of reactive co-repressor (Ohtake et al., 2003; PCBs can also stimulate hepatic cell
oxygen species upon uncoupling Labrecque et al., 2012). proliferation, but this is not consis-
of the catalytic cycle of these en- Mediated by AhR, TCDD down- tently found and may or may not be
zymes, as has been shown for ex- regulates the EGF receptor and in- AhR-dependent.
posure to dioxin-like coplanar PCBs hibits binding of EGF to its receptor The coplanar PCB 126 and the
(Schlezinger et al., 2006; Green et al., in several tissue types (Madhukar non-coplanar PCB 153 both in-
2008). In addition, in experiments et al., 1984; Kitamura et al., 2006; duced proliferation, but only af-
with mice, AhR activation has been Haarmann-Stemmann et al., 2009). ter a tumour-initiating dose of
associated with mitochondrial pro- This reduces EGF signalling, which diethylnitrosamine, and both had
duction of reactive oxygen species may be an anti-carcinogenic rath- liver tumour-promoting activity
in a process that does not appear er than a pro-carcinogenic effect. (Rignall et al., 2013). However, in
to involve CYP450 enzymes (Senft Conversely, EGF receptor signalling other studies, PCB 153 stimulated
et al., 2002). appears to inhibit AhR action at the hepatocellular proliferation in rats
Many signalling pathways are DNA level (Sutter et al., 2009), indi- but not when preceded by treatment
mechanistically involved in carcino- cating significant cross-talk with EGF with diethylnitrosamine, whereas
genesis, including those involved pathways. the coplanar 3,3′,4,4′-tetrachlorobi-
in regulation of cell proliferation, Induction of cell proliferation has phenyl (PCB 77) inhibited or stim-
apoptosis, senescence, and angio- long been considered to be a causal ulated hepatocellular proliferation
genesis (Hanahan and Weinberg, factor in carcinogenesis in humans (Tharappel et al., 2002; Lu et al.,
2011) (see Chapter 10, by Smith). and experimental animals (Preston- 2003, 2004). PCB 126, but not PCB
There is considerable evidence of Martin et al., 1990; Schwarz et al., 153, stimulated proliferation of cul-
extensive cross-talk of AhR with 1995), with receptor mediation and tured liver cells (Vondrácek et al.,
several of these and other path- an imbalance between proliferation 2005). In studies with exposures of
ways, including various nuclear and apoptosis in favour of cell growth up to 2 years, PCB 153 did not stim-
transcription factors (Haarmann- as major mechanisms (Roberts ulate hepatic cell proliferation and
140
2011), even though it is a liver tu- liferation or reduction of apoptosis; compounds, such as those used in
mour promoter after treatment with in that concept, receptor-mediated combined oral contraceptives and
diethylnitrosamine (Hayashi et al., carcinogens are tumour promoters, hormonal menopausal therapy, the
2012). Omeprazole also activates co-carcinogens, enhancers of sus- dose–response is typically biphas-
AhR and induces CYP1A1 but is not ceptibility, or indirect inducers of ge- ic (inverted U-shaped), and the ef-
carcinogenic (Kleeberg et al., 1999). notoxicity, for example via induction fect threshold is observed at very
However, many other agents that of oxidative stress. For example, in- low doses (Reddel and Sutherland,
activate AhR and induce CYP1A1 creased cell proliferation has been 1987; Groshong et al., 1997).
and CYP1A2 are carcinogenic. shown to neoplastically transform rat A further complicating issue is the
Furthermore, induction of oxidative hepatocytes only after treatment with evidence for a wide range of modi-
stress by TCDD and dioxin-like com- a genotoxic agent (Lee et al., 1989). fying factors that can affect the re-
pounds is non-specific and is – like NIH 3T3 cells will undergo complete ceptor-mediated action of suspected
various other pleiotropic effects of neoplastic transformation under fa- carcinogenic agents; not only is the
these agents – perhaps not required vourable conditions after sustained dose critical, but species, sex, age,
for AhR-mediated carcinogenesis. proliferation, but these cells are al- tissue or cell context, duration and
Such effects can only be considered ready immortalized (Yao et al., 1990; timing of exposure, and route of ex-
CHAPTER 14
Chow and Rubin, 2000). posure are all crucially important
PART 2
additional evidence suggesting that
a compound that activates AhR and Thus, it appears that stimula- modifying factors, as pointed out
induces CYP1A1 and CYP1A2 is car- tion of cell proliferation by itself is above. Often neglected are co-ex-
cinogenic to humans or experimental not sufficient to induce cancer, but posures that may be important in de-
animals. that it can be a powerful enhancer termining the ultimate effect; for ex-
Stimulation of cell proliferation of carcinogenesis by facilitating ini- ample, exposure to cigarette smoke
is often invoked as an effect that tiating events, for example through and its constituents may influence
indicates carcinogenic potential of fixation of pro-mutagenic DNA le- the outcome of exposure to TCDD
sions, affecting DNA repair, inducing or other dioxin-like compounds
chemicals and as a cause of human
error-prone DNA synthesis (Mimura (Kitamura and Kasai, 2007).
cancer (Preston-Martin et al., 1990;
and Fujii-Kuriyama, 2003), and/or The diversity of ER-, PR-, and
Oliver and Roberts, 2002). But one
by acting as a driving force during AhR-mediated effects observed
can ask whether receptor-mediated
tumour promotion and progression. across species, sexes, tissues, and
effects resulting in enhancement of
These notions obviously have impli- cell types and across exposure con-
cell proliferation and/or reduction of
cations for the use of cell prolifera-
apoptosis are sufficient for carcino- ditions (dose, duration, timing, and
tion as a criterion in hazard identi-
genicity, or whether more is needed. route of exposure) poses consid-
fication of suspected carcinogens
Induction of cell proliferation erable obstacles to rational testing
and in carcinogen risk assessment
by estrogens and progestins or by for carcinogenic and mechanistic
(Melnick et al., 1996).
TCDD and dioxin-like compounds effects that predict human carcino-
Receptor-mediated events are
is not a simple effect but is highly genicity of agents that act via these
typically dose-dependent, and
complex and dependent on a wide receptors. Whole-animal models are
dose–response relationships be-
variety of factors, as was pointed out essential to sort out these effects,
tween ligands and receptor-mediated
above. Only in certain circumstances effects are often nonlinear. This has and animal bioassays that are de-
will these agents stimulate cell pro- led to the concept of a dose thresh- signed to detect relevant carcino-
liferation in target tissues, whereas old for receptor-mediated carcino- genic effects remain indispensable.
in other situations they may inhibit gens that is used in carcinogen risk However, no good animal models
proliferation (Hushka and Greenlee, assessment. However, non-thresh- exist for exposures to some of the
1995). Furthermore, there is only old dose–responses also occur, and important receptor-mediated carcin-
scant direct evidence that increased there are many factors that can af- ogens. It is not clear how to best test
cell proliferation by itself causes tu- fect the shape of dose–responses of for effects of agents that are used or
mours or malignant transformation. non-genotoxic or receptor-mediated intended as oral contraceptives, and
Most likely, genetic damage is re- carcinogens (Melnick et al., 1996). there are no truly relevant animal
quired in combination with cell pro- Moreover, for steroid hormone-like models reflecting conditions found
142
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152
part 2.
mechanisms of carcinogenesis
chapter 15.
CHAPTER 15
PART 2
Throughout evolution, aerobic An imbalance between the normal Pierre et al., 2002). Peroxisomes are
organisms have developed mul- production of oxygen radicals and a source of H2O2, through reactions
tiple defence systems to protect their capture and disposal by pro- involving acyl-CoA oxidase (which
themselves against oxygen radicals tective enzyme systems and antiox- is involved in oxidation of long-chain
(Benzie, 2000). One-, two-, and idants results in oxidative stress, and fatty acids), d-amino acid oxidase,
three-electron reductions of molecu- this condition has been proposed and other oxidases (Schrader and
lar oxygen give rise to, respectively, to be the basis of many deleterious Fahimi, 2006).
superoxide (O2• −), hydrogen peroxide chronic health conditions and dis- When stimulated, inflammatory
(H2O2, a radical precursor), and the eases, including cancer. cells such as neutrophils, eosino-
highly reactive hydroxyl radical (•OH) phils, and macrophages produce ox-
or equivalent transition metal–oxy- Sources of oxygen radicals ygen radicals during the associated
gen complexes (Miller et al., 1990). respiratory burst (the rapid release of
Reactions of oxygen radicals with Mitochondrial oxidative phosphor- reactive oxygen species from cells)
cellular components can deplete an- ylation is a major source of oxy- that involves nicotinamide adenine
tioxidants, can cause direct oxidative gen radicals of endogenous origin. dinucleotide phosphate (NADPH)
damage to lipids, proteins, RNA, and Mitochondrial complex I (reduced oxidase (Babior, 1999). This reac-
DNA, and can result in the forma- nicotinamide adenine dinucleotide tion produces superoxide, which is
tion of a variety of other reactants [NADH]:ubiquinone oxidoreductase) converted by superoxide dismut-
with varying oxidative potentials, in- and complex III (ubiquinol:cy- ase to the more readily diffusible
cluding carbon- or nitrogen-centred tochrome c oxidoreductase) are oxidant H2O2 and is involved in cell
radicals (West and Marnett, 2006). sites of superoxide production, with killing functions. Inflammatory cells
A growing body of literature presents as much as 1–2% of the electron such as macrophages are also ca-
radicals as mediators of various cell flux shunted through one-electron pable of producing nitric oxide (•NO),
signalling processes (Ma, 2010). reduction of molecular oxygen (St- through an inducible form of nitric
154
Clearly, high levels of oxygen rad- tions of glutathione peroxidases neonates of certain of these species
icals can be fatal to the cell through along with thyroid peroxidase, to survive such exposures with little
overt necrosis or the induction of and high levels of glutathione per- evidence of injury. The neonates of
apoptosis, but lower levels may also oxidases can interfere with the species resistant to pulmonary injury
contribute to the process of carcino- synthesis of thyroid hormones. are capable of increasing their levels
genesis through stimulation of cellu- Immunostaining for 8-oxo-2′-deoxy- of antioxidant enzymes in response
lar proliferation and alterations in oth- guanosine shows greater intensity in to hyperoxia, in contrast to the adults,
er cellular functions. There appear to thyroid follicular cells near the lumen which are incapable of mounting a
be a myriad of potential mechanisms where H2O2 is generated than in the similar response (Frank et al., 1978).
for these effects, involving induction spleen, liver, or lung, suggesting a Several metals, metalloids, and
of transcription factors for numer- high level of oxidative DNA damage fibres that contain metals or are fre-
ous signalling pathways, particular- in the thyroid (Maier et al., 2006). quently contaminated with metals
ly nuclear factor erythroid 2-related Environmental insults may aug- have been demonstrated to cause
factor 2 (Nrf2), mitogen-activated ment oxidative DNA damage in the cancer of the lung in humans and
protein kinase (MAPK)/AP1, nucle- thyroid. Thyroid uptake of iodine-131 experimental animals (IARC, 2012a).
ar factor kappa-light-chain-enhanc- released during the accident with the These include certain forms of ar-
CHAPTER 15
er of activated B cells (NF-κB), and
PART 2
Chernobyl Nuclear Power Plant in senic, asbestos, beryllium, cadmi-
hypoxia-inducible transcription fac- Ukraine is thought to be responsible um, chromium, and nickel. Although
tor 1 alpha (HIF-1α) (reviewed by for the high rate of papillary carci- carcinogenesis induced by metals
Klaunig et al., 2011). Protein kinase noma observed in exposed children appears to involve many mecha-
C, which is also susceptible to acti- (Bennett et al., 2006). Rats and mice nisms common to the process for
vation by cellular oxidants, is a fam- exposed to iodine-131 develop fol- other carcinogens, oxidative stress
ily of serine/threonine kinases that licular cell tumours (IARC, 2012b). has been implicated as an important
is central to the regulation of many Thiocyanate from cigarette smoke contributing factor for several met-
cellular functions, including prolifer- may, by inhibiting uptake of iodine, als (reviewed by Beyersmann and
ation, cell-cycle control, differentia- cause oxidative damage through Hartwig, 2008).
tion, cytoskeletal organization, cell iodine deficiency. Production of Certain metals may undergo di-
migration, and apoptosis (Wu, 2006). thyroid-stimulating hormone is in- rect redox cycling, as demonstrated
There is also evidence that the ac- creased during periods of iodine by the participation of nickel(II) in a
tivated oncogene v-Ha-Ras may act deficiency, and this hormone stimu- Fenton-like reaction with H2O2, or in
as a sustained proliferative stimulus lates H2O2 production in the thyroid. the metabolism of trivalent to pen-
in transformed fibroblasts through Levels of antioxidant enzymes have tavalent arsenic. Other metals, such
superoxide-mediated signalling been shown to be elevated by iodine as cadmium, may inhibit antioxidant
pathways (Irani et al., 1997).
deficiency (Krohn et al., 2007). enzymes or deplete antioxidants
The lung is also a vulnerable tar- (cadmium and arsenic bind with
Vulnerable tissue sites
and selected carcinogenic get for oxidative damage, by virtue sulfhydryl groups in glutathione) or
exposures of its exposure to air, which contains potentially delocalize iron or copper
21% oxygen, as opposed to the from protected storage sites (e.g. tri-
The synthesis of thyroid hormones much lower oxygen concentrations valent arsenic can release iron from
requires iodination of thyroglobu- in systemic tissues (Carreau et al., ferritin), making them available for
lin in a peroxidase-catalysed re- 2011). A key role of oxygen radicals participation in oxygen radical reac-
action that is dependent on H2O2. in the pulmonary toxicity resulting tions. Still other metals, such as ar-
Krohn et al. (2007) reviewed evi- from prolonged exposure to hyper- senic (reviewed by Shi et al., 2004),
dence suggesting that the thyroid is oxia is demonstrated by the dramatic may activate signalling pathways
particularly sensitive to formation of difference in the sensitivity of adult through increased production of oxy-
malignant nodules induced by oxida- animals of various species, which gen radicals, and potentially promote
tive stress. During active hormone succumb to oxygen toxicity after less radical reactions through a variety
synthesis, H2O2 levels are held in than a week of exposure to 100% of mechanisms. Finally, many stud-
check with increased concentra- oxygen, compared with the ability of ies have shown that asbestos or
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chapter 16.
Immunosuppression
Jerry M. Rice
CHAPTER 16
PART 2
Introduction from exposure to non-viral antigens, pharmaceutical drugs or by ionizing
such as after organ transplantation or ultraviolet radiation is dose-de-
Immunosuppression is a reduction (Ponce et al., 2014). pendent – the intensity and duration
in the capacity of the immune sys- Potentially neoplastic cells that of the effect increases with increasing
tem to respond effectively to foreign arise naturally, or that have been dose or continuing exposure – and is
antigens, including surface antigens transformed by carcinogens acting usually transient: immune function
on tumour cells. Immunosuppression by a mechanism such as genotox- generally recovers after cessation
can result from killing of immune ef- icity or by the various mechanisms of exposure. In contrast, infection
fector cells or from blockage of intra- of action associated with oncogenic with certain pathogens, such as hu-
cellular pathways essential for anti- viruses, may escape immune sur- man immunodeficiency virus type 1
gen recognition or of other elements veillance in immunosuppressed indi- (HIV-1) or malaria parasites, is per-
of the immune response. viduals. As a result, survival of these sistent, and the immune deficiency
Persistent immunosuppression cells and their replication to form that results is progressive unless the
presents a risk of cancer. Individuals tumours is greatly facilitated. infection is effectively treated.
who are latently infected with an on- Certain pharmaceutical drugs, Immunosuppression as a medi-
cogenic virus are at greatly increased ionizing and ultraviolet radiation, cal therapy is used to treat autoim-
risk for developing virus-related or infection with certain viruses mune diseases such as lupus ery-
cancers when they become immu- and parasites can cause immu- thematosus or rheumatoid arthritis.
nosuppressed (Grulich et al., 2007; nosuppression. After exposure to Immunosuppressive drugs, usually
Schulz, 2009; Wieland et al., 2014), X-rays or other types of ionizing in much higher dosage, are used to
and there is excess risk of B-cell radiation, immunosuppression is maintain the functional and anatom-
non-Hodgkin lymphoma (NHL) when most pronounced if the entire body, ical integrity of foreign tissues graft-
immunosuppression is accompanied rather than a limited area, is irra- ed onto another individual, such as
by continuing immune stimulation diated. Immunosuppression by a kidney or heart transplant. A graft
160
in patients with HIV-1 infection. Its virus and hepatitis C virus, and are al population (Kasiske et al., 2004).
occurrence is highly correlated with therefore at elevated risk for hepa- Non-melanoma skin cancers other
the severity of suppression of CD4- tocellular carcinoma (Grulich et al., than Kaposi sarcoma also occur at
positive T lymphocytes. The stan- 2007). high frequency in organ transplant
dardized incidence ratio for Kaposi recipients (Forchetti et al., 2014).
Therapeutic
sarcoma in a Swiss cohort was more There is a 65-fold increase in the
immunosuppression
than 500 in patients with a CD4- incidence of squamous cell carci-
positive lymphocyte count of less Therapeutic immunosuppression, noma and a 10-fold increase in the
than 100 cells/mm3 but approximate- generally by various combinations incidence of basal cell carcinoma in
ly 76 in patients with a CD4-positive of drugs such as ciclosporin and organ transplant recipients relative
lymphocyte count of greater than azathioprine, is administered to or- to the general population (Yu et al.,
500 cells/mm3 (Clifford et al., 2005; gan transplant recipients to maintain 2014).
IARC, 2012a). their transplanted organ or organs.
Ciclosporin
NHL, chiefly of the B-cell type, Recipients are at high risk for some
is the second most common ma- of the same cancers that occur in Ciclosporin, a cyclic lipophilic un-
lignancy in patients with AIDS. In a
CHAPTER 16
patients with AIDS. A comparison decapeptide, is a calcineurin inhibi-
PART 2
meta-analysis of six studies, NHL of AIDS-related and transplanta- tor and a potent immunosuppressant
had a standardized incidence ratio tion-associated tumours, from which that is virtually non-myelotoxic but
of 77 in patients with HIV-1 infection this text is excerpted, is presented in is markedly nephrotoxic. It is used
relative to the general population IARC (2012a). in organ and tissue transplanta-
(Grulich et al., 2007), and NHL is Although individuals with AIDS tion to prevent graft rejection after
frequently associated with Epstein– and those with iatrogenic immuno- bone marrow, kidney, liver, pan-
Barr virus (EBV) co-infection. The suppression after organ transplan- creas, heart, lung, and heart–lung
severe depletion of CD4-positive T tation have immunodeficiency in transplantation, and for prophylaxis
lymphocytes induced by HIV-1 leads common, the immunological abnor- and treatment of graft-versus-host
to dysregulated control of B lympho- malities appear to differ consider- disease (IARC, 2012b).
cytes and to the expression of co-in- ably between these two conditions. The immunosuppressive activity
fecting lymphotropic viruses (Engels, However, the spectra of neoplasms of ciclosporin is consistent with an
2007). that occur in patients with AIDS and increased risk of cancer as a result
The third most common malig- in organ transplant recipients large- of impaired immune surveillance,
nancy in HIV-1-positive individuals, ly overlap. An obvious similarity be- particularly for virus-related can-
and also an AIDS-defining condition, tween organ transplant recipients cers such as EBV-related NHL and
is cervical carcinoma associated and patients with AIDS is the in- HPV-related cervical cancer (IARC,
with human papillomavirus (HPV) creased incidence of B-cell NHL as- 2012b). Patients who receive ciclo-
infection. Anogenital intraepitheli- sociated with EBV infection. Specific sporin also are at increased risk for
al neoplasms and carcinomas are differences include more frequent squamous cell tumours of the skin,
also increased in frequency, and so high-grade lymphomas in patients which may be due in part to effects
are skin cancers associated with with AIDS and a more frequent EBV of the drug other than immunosup-
HPV infection (IARC, 2012a). In ad- association and polymorphic lesions pression. Ciclosporin has the ability
dition to NHL and Kaposi sarcoma, in organ transplant recipients. to generate reactive oxygen species,
infection with HIV-1 causes cancer The second important malignan- and this is probably relevant to its
of the cervix, anus, and conjunctiva, cy that is greatly increased in inci- carcinogenicity (IARC, 2012b).
as well as of the vulva, vagina, and dence in both individuals with HIV-1
Azathioprine
penis (IARC, 2012a). The primary infection and transplant recipients is
cause of these squamous epithelial Kaposi sarcoma (Zattra et al., 2014). Azathioprine, a substituted 6-mer-
neoplasms is co-infection with HPV. A study of renal transplant recipi- captopurine, is used in immunosup-
Finally, individuals with HIV-1 infec- ents reported a more than 20-fold pressive treatments to prevent re-
tion have a greatly increased inci- increase in the incidence of Kaposi jection of kidney allografts. The drug
dence of infection with hepatitis B sarcoma compared with the gener- is usually used in conjunction with
162
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chapter 17.
Inflammation
Agnes B. Kane
CHAPTER 17
PART 2
Introduction has also been associated with devel- Intrinsic and extrinsic
opment of lung cancer and malignant pathways linking
In 1863, Virchow proposed that mesothelioma (Table 17.1). Cancer- inflammation and cancer
cancer originates at sites of inflam- related inflammation has been de-
matory responses (Virchov 1863a, Acute inflammation is a beneficial
fined as “the seventh hallmark of
b; Balkwill and Mantovani, 2001). host response against tissue injury
cancer” (Colotta et al., 2009), and
Based on extensive epidemiologi- and microbial invasion that usually
Hanahan and Weinberg (2011) add-
cal studies in the 20th century (de resolves after killing of the invading
ed “tumour-promoting inflammation”
Martel et al., 2012; Elinav et al., organisms, followed by tissue regen-
as an enabling characteristic of hu-
2013; Okada, 2014), the association eration or repair. Persistent infections
man tumours.
between persistent infections, in- or inadequate resolution of acute in-
This chapter focuses on the con-
flammation, and the development flammatory responses perpetuate
tribution of inflammation to multiple
of human cancers was conclusively tissue injury and lead to prolonged
steps during the evolution of cancer,
established for several types of car- chronic inflammation accompanied
including genetic and epigenetic al- by fibrosis or scarring (Kundu and
cinomas and lymphomas (Table 17.1
and Table 17.2). terations, disruption of tissue organi- Surh, 2012).
Worldwide, infections have been zation and homeostasis, and estab- Persistent infection and inflamma-
linked with 16.1% of human cancers, lishment of a local microenvironment tion disrupt local tissue homeostasis
accounting for 22.9% of cancers in that contributes to tumour growth, and dysregulate cell signalling path-
developing countries (de Martel et al., invasion, and metastasis (Fig. 17.1). ways, leading to recruitment and acti-
2012). Sterile inflammation associat- The key mechanistic pathways and vation of inflammatory cells (Balkwill,
ed with inhalation of crystalline silica mediators involved in inflamma- 2012). Persistent inflammatory con-
or asbestos fibres (Volume 100C of tion-associated carcinogenesis are ditions triggered by infectious or
the IARC Monographs; IARC, 2012a) summarized. environmental agents are defined
166
Table 17.2. Human lymphomas associated with persistent infections and by macrophages, resulting in acti-
inflammation vation of the NLRP3 inflammasome
(Biswas et al., 2011; Li et al., 2012).
Agent Malignancy Amphibole asbestos fibres, after
inhalation into the lungs, translocate
Borrelia burgdorferi Cutaneous lymphoma to the pleural cavity, where they may
Chlamydia psittaci Ocular adnexal lymphoma
also activate the inflammasome in
the mesothelial cell lining, leading to
Helicobacter pylori Gastric lymphoma
sustained inflammation that contrib-
Epstein–Barr virus Burkitt lymphoma utes to the development of diffuse
Large B-cell lymphoma malignant pleural mesothelioma
Hodgkin lymphoma
(Broaddus et al., 2011; Mossman
Human T-cell lymphotropic virus type 1 Adult T-cell lymphoma et al., 2013). Particles of carbon black
Source: Compiled from de Martel et al. (2012) and IARC (2012b). have also been shown to induce ac-
tivation of the inflammasome and
pyroptosis of alveolar macrophages
CHAPTER 17
of transcription 3 (STAT3) (Lin and sis is usually not associated with an
PART 2
Karin, 2007). IL-6 also promotes inflammatory response, extensive at high doses (Reisetter et al., 2011).
tumour angiogenesis and invasion apoptosis and necrosis do trigger in- After assembly of the inflam-
(Multhoff et al., 2011). Constitutive flammation by releasing damage-as- masome or release of cathepsin B
activation of NF-κB and STAT3 is sociated molecular factors, includ- from lysosomes, pro-caspase-1 is
found in several human tumours, and ing adenosine triphosphate (ATP), activated by proteolytic cleavage
these factors act synergistically to nucleic acids, heat shock proteins, to produce active caspase-1 that
sustain and enhance tumour-associ- S100 proteins, and the high-mobil- cleaves pro-IL-1β and pro-IL-18 to
ated inflammation (Chai et al., 2015). ity group box 1 protein (HMGB1) their active forms, which initiate and
The ultimate impact of intratu- (Pandey et al., 2015). amplify inflammation after release
moural inflammation on tumour Pyroptotic cell death – which is in the local environment (Fig. 17.2).
growth is to stimulate proliferation similar to apoptosis but is dependent Active caspase-1 can also cleave
and survival of tumour cells, resis- on a different set of initiator caspas- pro-caspase-7, triggering cell death
tance to apoptosis, evasion of host es – is associated with necrosis and by pyroptosis (Zitvogel et al., 2012).
immune attack, angiogenesis, and in- depends on activation of the inflam- Active IL-1β and IL-18 can suppress
masome, a multiprotein cytoplasmic immune surveillance in addition to
vasion, which are all major hallmarks
complex assembled in response to promoting growth of tumour stromal
of cancer (Hanahan and Weinberg,
generation of reactive oxygen spe- cells by paracrine signalling path-
2011). These authors identified tu-
cies, potassium ion efflux, or perme- ways (Fig. 17.2). Persistent inflam-
mour-promoting inflammation as an
abilization of lysosomes, resulting mation and pyroptosis may enhance
enabling characteristic of cancer, in
in cytoplasmic release of neutral damage to epithelial barriers and
addition to genomic instability, which
proteases, such as cathepsin B thus contribute to gastric cancer
is discussed later in this chapter.
(Kuraishy et al., 2011; Zitvogel et al., associated with Helicobacter pylori
How do exogenous infectious 2012). infection (Grivennikov et al., 2010).
agents and environmental Environmental exposures to, for Persistent infection with hepatitis B
exposures trigger tumour- example, crystalline silica and as- or C virus can also lead to chronic re-
associated inflammation? bestos fibres also trigger activation lease of pro-inflammatory cytokines
of the inflammasome, which results (Grivennikov et al., 2010; Read and
Exogenous agents responsible in lung epithelial injury, release of Douglas, 2014).
for inflammation cause persistent pro-inflammatory mediators, and Chronic exposure to irritants
tissue injury, aberrant tissue regen- lung fibrosis (Fig. 17.2; Dostert present in tobacco smoke, or to ac-
eration and healing, and a favour- et al., 2008, 2013; Luna-Gomes etaldehyde generated by ethanol
able environment for tumour growth et al., 2015). Crystalline silica and metabolism after consumption of al-
(Trinchieri, 2012). Although apopto- asbestos fibres are phagocytosed coholic beverages, induces epithelial
Prostaglandins
Cytokines (IL-1, TNF-α, IL-6)
Chemokines DNA and Dysregulated DNA
Heat shock proteins chromosomal repair and epigenetic
damage pathways
Intratumoural inflammation;
tumour cell proliferation and survival
Resistance to apoptosis
Evasion of host immune attack
Angiogenesis
Invasion and metastasis
cell injury in the oral cavity and the Inflammation and genomic which generates excess reactive ni-
upper respiratory tract. These le- instability trogen species (Laskin et al., 2011).
sions synergize with potent chemical Constitutive activation of STAT3 in
carcinogens in tobacco smoke and Activation of the NF-κB and STAT3 cancers maintains NF-κB activation,
smokeless tobacco, thereby increas- signalling pathways and activation creating a self-sustaining amplifica-
ing the risk of cancers of the oral cav- of macrophages by TNF-α are the tion loop (Chai et al., 2015).
ity, larynx, and oesophagus (Smith key contributors to sustained gen- NF-κB activity is prolonged in the
et al., 2006). Persistent chronic in- eration of reactive oxygen species presence of mutant p53 protein and
flammation associated with hepatitis and reactive nitrogen species in upregulates activation-induced cyti-
B viral infection acts synergistically cancer-related inflammation (Colotta dine deaminase, an error-prone DNA
with aflatoxin, a genotoxic carcin- et al., 2009). Activated macrophag- repair enzyme (Cooks et al., 2014).
ogen, in the development of hepa- es release large quantities of re- Reactive oxygen species inactivate
tocellular carcinoma (Kew, 2003; active oxygen species, and NF-κB mismatch DNA repair enzymes by
Cougot et al., 2005). upregulates nitric oxide synthase, inducing oxidative damage; although
168
Fig. 17.2. Crystalline silica and asbestos fibres activate the NLRP3 inflammasome. IL-1β, interleukin 1 beta; IL-
18, interleukin 18. Source: Compiled from Dostert et al. (2008), Biswas et al. (2011), Zitvogel et al. (2012), and
Mossman et al. (2013).
Pro-caspase-1 Caspase-1
CHAPTER 17
Pro-IL-1β IL-1β
PART 2
Pro-IL-18 IL-18
Autocrine or
paracrine signalling
Amplification of
inflammation;
tumour cell proliferation;
immunosuppression
reactive oxygen species induce the or bromination have been proposed oping tumours. Tumour-associated
base excision repair pathway, over- to induce heritable epigenetic al- inflammation and genomic insta-
expression of these repair enzymes terations due to cytosine methyl- bility drive tumour growth and pro-
enhances microsatellite instability ation (Valinluck and Sowers, 2007). gression, which enable acquisition
(Colotta et al., 2009). Upregulation Chronic infection with Helicobacter of the six core hallmarks of cancer
of NF-κB and sustained production pylori is also associated with hyper- (Hanahan and Weinberg, 2011).
of cytokines cooperate with mutated methylation and silencing of p16 as
Inflammation, fibrosis, and
p53 protein to enhance genomic in- well as E-cadherin (Kundu and Surh,
cancer
stability (Fig. 17.1; Grivennikov et al., 2012).
2010; Cooks et al., 2014). In summary, chronic or persistent In 1986, Dvorak described cancers
Tumour-associated inflammation inflammation favours accumulation of as “wounds that do not heal”, based
is also linked with epigenetic alter- DNA lesions and chromosomal dam- on evidence of inflammatory cells in-
ations that lead to silencing of key age induced by persistent production filtrating into tumours, accompanied
tumour suppressor genes, such as of reactive oxygen species and reac- by angiogenesis and fibrosis, similar
INK4a or p16 in lung cancers and tive nitrogen species, impaired DNA to wound healing (Dvorak, 1986; see
malignant mesothelioma (Blanco repair pathways, and heritable epi- also Dvorak, 2015). Persistent infec-
et al., 2007; Christensen et al., 2009, genetic alterations, leading to activa- tions accompanied by parenchymal
2010; Nelson et al., 2012). Oxidative tion of oncogenes and inactivation of cell injury and chronic inflamma-
damage to cytosine and chlorination tumour suppressor genes in devel- tion, and fibrosis associated with
170
are associated with lung cancer in contaminant aflatoxin in the devel- occupational, personal, and infec-
humans and experimental animals, opment of hepatocellular carcinoma tious exposures resulting in per-
and asbestos fibres may also induce (Kew, 2003; IARC, 2012b; Simet sistent or chronic inflammation are
cancer at distant sites, including et al., 2012). In combination with po- preventable, and modifying these
the mesothelial lining and the ovary tent carcinogens in tobacco smoke circumstances of exposure would
(IARC, 2012a). and smokeless tobacco (e.g. ar- diminish the worldwide burden of
Persistent bacterial, viral, and ylamines, polycyclic aromatic hydro- cancer.
parasitic infections (IARC, 2012b) carbons, and nitrosamines), ethanol
Acknowledgement
are also associated with a variety of consumption may increase epithelial
human carcinomas as well as leu- permeability and injury, which to- The author’s research is support-
kaemias and lymphomas (Table 17.1 gether with oxidative stress enhance ed by a National Institute of Envi
and Table 17.2). Persistent or repeat- the development of cancers of the ronmental Health Sciences (NIEHS)
ed episodes of tissue injury and in- oral cavity, larynx, and oesophagus Superfund Research Program grant,
flammation may also synergize with (Bor and Capanoglu, 2009; IARC, P42 ES013660.
viral oncoproteins and the fungal 2012c). Exogenous environmental,
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chapter 18.
Ionizing radiation
Mark A. Hill and Robert L. Ullrich
CHAPTER 18
PART 2
Introduction The rationale for this was that all and international reviews of the liter-
types of ionizing radiation transfer ature on radiation, as well as radia-
The carcinogenic risk associated their energy to biological material in tion risk estimates. These include the
with exposure to ionizing radiation clusters of ionization and excitation publications of the United Nations
has been evaluated previously in the events, primarily through a mecha- Scientific Committee on the Effects
IARC Monographs: radon in Volume nism mediated by free electrons. In of Atomic Radiation (UNSCEAR,
43 (IARC, 1988), X-rays, γ-rays, and addition, DNA damage is a common 2000, 2008, 2010) and the reports
neutrons in Volume 75 (IARC, 2000), biological outcome of exposure to all from the United States National
and some internally deposited radio- ionizing radiation; energy deposition Research Council (NRC, 1999,
nuclides in Volume 78 (IARC, 2001). results in a wide variety of molecular 2006), the United States National
An updated review on all carcinogen- damage, such as base damage and Council on Radiation Protection and
ic types of radiation, also including single- and double-strand breaks, Measurements (NCRP, 1993, 1999,
solar and ultraviolet radiation, was some of which may be clustered to 2001, 2005), and the International
published as Volume 100D (IARC, form complex lesions. Subsequent Commission on Radiologic al
2012). processing of these lesions may lead Protection (ICRP, 2003, 2007;
For certain types of ionizing radi- to chromosomal aberrations and mu- Valentin, 2005).
ation, the evidence of carcinogeni- tations. The generality of induction of Two major issues faced when
city in humans is clear, but in other and response to radiation damage studying radiation carcinogenesis is
cases the data are few or non-exist- is discussed for all types of ionizing that radiation-induced cancers are
ent. However, the overall conclusion radiation in greater depth later in this indistinguishable from those that oc-
reached in Volume 100D of the IARC chapter. cur naturally, and that risk estimates
Monographs was that all types of ion- In addition to the above-mentioned rely on epidemiological data for which
izing radiation should be considered reviews in the IARC Monographs, statistical significance is reached
as carcinogenic to humans (Group 1). there have been many major national only at high doses. The existing data
176
Ionizing radiation can cause DNA (Nikjoo and Goodhead, 1991). These tion, which ultimately leads to stalled
damage either by direct ionization more complex forms of damage are replication forks that may give rise to
of the constituent atoms in the DNA essentially unique to ionizing radia- DSBs or mutations. Therefore, non-
or indirectly by reactions with free tion and are not seen spontaneously DSB clusters are potentially highly
radicals produced by interactions or with other DNA-damaging agents. mutagenic and are likely to play a
with water molecules (most notably The number of DSBs induced in more important role at low doses
the hydroxyl radical, which can in- DNA is approximately 20–40 per
of low-LET radiation; because non-
duce DNA strand breakage or base cell per gray for low-LET X-rays and
DSB damage is produced at a higher
damage), or by a combination of di- γ-rays, and a similar number is ob-
frequency than DSBs at these lower
rect and indirect effects. In the cell, served for α-particles in standard
doses, more cells will contain non-
hydroxyl radicals will typically only assays. However, the percentage
diffuse a few nanometres (< 6 nm), of complex DSBs (with extra strand DSB clustered damage compared
thus preserving the spatial structure breaks and/or associated base dam- with DSBs (reviewed by Eccles et al.,
of the radiation tracks. age within 10 base pairs) is about 2011).
Ionizing radiation can thus induce 30–50% for electrons (similar to the DNA is wrapped around histone
a range of different types of molecular percentage produced by X-rays and proteins to form nucleosomes, which
CHAPTER 18
PART 2
damage in DNA, such as base dam- γ-rays) based on Monte Carlo calcu- are organized into 30 nm chromatin
age (including apurinic/apyrimidinic lations, and this percentage increas- fibres that are typically arranged in
sites), strand breaks, DNA–protein es with increasing ionization den- loops. As a result of the sequence of
cross-links, and combinations of sity (LET) of the radiation, to about ionization events along individual ra-
these within a few base pairs of each 90% for 0.3 MeV protons and about diation tracks, especially in the case
other. Examples are double-strand 96% for high-LET 2 MeV α-parti- of densely ionizing high-LET parti-
breaks (DSBs) and non-DSB clus- cles (Nikjoo et al., 1991; Goodhead,
cles such as α-particles, these tracks
ters (two or more base damages 2006). In addition to this increase in
can lead to multiple correlated DSBs
and/or strand breaks within about the frequency of complex DSBs with
over short sections of DNA arranged
10 base pairs, but not resulting in a increasing LET, there is also an in-
in these structures. Conventional
DSB). The pattern and frequency of crease in the overall complexity of
these lesions are determined by the the damage spectrum produced. DSB assays (e.g. pulsed-field gel
clustering of ionization and excita- Clustering of damage is not con- electrophoresis and γH2AX assays)
tion events on the nanometre scale, fined to DNA but can occur in all are not able to resolve these addi-
which ultimately produces clustering biomolecules. tional DSBs and therefore typically
of damage over the dimensions of Complex non-DSB damage has underestimate the absolute yields
the DNA helix and larger. been shown to be a significant com- (Friedland et al., 2008). However,
Theoretical analyses show that ponent of the lesions induced by experimental and theoretical data
clustered DNA damage that is more radiation, occurring 4–8 times as have demonstrated the existence of
complex than a single-strand break frequently as direct DSB formation. these short fragments for these par-
can occur at biologically relevant Whereas isolated lesions (e.g. base ticles, showing a significant deviation
frequencies with all types of ionizing damage or single-strand breaks) are from a random distribution (Rydberg
radiation (Goodhead 1987, 1994; repaired quickly and generally with
et al., 1998; Friedland et al., 2008).
Brenner and Ward, 1992). Such clus- high fidelity, for non-DSB clusters
Whereas viable radiation-induced
tered damage in DNA is produced the rate of repair is typically impaired
mutations are rarely associated with
mainly within a single track, with a by the presence of additional lesions
visible chromosomal exchanges
probability that increases with in- within the cluster. The delay and the
creasing ionization density (LET). ultimate consequence depend on observed by use of fluorescence in
Calculations show that a dose of the types of lesion and their rela- situ hybridization (FISH), molecular
greater than 10 000 Gy is required tive positions. The longer lifetime of analysis of these sites shows that
for a second track to have a reason- these clusters also results in an in- high-LET particles can induce gene
able chance of contributing to the creased probability that the damage mutations of greater complexity than
local complexity of DNA damage will be present during DNA replica- simple deletions or point mutations,
178
reduced ability to replicate the geno- (Kadhim et al., 2004; Barber et al., ination route and rate, and uptake
type faithfully and therefore showing 2009; Filkowski et al., 2010; Rugo and retention in organs. In some cas-
a permanently increased rate of ac- et al., 2011). Genomic instability has es, for example for radioactive heavy
quisition of alterations in the genome also been observed in non-irradiated metals, the health effects and carci-
(Kadhim et al., 1992, 1994; Little, cells that were in the neighbourhood nogenic potential may also be relat-
2000; Morgan, 2003a, b; Barcellos- of irradiated cells, demonstrating the ed to, and potentially dominated by,
Hoff et al., 2005). This may lead to importance of intercellular signalling the chemical properties rather than
an increased probability that the cell in initiating this instability response
the radiation emitted.
and its progeny will undergo the var- (Lorimore et al., 1998). Although
In some cases, a radionuclide
ious genetic and epigenetic changes genomic instability is a plausible
may spread throughout the whole
necessary in multistage carcino- mechanism for cancer induction, its
body; in other cases, it will concen-
genesis. It is thus possible that the precise role, if any, remains to be
trate in specific organs or locations
instability phenotype plays a major proven.
within the body. If the emitted ra-
role in radiation-induced cancer, es-
pecially because genomic instability
The importance of dose diation has a short range (e.g. for
distribution with respect to α-particles and β-particles), this can
is a well-recognized feature in many
CHAPTER 18
tumour sites lead to significant heterogeneity in
PART 2
tumours (Bielas et al., 2006).
Radiation-induced genomic insta- the resulting dose distribution, with
The passage of ionizing radiation
bility typically becomes manifest sev- certain organs receiving a significant
through the body results in the depo
eral cell generations after irradiation dose while for others the radiation
sition of energy within the irradiat-
and can be detected via a range of dose is minimal. Biokinetic models
ed tissue volume. External irradia-
end-points, including chromosomal (ICRP, 1989, 1993, 1994, 1995a, b,
tion with photons is typically highly
and chromatid aberrations, micro- c, 2001) are used to estimate the
penetrating and will often result in all
nuclei, changes in ploidy, gene mu- cells and tissues in the radiation field spatial and temporal uptake of radio-
tations and amplifications, and mini- being irradiated. In contrast, emis- nuclides as well as their subsequent
and microsatellite instabilities. The sion from internalized radionuclides distribution and ultimate excretion.
frequency of genomic instability was typically occurs from specified lo- Dosimetry models (Eckerman, 1994)
observed to be too high to be ex- cations occupied by the emitting nu- are then used to calculate the result-
plained by the induction of a mutator clide source. This will often lead to a ing dose distribution over the body
genotype. Several mechanisms have non-uniform dose distribution in the and organs, based on the physical
been proposed, including dysfunc- body, especially if the emitted radia- characteristics of the radionuclides.
tional telomeres (Goytisolo et al., tion has only a short range (e.g. for The ability of internal radionu-
2000; McIlrath et al., 2001; Williams α-particles and β-particles). clides to produce a biological re-
et al., 2009) and inflammatory (free The biological effects of deposit- sponse and ultimately cancer in
radical) responses (Barcellos-Hoff ed radionuclides in the body depend various organs is related to the bio-
et al., 2005; Natarajan et al., 2007; on the amount and activity of the distribution of these emitters within
Coates et al., 2008; Lorimore et al., radionuclide deposited, the type of
the body (which will depend on the
2008), along with DNA damage and radiation emitted, the physical half-
chemical and physical properties of
response, for example long-term life of the isotope, the mode of entry,
the particles and the route of entry).
response to directly induced DNA the organs and tissues in which the
Examples are iodine-131, which con-
damage and reduced ability to han- radionuclide is retained, the duration
dle subsequent damage or cell di- centrates largely in the thyroid, and
of retention, and the rate of excretion
vision (Snyder and Morgan, 2005; from the body. The chemical char- strontium-90 and plutonium-239,
Maxwell et al., 2008; Toyokuni et al., acteristics of the radionuclide (or the which are deposited mainly in the
2009). compound in which it is incorporat- bone. The same radionuclide may
Epigenetic modification has been ed) along with its physical properties result in a different range of tumours
implicated as playing an important (such as size and shape) determine if it is delivered in such a way as to
role in the promotion and mainte- its behaviour, including absorption produce a different biodistribution
nance of transmissible instability and transport within the body, elim- pattern. In addition, there may be
180
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chapter 19.
Host susceptibility
Jane C. Caldwell, Ronald L. Melnick, and Lauren Zeise
CHAPTER 19
PART 2
Introduction experimental design of animal bio- within species, and how host sus-
assays, in methods used to identify ceptibility factors may affect evalua-
For several tumour sites (i.e. lung, concordance, and in the degree to tions of tumour site concordance.
lymphoid tissue, and digestive tract), which the animal model captures the It can be difficult to parse out
concordance has often been ob- range of potential human response reasons for lack of tumour site con-
served among different species after to the particular agent tested. An cordance (i.e. lack of response or
exposure to a given IARC Group 1 integral consideration for the devel- common responses between spe-
human carcinogen (see Chapter 21, opment and use of these models is cies). The factors alluded to above
by Krewski et al.). When reported in host susceptibility – the intrinsic and that are not strongly associated with
epidemiological studies, these tu- extrinsic factors that have an impact host susceptibility include the follow-
mour sites are also noted in some on variable response to carcinogens: ing. Competing causes of mortali-
or all of the animal species tested genetic variation, health status, life ty may prevent the development of
experimentally. There are several stage, lifestyle, sex, and the impact late-developing tumours, or studies
other tumour sites with fewer, or less of co-exposures. The microbiome may lack statistical power to detect
common, tumour site concordances can also play a critical part in host an increase in tumour incidence at
among the species studied. susceptibility. sites with high background rates.
Evaluation of concordance of This chapter focuses on exam- Limitations in how the database on
cancer development in specific ples in the IARC Monographs and in tumour site concordance was con-
target organs between and within recent literature on how well animal structed may affect the types of re-
species is dependent on several fac- models reflect the range of human sponses observed (e.g. some stud-
tors. There are various limitations in susceptibility, how host susceptibility ies may focus only on specific tumour
epidemiological studies (e.g. statis- factors may modulate the impact of outcomes or may not be designed to
tical power, exposure assessment, mechanistic events leading to tumour detect some types of tumours). Also,
follow-up, and misclassification), in development between species and when the concordance database
186
are tested, and when more suscep- hypotheses for the inherited basis of well as 730 novel non-synonymous
tible human populations are studied complex genetic traits are that they alleles with uncommon deleterious
for carcinogenic effects. result from “common disease–com- variations that, although individually
mon variant” (i.e. many common al- rare, were present in 7.6–11.7% of
Analogous transgenic, strain- leles of small effect) or “common dis- the population studied (Gordon et al.,
specific, or species-specific ease–multiple rare variants” (i.e. few 2014). Genetic variability in cell sig-
animal models rare alleles of large effect). Although nalling and gene expression may be
genome-wide association study the result of the variants in regulato-
Human and animal studies on cancer
(GWAS) approaches have been ry regions of the genes, rather than
may be more effective in discerning
based on the “common disease– being a consequence of variants in
tumour responses when those most
common variant” hypothesis, they the genetic code that instructs how
at risk are studied, such as a suscep-
have not been successful in explain- to build proteins, or in the regulato-
tible subgroup within a human cohort
ing genetic predisposition to disease ry code itself (see Chapter 13, by
and susceptible animal species and
(Zhang et al., 2011). Caldwell).
strains in a bioassay. Concordance
The understanding of the scope Just as there is genetic variabili-
of response between species may
of human genetic variability now ty in the human population that has
CHAPTER 19
increase for a particular agent when
PART 2
shows that although there is a great an impact on host susceptibility to
mechanisms of carcinogenesis and
deal of similarity in the DNA se- cancer, there is also variability within
subpopulations at risk are identified
quences between individuals, rare rodent strains and species. Genetic
and more analogous transgenic or
gene mutations are abundant, are heterogeneity resulting from cross-
strain-specific animal models are ex-
geographically localized across the ing different mouse strains has long
amined. However, these are general-
world, are difficult to catalogue, and been recognized as an issue of con-
ly not known before an animal study
are possibly a consequence of the cern in the development of experi-
is conducted. There may be gaps in
rapid spread and growth of the hu- mental mouse models, and has been
the understanding of the impact of
man population and weak purifying used as an argument to create ge-
inherent variability on tumorigenesis,
selection (Nelson et al., 2012). The netically inbred strains. Transgenic
in the identification of susceptible
breadth and scope of rare mutations mice carrying exogenous DNA and
human populations, and in the devel-
have also been illustrated through gene-targeted knockout mice have
opment of adequate animal models studies of asthma that have attempt- both been used as models for stud-
to detect a carcinogenic risk from an ed to discover the role of rare muta- ies on cancer and for identifying car-
agent or exposure condition. tions in the “missing heritability” of cinogenic properties of chemicals
Inherent variability the genetic contributions to disease. (Lunardi et al., 2014).
Although common variants at many Two examples illustrate the com-
Most animal studies used to identify loci have been associated with asth- plexity and usefulness of studying
a potential carcinogenic risk in hu- ma, they do not account for overall cancer susceptibility with such mod-
mans are conducted in rodents un- genetic risk. A study of rare and els. Although they carried exactly
der standard conditions (e.g. 2-year low-frequency variants has reported the same mutation in K-Ras, mouse
cancer bioassays) with one particu- ethnic specificity but was unable to lung tumours that resulted from car-
lar agent. However, humans are ex- account for the missing heritability cinogen-induced versus genetical-
posed throughout their lifetime to a of the disease (Igartua et al., 2015), ly engineered models appeared to
mixture of agents (see below), and which is relevant to that associated develop along different mechanistic
inherent biological variability among with cancer risk. pathways (Westcott et al., 2015).
individuals is due to epigenetic and Whole-genome (i.e. exome) se- Exposure of two strains of mice of
genetic variance (Zeise et al., 2013). quencing of common (i.e. minor al- different susceptibility (i.e. A/J and
The contribution of the inherited lele frequency > 5%) and rare (i.e. BALB/cBy) to the same treatment
predisposition to diseases, such as minor allele frequency < 1%) alleles (3-methylcholanthrene, a polycyclic
cancer, has been an active area of across 12 cytochrome P450 genes aromatic hydrocarbon found in to-
research and has an impact on sus- has identified many polymorphisms bacco smoke, and butylated hydrox-
ceptibility analyses. Two proposed with pharmacogenetic effects, as ytoluene) produced lung tumours
188
separated geographic locations, on ADME considerations and spe- DNA from electrophilic metabolites.
with familial clustering for both in- cies-specific vulnerabilities to biolog- Cancer of the bladder is associated
creased and decreased methylation ical agents. with exposure to 2-naphthylamine in
(Bjornsson et al., 2008). The same For example, with regard to in- humans, rats, dogs, hamsters, and
study also showed considerable in- duction of cancer of the bladder by monkeys, as well as with exposure
ter-individual variation with age, with aromatic amines, increased risks to o-toluidine in humans and rats.
differences in DNA methylation ac- are consistently found in humans In mice, however, tumours are seen
cruing over time among individuals and in dogs exposed to, for exam- in other tissues but not in the blad-
who would be missed by studies that ple, 4-aminobiphenyl, benzidine, der. Exposure to benzidine is asso-
apply group averaging. Thus, a focus 4,4′-methylenebis(2-chloroaniline), ciated with cancer of the bladder in
only on genetic polymorphisms does and 2-naphthylamine. Several aro- humans, but in rodents liver tumours,
not consider the fact that epigenetic matic amines (e.g. o-toluidine and not bladder tumours, are observed.
programming plays an equally impor- 2-naphthylamine) induce bladder tu- Conflicting findings between studies
tant part in generating inter-individu- mours in rats (IARC, 2012c; see also are potentially a consequence of the
al differences in phenotype (Szyf, Chapter 2, by Beland and Marques). interdependence of pathways to ac-
Multiple organ site carcinogenicity tivate the parent compound and de-
CHAPTER 19
2007), and that it should be taken
PART 2
of aromatic amines in experimental toxify reactive metabolites at differ-
into account in the analysis of such
animals is associated with metabolic ent rates in different tissues (IARC,
phenotypic diversity. Such inter-indi-
activation of these agents to DNA- 2012c).
vidual differences would also not be
reactive intermediates via multiple Human exposure to asbestos
readily observed with conventional
pathways in target organs. For dogs, has resulted in lung cancer, pleu-
rodent models, for several reasons
lack of N-acetylation of aromatic ral and peritoneal mesothelioma,
(see below).
amines reduces elimination of the and cancer of the larynx and ovary
Strain- and species-specific parent compound via a detoxification (IARC, 2012a). The targets of this
differences in ADME and pathway (IARC, 2010), and their abil- carcinogen are associated with its
susceptibility to biological ity to store urine – as humans do – distribution. After inhalation, fibres
agents increases exposure to urinary me- may penetrate into the interstiti-
tabolites that are hydrolysed in the um and translocate to the pleura or
Most cancer bioassays have
bladder lumen epithelium to reac- peritoneum or more distant sites.
been conducted in rodents (see
tive electrophilic metabolites (IARC, Asbestos has been shown to accu-
Chapter 21, by Krewski et al.). The
2012c). Indeed, infrequent voiding mulate in the ovary in women (IARC,
genetic code has been described
has been associated with increased 2012a). Bronchial carcinomas and
as conserved between humans and
DNA adduct formation in the bladder pleural mesotheliomas have been
mice in terms of genome size, struc- in dogs (Kadlubar et al., 1991). Thus, observed in rats after exposure to
ture, and sequence composition, similarities between the metabolism asbestos fibres, with no consistent
and although candidate regulatory of aromatic amines in dogs and met- increases reported for tumours at
sequences have been conserved abolic polymorphisms in susceptible other sites. However, the Working
and the chromatin landscape in humans, and physiological similari- Group for Volume 100C of the IARC
cell lineages is relatively stable, ties (i.e. the ability to store urine) be- Monographs (IARC, 2012a) noted
there are interspecies differences tween dogs and humans contribute that in many studies complete histo-
in gene expression and regulation to a stronger correspondence with pathology was not done, so it was not
(see Chapter 13, by Caldwell), which respect to the target organ. possible to observe a similar tumour
may account for some apparent dif- The mechanism of tumour induc- pattern associated with carcinogen
ferences in susceptibility or specific tion by aromatic amines is similar distribution.
tumour site concordance after expo- between humans and rodents, but The complexity of developing an
sure to a carcinogenic agent or con- the target organ is not always the appropriate animal model that takes
dition. Other factors described for same; in rodents, there are multi- into account similar distribution fac-
some agents in Volume 100 of the organ targets for exposure to these tors is further illustrated by the exam-
IARC Monographs focus primarily agents through similar effects on ple of cancer induced by asbestos.
190
and the central nervous system, lym- response (i.e. potency) may also may enhance fixation of mutations,
phomas, bone cancers, soft-tissue be increased. There are examples and the absence of key DNA repair
sarcomas, kidney cancers, eye can- of IARC Group 1 carcinogens for enzymes in some embryonic cells,
cers, and adrenal gland cancers), which potency is greatly increased in such as brain cells. In addition, in-
whereas adults generally develop the young. For example, vinyl chlo- creased risk may result from lack of
more carcinomas (i.e. cancers of ride is an agent for which young ro- fully functional components of the
the skin, prostate, breast, lung, and dents are more susceptible for the immune system during development,
colorectum). In addition, some tu- target site and cell types (i.e. rare different functional operation of hor-
mours appear to be unique to the liver angiosarcomas and more com- monal systems during different life
young, for example tumours of the mon hepatocellular carcinomas) that stages, and induction of develop-
kidney (Wilms tumour) or eye (ret- are also observed in humans (see mental abnormalities that can result
inoblastoma) (EPA, 2005b). Thus, Chapter 1, by Bond and Melnick). in a predisposition to carcinogenic
another aspect of tumour site con- The literature on cancer induced by effects later in life (e.g. diethylstilbes-
cordance between species is the dif- exposure of animals to vinyl chlo- trol) (EPA, 2005b). However, several
ference in tumour types that may be ride is extensive and includes trans- other factors may also increase sus-
observed in children versus adults. placental and perinatal exposures ceptibility in the young. The develop-
CHAPTER 19
A full assessment of cancer risks
PART 2
(IARC, 2012c). Barton et al. (2005) mental origins of health and disease
from childhood exposure to chemi-
estimated the increase in potency of (DOHaD) hypothesis posits that
cals in the environment has been im-
vinyl chloride for liver angiosarcomas environmental exposures during de-
peded by the relative rarity of child-
to be 30-fold and for hepatomas to velopment increase susceptibility to
hood cancers, the lack of studies of
be about 50-fold in female rats after cancer in adulthood through epige-
the late effects of childhood expo-
early-life exposure compared with nomic reprogramming (Walker and
sure with sufficiently long follow-up,
exposure as adults. Ho, 2012).
and the lack of relevant animal test-
As noted above, exposure to ben- In some cases, the newborn or
ing guidelines and assays focused
zidine is associated with bladder young rodent may be a better model
on early-life or perinatal exposures
cancer in humans and liver tumours to assess human cancer risk for ei-
(EPA, 2005b). However, some hu-
in mice (IARC, 2012c). The ratio of ther children or adults. Components
man carcinogens listed in Volume
potency after early-life versus adult of diesel exhaust, an IARC Group 1
100 of the IARC Monographs have
exposure in studies with repeat ex- carcinogen (Benbrahim-Tallaa et al.,
been specifically identified as asso-
posures of juvenile and adult ani- 2012; IARC, 2013), appear to be
ciated with increased risk of child-
hood cancer (i.e. radiation and cer- mals to benzidine is about 100 for metabolized in a similar fashion in
tain pharmaceutical agents used in liver cancer induction in male mice rodents and humans at different
chemotherapy), as well as cancers (Barton et al., 2005). This example stages of development. Nitroarenes
occurring later in life after exposure illustrates an increased susceptibility (and, by extension, diesel exhaust)
during childhood. in the young but an apparent lack of are activated to mutagens in humans
In animals, several agents in- site concordance between humans and young rodents. Concordance
duce a higher incidence of tumours and mice. of lung cancer risk is observed
occurring later in life after perinatal For most of the IARC Group 1 hu- between young rodents and hu-
exposure, for example diethylnitros- man carcinogens, there are data indi- mans (see Chapter 5, by Hecht and
amine, benzidine, polybrominated cating genotoxicity as defined by the DeMarini). Specifically, 1-nitropyr-
biphenyls, and dichlorodiphenyl- toxicological end-point of DNA dam- ene (a component of diesel exhaust)
trichloroethane (DDT). For vinyl chlo- age (see Chapter 12, by DeMarini, is a compound that lacks evidence
ride, there appears to be greater and Chapter 22, by Krewski et al.). of carcinogenicity when exposure
susceptibility of weanling animals to DNA damage has been noted to po- occurs in adult rodents, but it is
the formation of DNA adducts (EPA, tentially exhibit a greater effect after carcinogenic in young adult or new-
2005b). early-life versus later-life exposure; born rodents because of its more
Along with the potential for more this increased susceptibility has extensive metabolism to mutagens.
tumour types occurring after ear- been attributed to more frequent cell Metabolism of 1-nitropyrene by adult
ly-life exposure, the strength of the divisions during development, which humans resembles that of newborn
192
age 30 years, and for squamous cancer induced by aromatic amines. genitors overlap in haematopoietic
cell carcinoma when first exposure Epidemiological studies of aromatic cancers and complicate determina-
occurs before age 20 years (IARC, amines have not considered breast tions of “target organ or target cell”.
2012f). In mice exposed to this type cancer, because industrial cohorts For studies in humans, changes in
of radiation, squamous cell carcino- were generally small and the relevant classification schemes for haemato-
ma is regularly observed, but no ma- poietic cancers can present diffi-
workforce did not include women.
lignant melanoma has been report- culties in target organ identification
The lack of studies involving female
ed. However, transgenic mice that from different studies. Modern clas-
subjects not only affects species
spontaneously develop malignant sifications of leukaemia and other
concordance but also influences the
melanomas or that have melanocyte lymphatic and haematopoietic ma-
hyperplasia can develop early-onset weight of evidence of an effect when
lignancies are based on cytogenetic
malignant melanoma if exposure to data on both sexes are required to and molecular principles (Swerdlow
ultraviolet radiation occurs neonatal- identify a target site in experimental et al., 2008) that do not always co-
ly, but not after the age of 6 weeks animals. For example, in the con- incide with those of the ICD (IARC,
(IARC, 2012f). This example illus- struction of the animal database to 2012f). Although there may be con-
trates the complexity of developing assess tumour site concordance cordance of haematopoietic cancers
CHAPTER 19
an animal model that mimics human
PART 2
(see Annex 1, by Grosse et al.), the between or within species, the mani-
susceptibility. Target site suscepti- same neoplastic effect is required in festation of disease may differ. Thus,
bility as well as age at which expo- two animal species or in both sexes the determination of tumour site con-
sure occurs must be taken into ac- cordance can be dependent on the
of one species. Breast cancer is rare
count when evaluating tumour site definition and level of specificity of
in male rats as well as in men. Thus,
concordance between species. the target.
limitations in epidemiological stud-
The highest likelihood of identify-
Influence of study design ies and sex differences in cancer
ing a human cancer risk may come
on determination of site response can also account for lack
from the study of sensitive subgroups
concordance of tumour site concordance between
with increased susceptibility to an
humans and experimental animals.
Host susceptibility as well as the agent or groups of agents. If multiple
Inaccurate diagnoses of disease disease categories are lumped to-
type of information collected in either
or incorrect entries on death certif- gether and sensitive subpopulations
human or animal studies influence
icates can affect concordance de- are not distinguished, it may be diffi-
the degree of tumour site concor-
dance that can be identified and terminations, especially for myelo- cult to detect a subtle but real cancer
evaluated. Epidemiological research proliferative and lymphoproliferative response in epidemiological studies.
is often done in men, especially for disorders, which can be described For example, taking into account the
occupational exposures. This can as extranodal or predominantly nod- influence of genetic polymorphisms
limit or preclude the detection of fe- al, precursor or mature neoplasms, or the heterogeneity of tumour phe-
male-specific cancers in humans and which may have multiple cellular notypes will improve the ability to
and thus site concordance between phenotypes. Changing codes in determine the risk to specific sub-
species. the International Classification of populations for colon cancer after
The Working Group for Volume excessive alcohol consumption
Diseases (ICD) can make it difficult
100F of the IARC Monographs (Schernhammer et al., 2010).
to develop a conclusion from hu-
(IARC, 2012c) specifically noted Similarly, designing animal stud-
man studies. However, a multipo-
that many plausible tumour sites ies in such a way that rare tumours
tent haematopoietic stem cell is the
identified in rodents have not been can be detected may increase the
precursor of myeloid or lymphoid ability to determine a response and
reported in humans, and gave the
example of rats treated with aromat- progenitors that further give rise to establish site concordance or mech-
ic amines that developed tumours in several cell types (Greaves, 2004). anistic concordance between spe-
the mammary gland, an organ that Although the disease induced by an cies. In epidemiology, rare tumours
has not been studied adequately as agent may be considered a “lympho- are considered a special type of find-
a potential target site in humans for ma or leukaemia”, the common pro- ing, and they constitute a data set
194
2014). The exposome includes three genetic control and cell signalling few decades. Type 2 diabetes,
broad domains of non-genetic ex- can affect cancer susceptibility. In non-alcoholic fatty liver disease, car-
posures: the internal environment addition, exposures to preceding diovascular disease, and increased
(e.g. endogenous hormones, the gut generations have been identified body mass index are risk factors for
microflora, and ageing), specific ex- as affecting susceptibility to cancer. liver cancer, and diabetes induces
ternal exposures (e.g. chemical con- In experimental studies, transgen- synergistic actions with other var-
taminants, lifestyle factors such as erational endocrine effects have iables, such as viral hepatitis and
tobacco use, and occupation), and been identified in the third gener- alcohol consumption (Fan et al.,
the general external domain (which ation of mice after the exposure 2009).
includes influences such as stress, to diethylstilbestrol (Ziv-Gal et al., Immune system status can af-
the urban–rural environment, and 2015). fect human responses to carcino-
climate) (Wild, 2012). Obesogens have not been eval- gen exposures, and thus influence
Tumour site concordance can be uated for carcinogenicity by the the ability to determine site concor-
affected by the inherent nature of the IARC Monographs. However, pre- dance between species (e.g. lack of
conditions under which each spe- natal exposure to obesogens that concordance in responses because
cies is studied to assess cancer risk. activate the constitutive androstane animal models are used that do not
CHAPTER 19
PART 2
Human study subjects have a wide receptor in neonates may affect also take immunosuppression into
and varied range of co-exposures, susceptibility by causing permanent account). With the increasing surviv-
whereas studies in experimental changes in enzyme expression and al of patients with the acquired im-
animals involve relatively uniform metabolism of environmental agents mune deficiency syndrome (AIDS),
exposures in highly controlled envi- encountered as adults (Caldwell, associated cancers in West Africa
ronments. As noted above, chang- 2012). Consequently, obesity asso- have been reported to be Kaposi
es in expression levels of metab- ciated with prenatal environmental sarcoma, non-Hodgkin lymphoma,
olizing enzymes through genetic exposures may render the subject cervical cancer, anogenital cancer,
polymorphisms have been a focus more susceptible to cancer later in and liver cancer (Tanon et al., 2012).
of research, but metabolism is also life. Increased background levels Infection with human immunodefi-
affected by environmental co-expo- of all cancers have been observed ciency virus (HIV) or immunosup-
sures, which are less well studied. in conjunction with increased body pression causes a higher risk for
Also, many solvents have similar ex- weight and obesity in rodent bio- lymphomas, i.e. a 400-fold increase
posure targets, and in humans these assays (Rao et al., 1987; Leakey in risk of non-Hodgkin lymphoma in
exposures often occur together with et al., 2003). the presence of HIV infection (Bassig
co-exposures that have the potential Such changes in background et al., 2012). However, the increas-
to increase the effects of solvents tumour incidence and altered sus- es in the incidence of non-Hodgkin
(Caldwell et al., 2008). However, ceptibility will affect the detection of lymphoma can only be partially ex-
studies of solvents in general may site concordance, especially across plained by the HIV epidemic (Bassig
mask effects of specific agents, data sets that span many decades et al., 2012).
for example trichloroethylene of research. Site concordance may An example of a common co-ex-
(Vermeulen et al., 2012). Lifestyle be more difficult to detect, because posure that affects cancer risk is that
and co-exposures (e.g. obesity, al- exposure-induced and background of aflatoxin B1 contamination of food
coholism, nutritional status, a com- tumours are harder to distinguish in supplies, which tends to be highest
promised immune system, and viral small groups of animals. Site con- in areas with high prevalence rates of
infections) can affect environmental cordance may be detected more fre- infection with hepatitis B and C virus-
cancer risk, but they are often not quently between animal models and es. While aflatoxin B1 and particularly
considered in animal models of car- humans when obesity status is taken its epoxide metabolite are potent mu-
cinogenicity, nor are they typically into account. Such is the case with tagens by themselves, infection with
addressed in human studies. liver cancer (Caldwell, 2012). hepatitis B virus greatly amplifies the
In humans, lifestyle choices and The proportion of the population risk of liver cancer from aflatoxin ex-
previous exposure during develop- that is overweight or obese has in- posure (IARC, 2012b), i.e. from 4-fold
ment that may change set points in creased substantially over the past with aflatoxin alone to 60-fold in the
196
immune response against tumours its attendant co-exposures to exoge- to obtain the same precision as with
(Iida et al., 2013; Viaud et al., 2013). nous chemicals and its influences on isogenic mice (French et al., 2015).
The interplay between human carci- the microbiome. Other issues to be considered for
nogenic pathogens and the microbi- The analyses of tumour site con- Diversity Outbred models would be
ome as well as the linkage between cordance are dependent on the the percentage survival, the tumour
dysbiosis and carcinogenesis have types of information and databases rates in the controls, and the limited
available at present. Such analyses historical database that is used in the
recently been reviewed (Dzutsev
are limited by the underlying avail- interpretation of data from current
et al., 2015).
able studies, which may not provide animal models. When these models
Conclusions adequate coverage of host suscep- are applied to address these issues,
tibilities. Animal models that cannot they may prove to be an invaluable
This chapter discusses the impor- reflect the intrinsic and extrinsic fac- resource for determining the impact
tance of considering host suscep- tors that have an impact on biological of host susceptibility and of the intrin-
variability in humans may not have sic and extrinsic factors on variable
tibility factors and their modulation
adequate sensitivity to detect all tar- responses to carcinogens.
of tumour response in interpreting
gets of carcinogenicity occurring in
CHAPTER 19
findings of tumour site concordance
humans. Similarly, limitations in epi- Acknowledgements
PART 2
between species, or lack thereof.
demiological studies affect their abil-
Examples are given of how discor- The authors wish to thank D.M.
ity to detect many tumour responses
dance can result from lack of studies observed in animals. DeMarini, M. Marty, S. Vulimiri, V.J.
covering sensitive sexes, subgroups, Transgenic animal models as well Cogliano, and N. Keshava for their
or life stages. Examples are also as highly diverse outbred mouse helpful comments on this manuscript.
provided in which polymorphisms strains and panels of diverse inbred
in metabolizing genes were associ- strains have been developed as an Disclaimer
ated with sensitive subpopulations, approach to model the genetical-
ly highly diverse human species. This article was reviewed and
and where experimentally sensitive
Diversity Outbred mouse models approved for publication by the
rodent strains were studied that also
may be used for future bioassays National Center for Environmental
had sensitivity because of similar
to obtain a better direct estimate Assessment, United States
capacity for increased activation or
of genetic contribution to variance, Environmental Protection Agency.
reduced detoxification (e.g. in the
and these assays may detect po- Approval does not signify that the
case of butadiene, aromatic amines,
tential human tumour sites missed contents reflect the views of the
and alcohol consumption). For aro-
by studies in genetically homoge- agency, nor does mention of trade
matic amines, anatomical and physi- names or commercial products con-
neous strains. These models may
ological similarity (infrequent voiding stitute endorsement or recommen-
also provide a platform to study
of the bladder) between humans other susceptibility factors, such as dation for use. The views expressed
and dogs increases DNA adduct co-exposures or obesity. However, are those of the authors and do
formation and ultimately tumour de- the use of such mouse models will not necessarily reflect those of the
velopment at the same site, i.e. the involve greater expense; heritability California Office of Environmental
bladder. More challenging in study estimates suggest that sample sizes Health Hazard Assessment.
design is to account for lifestyle, with should be increased by a factor of 3
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part 2.
mechanisms of carcinogenesis
chapter 20
CHAPTER 20
PART 2
Introduction with chemical agents. Experimental fetus or infant than that experienced
evidence for susceptibility in utero by the mother.
There is abundant experimental evi- and during infancy to chemical car- However, in some cases the tu-
dence from studies in animals, espe- cinogens and, to a lesser extent, to mours that result from prenatal or
cially rats and mice, that susceptibili- various sources of ionizing radiation perinatal exposures are different
ty to certain chemical carcinogens is has been summarized in reviews and from those that occur in exposed
higher, and sometimes much higher, symposium proceedings (Tomatis adults. Tumours induced prenatally
during prenatal and early postnatal and Mohr, 1973; Rice, 1979; Napal become manifest only during adult
life than in adulthood. There is also an kov et al., 1989; Rice, 2004). life in rats and mice, except in certain
extensive epidemiological literature At least in experimental animals, genetically modified strains, because
on the differential effects of a wide greater susceptibility to chemical in these species the interval between
variety of carcinogens in humans at carcinogens in utero and during birth and sexual maturity is only a
different stages of life, including var- early postnatal life is usually man- few weeks. Therefore, the types of
ious forms of radiation, carcinogen- ifested as a higher incidence of the tumours that occur during childhood
ic infectious agents, and chemicals
same kinds of tumours that occur in in humans, including various embry-
and chemical mixtures. This chapter
exposed adults, with a shorter laten- onal solid tumours, are observed as
summarizes the literature that docu-
cy period from the time of exposure tumours of adult life in conventional
ments this high susceptibility of the
to the carcinogen until the appear- rodents. An example is the develop-
fetus, infant, and child to many po-
ance of the tumour. In bioassays for ment of nephroblastomas – embryo-
tentially carcinogenic exposures.
carcinogenicity in adult rodents, the nal kidney tumours that correspond
Studies in experimental incidence and multiplicity of tumours to Wilms tumour in humans – in the
animals increase and the latency period de- adult rat after perinatal exposure to a
creases with increasing dose. Thus, chemical carcinogen. Such tumours
Most experimental studies of the predominant results of early-life do not develop in rats exposed to the
carcinogenesis during prenatal life exposure are what would be expect- same carcinogen during adult life
and infancy have been conducted ed from a higher effective dose to the (Diwan and Rice, 1995).
202
causing distinctive mutations in DNA mice exposed to transplacental car- increasingly effective and in many
(Agar et al., 2004; IARC, 2012e). cinogens, presumably because the cases is curative, but it imposes a
Results from experiments with ge- probability of such a combination of long-term risk of second cancers in
netically engineered transgenic and events without concomitant lethal survivors. The most intense expo-
knockout mice, especially double genetic damage is immeasurably sure of children to ionizing radiation
knockouts, provide information about low. and to genotoxic chemicals most
the significance of individual genes Although the importance of spe- commonly occurs in the context of
and gene combinations in suscepti- cific genetic events, including muta- anticancer therapy. Carcinogenic
bility to and pathogenesis of specific tions and chromosomal alterations, effects resulting from early-life expo-
tumours, including embryonal neu- in the genesis of cancers is clear, sures are most clearly seen among
rogenic tumours of childhood such evidence is accumulating that many the long-term survivors of childhood
as medulloblastoma (reviewed in carcinogens also cause intracellu- cancers who were successfully treat-
Rice, 2004), and offer some insight lar changes that may contribute to ed with high doses of radiation and/
into why embryonal tumours appear the carcinogenic process but do not or chemotherapy. The examples
relatively later in life in mice than in involve carcinogen-induced alter- given here and in the next section
humans. are representative rather than
CHAPTER 20
ations in genetic sequences. These
PART 2
For example, the gene PTCH1, the changes, which may occur several comprehensive.
human homologue of the Drosophila cell generations after exposure to the The risk of acute myeloid leu-
segment polarity gene patched, is a carcinogen, are termed epigenetic kaemia, non-Hodgkin lymphoma,
tumour suppressor gene associated and can be caused by ionizing radi- and solid cancers of the breast, thy-
with nevoid basal cell carcinoma syn- ation, chemicals, and ultraviolet light. roid, bone, central nervous system,
drome. Patients with this syndrome They include genomic instability, a colorectum, and stomach increased
are predisposed to develop primi- reduced ability to replicate the geno- significantly in survivors of Hodgkin
tive neuroectodermal tumours of the type faithfully (Barcellos-Hoff, 2005), lymphoma diagnosed before age
central nervous system, including and various other effects (IARC, 16 years and successfully treated
medulloblastomas, and mutations 2012e). It is not yet clear how epige- with radiation, chemotherapy with
in PTCH1 have been identified in netic events in carcinogenesis may alkylating agents, or both. Breast
a subset of sporadic primitive neu- vary with age at time of exposure to cancer occurred only in women
roectodermal tumours. Genetically the carcinogen. who had received X-radiation alone
engineered knockout mice with only or chemotherapy and X-radiation
a single normal allele of Ptc1, the Epidemiological findings in combined to treat Hodgkin lympho-
mouse homologue of PTCH1, devel- humans ma. Breast cancers developed usu-
op medulloblastoma-like cerebellar ally within the radiation field, and the
tumours (7–14% incidence). Neo- The consequences of environmen- risk of breast cancer was 75 times
natal exposure of these Ptc1+/− mice tal exposures to chemicals and ra- as great as that in the general pop-
to 3 Gy X-radiation increased this diation during childhood for the risk ulation. Second cancers occurred
incidence to 50%, but irradiation in of cancer later in life have been at increased rates in patients orig-
adulthood had no effect on medullo- reviewed (Carpenter and Bushkin- inally treated with chemotherapy
blastoma incidence (Pazzaglia et al., Bedient, 2013). In patients who re- alone, X-radiation alone, or chemo-
2002). ceive anticancer therapies, the ex- therapy and X-radiation combined,
Dramatically, 95% of Ptc1+/− mice posures are much more intense, and but at different sites; breast cancers
that had also been genetically engi- consequently the risk of cancer is occurred only in patients who had
neered to remove both alleles of the higher. received X-radiation with or with-
tumour suppressor gene p53 devel- Anticancer therapy out chemotherapy, and leukaemia
oped medulloblastomas, and did so was observed only in patients who
very early in life, at younger than Non-surgical therapy for cancer in had received chemotherapy (Bhatia
12 weeks (Wetmore et al., 2001). childhood and adolescence – by ion- et al., 1996). In survivors of childhood
This combination of inactivating gene izing radiation, combination chemo- cancers overall, the risk of gastroin-
mutations is not seen in conventional therapy, or both – has become testinal second cancers increased
204
Chemicals and chemical These changes were found in spe- although the weight of evidence
mixtures other than cytotoxic cific genes (Fos and Ltf [lactoferrin]) favours the greater importance of
anti-tumour agents and persisted even after cessation prenatal exposures. Also, a posi-
of treatment. Interestingly, chang- tive association has been observed
Diethylstilbestrol (DES) is a synthet-
es in gene expression were asso- between parental smoking and risk
ic non-steroidal estrogen that was
ciated with epigenetic alterations: of childhood leukaemia (particular-
administered to pregnant women
specifically, the genes that were ly acute lymphoblastic leukaemia)
during the 1950s and 1960s in an
differentially expressed in animals (IARC, 2012c).
effort to maintain high-risk pregnan-
treated with DES also exhibited ab- A plethora of experimental studies
cies. Although DES is rarely used
normal DNA methylation (Newbold indicate that chemical components
now, it has been estimated that
et al., 2000, 2006). These findings, in tobacco smoke induce a wide
5–10 million women in the USA were
although limited in genome cover- range of genetic changes (Hainaut
treated with DES during pregnancy
age, strongly suggest that exposure and Pfeifer, 2001; Pfeifer et al.,
or were exposed to the drug in utero
to DES may have a significant and 2002; Wistuba et al., 2002; Lea et al.,
(Giusti et al., 1995).
long-term effect on gene expression 2007). More recent studies also im-
Female offspring of women treat-
through epigenetic mechanisms. plicate epigenetic events in human
CHAPTER 20
ed with DES developed an unusual
cancer associated with tobacco
PART 2
More recent studies that used mi-
cancer of the vagina and cervix, clear
croarray-based transcriptome anal- exposure (Herceg, 2007; Lin et al.,
cell adenocarcinoma, which became
ysis in both rats and mice identified 2010; Huang et al., 2011).
clinically evident during adolescence
DES-induced changes in expression In a study of the methylome in
and early adulthood (Herbst et al.,
of a wide range of genes (Hsu et al., cord blood of newborns in connec-
1971). DES caused breast cancer
2009; Warita et al., 2010; Lee et al., tion with maternal smoking during
and is positively associated with the
2011). Whether these changes are pregnancy, differential DNA methyl-
risk of endometrial cancer in women
caused by epigenetic deregulation ation changes in a specific set of
who were exposed while pregnant.
In addition, a positive association has not been tested. genes were associated with tobacco
has been observed between prena- Another interesting feature of exposure (Joubert et al., 2012). A ge-
tal exposure to DES and squamous exposure to DES is its potential im- nome-wide methylomics approach
cell carcinoma of the cervix in female pact on cancer incidence in subse- and measurement of cotinine (a
offspring and cancer of the testis in quent generations. In addition to validated and objective biomarker
male offspring (IARC, 2012d). DES is an increased cancer susceptibility of smoking) were used to identify
the only chemical carcinogen known associated with epigenetic chang- methylation alterations in newborn
to have caused cancer in humans by es in parents treated with DES, an cord blood samples from a mother–
transplacental exposure. epigenetic mechanism may operate child cohort in relation to maternal
The mechanism of action of DES in subsequent generations of mice smoking. Maternal smoking during
as a carcinogen is complex. DES is a (the second generation) (Newbold pregnancy influenced methylation
potent estrogen, and some of its ef- et al., 2006). These findings further changes in specific genes. CYP1A1
fects are mediated, at least in large support the notion that DES-induced and AHRR, which encode proteins
part, by estrogen receptor alpha. carcinogenesis may operate in part involved in the detoxification of
DES can also undergo oxidative through an epigenetic mechanism, chemicals in tobacco smoke, were
metabolism. In fetal mouse tissues, although studies extending to the among the differentially methylated
it causes aneuploidy, chromosomal third generation are needed to es- genes (Joubert et al., 2012), sug-
breaks, and other chromosomal tablish a true transgenerational gesting a potential epigenetic mech-
aberrations; it binds covalently to epigenetic inheritance. anism involved in adverse effects
DNA and thus probably acts in part Parental cigarette smoking caus- associated with in utero exposure to
through a DNA-reactive genotoxic es hepatoblastoma, an embryonal tobacco smoke.
mechanism. In mice, neonatal expo- tumour of the liver, in children. The Various forms of inorganic arsenic
sure to DES also causes persistent effects of prenatal and postnatal ex- have been collectively classified as
changes in gene expression in tar- posures to parental cigarette smoke carcinogenic to humans (Group 1).
get tissues (Newbold et al., 2006). cannot be evaluated separately, These compounds cause cancer of
206
but not sufficient to cause Kaposi Children whose mothers are in- leukaemia, non-Hodgkin lymphoma,
sarcoma or other cancers in the fected with HIV-1 can be infected dur- and solid cancers of the breast, thy-
absence of severe immunosup- ing gestation and at birth, and during roid, bone, central nervous system,
pression, for example by co-infection infancy by nursing (IARC, 2012b). colorectum, and stomach. Certain
with HIV-1 (IARC, 2012b). In the absence of any intervention, tissues are extremely radiosensitive
The bacterium H. pylori typically transmission of HIV-1 in utero and during childhood and adolescence,
establishes infection of the human during birth is estimated to occur in including the thyroid and the female
stomach during childhood, and un- approximately 25% of infants born breast. Cancers of these and other
treated infections may persist for to HIV-1-positive women (Connor tissues occur at increased frequency
life (Malaty and Graham, 1994; et al., 1994). The risk of mother-to- not only among survivors of child-
Goodman et al., 1996; Brown, 2000). child transmission increases steadily
hood cancer but also in individuals
The infection evolves to cause chron- towards the late stages of pregnan-
exposed as children and adoles-
ic atrophic gastritis, a pre-neoplastic cy; almost 80% of new HIV-1 infec-
cents to diagnostic X-rays (including
condition that leads to development tions occur during the period from
CT scans) and to ionizing radiation
of gastric adenocarcinoma and gas- 36 weeks of pregnancy to delivery
from nuclear weapons and nuclear
tric mucosa-associated lymphoid
CHAPTER 20
(Kourtis et al., 2006).
reactor accidents.
PART 2
tissue lymphoma later in life (IARC, In summary, infants and chil-
2012b). Other high-dosage circumstanc-
dren are exceptionally susceptible
Infestation with the bladder fluke es early in life that pose increased
to many carcinogenic infectious
S. haematobium causes squamous cancer risks include transplacental
agents. Some infections can result
cell carcinoma of the bladder as a in the onset of malignancy within the exposure to the non-steroidal estro-
result of chronic inflammation. The first decade of life. In children, HBV gen DES, which causes distinctive
parasite has a complex life-cycle infection causes HCC, and EBV ac- carcinomas of the reproductive tract
that includes an infective cercar- companied by P. falciparum malaria in female offspring of women treated
ia form present in freshwater bod- infection results in eBL. Infections with DES during pregnancy. Intense
ies in sub-Saharan Africa, the Nile with KSHV, H. pylori, and S. haema- and repeated exposures to solar ra-
valley in Egypt and Sudan, and the tobium typically occur within the first diation during childhood, including
Arabian Peninsula. Infections are few years of life but result in devel- sunburn, predispose to development
percutaneous and result from direct opment of cancer – Kaposi sarcoma, of cutaneous malignant melanoma.
contact with contaminated water. gastric adenocarcinoma and gastric Evidence is beginning to accumu-
Maintenance of transmission of the mucosa-associated lymphoid tissue late that exposure to inorganic ar-
infection depends on contamination lymphoma, and bladder carcinoma, senic in utero and during childhood
of fresh water with excreta contain- respectively – decades later. On a can cause cancer of the liver during
ing schistosome eggs, the presence global scale, in terms of the numbers childhood and of the lung or kidney
of snails as intermediate hosts, and of children exposed and the numbers decades later.
human contact with contaminated of cancer cases that result, oncogen- The consequences of exposures
water (Jordan and Webbe, 1993). ic infectious agents pose the greatest to lower doses or concentrations of
Children start to accumulate worms cancer risks during childhood. other carcinogens during prenatal
as soon as they are old enough to
and early postnatal life have been
have contact with water, and they Summary
more difficult to establish (Carpenter
may be continuously reinfected and
remain infected throughout their Treatment of childhood cancers with and Bushkin-Bedient, 2013). Parental
lives (IARC, 2012b). The incidence high doses of ionizing radiation and cigarette smoking can cause hepato-
of schistosome-related bladder combinations of cytotoxic drugs, blastoma in children, an extreme
cancer in Africa peaks at ages 40– many of which are carcinogenic to case of the danger of second-hand
49 years, whereas infection with S. humans (Group 1), has been very tobacco smoke. Possible environ-
haematobium begins as early as age successful in recent years, but sur- mental causes of other embryonal
6 months and usually peaks at ages vivors are at high risk of second tumours of childhood continue to be
5–15 years (Mostafa et al., 1999). cancers, including acute myeloid investigate.
208
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210
part 3.
statistical analyses of concordance and key characteristics
chapter 21.
CHAPTER 21
PART 3
Introduction Monographs (Cogliano et al., 2004; evaluations involve classifying the
IARC, 2006), are used to evaluate data from both the human and the
Since its establishment in the ear- and integrate the evidence provided animal studies as providing suffi-
ly 1970s, the IARC Monographs by human epidemiological studies, cient evidence of carcinogenicity,
Programme has evaluated more than animal cancer bioassays, and infor- limited evidence of carcinogenicity,
1000 agents with evidence of human mation on possible biological mech- inadequate evidence of carcinogen-
exposure for which some suspicion anisms of action, to classify agents icity, or evidence suggesting lack of
exists of an increased cancer risk into one of the following categories: carcinogenicity. The information on
to humans. The IARC Monographs carcinogenic to humans (Group 1), biological mechanisms of action may
Programme has developed detailed probably carcinogenic to humans be evaluated as strong, moderate, or
criteria against which to evaluate (Group 2A), possibly carcinogenic to weak, and is taken into consideration
the available scientific evidence on humans (Group 2B), not classifiable in the overall evaluation.
the carcinogenic potential of such as to its carcinogenicity to humans To date, IARC has developed 119
agents. These criteria, which are de- (Group 3), and probably not carcino- Monographs Volumes on more than
scribed in the Preamble to the IARC genic to humans (Group 4). These 1000 agents for which there exists
212
Table 21.1. Group 1 agents included in Volumes 100A–F, 105, 106, 107, and 109a
100A Pharmaceuticals 23 Aristolochic acid; Aristolochic acid, plants containing; Azathioprine; Busulfan; Chlorambucil; Chlornaphazine; Ciclosporin;
Cyclophosphamide; Diethylstilbestrol; Estrogen-only menopausal therapy; Estrogen–progestogen menopausal therapy
(combined); Estrogen–progestogen oral contraceptives (combined); Etoposide; Etoposide in combination with cisplatin and
bleomycin; Melphalan; Methoxsalen in combination with UVA; MOPP; Phenacetin; Phenacetin, analgesic mixtures containing;
1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU); Tamoxifen; Thiotepa; Treosulfan
100B Biological agents 11 Clonorchis sinensis (infection with); Epstein–Barr virus; Helicobacter pylori (infection with); Hepatitis B virus; Hepatitis C virus;
Human immunodeficiency virus type 1; Human papillomavirusesb; Human T-cell lymphotropic virus type 1; Kaposi sarcoma-
associated herpesvirus; Opisthorchis viverrini (infection with); Schistosoma haematobium (infection with)
100C Arsenic, metals, 10 Arsenic and inorganic arsenic compounds; Asbestos (all forms, including actinolite, amosite, anthophyllite, chrysotile, crocidolite,
fibres, and dusts and tremolite); Beryllium and beryllium compounds; Cadmium and cadmium compounds; Chromium(VI) compounds; Erionite;
Leather dust; Nickel compounds; Silica dust, crystalline, in the form of quartz or cristobalite; Wood dust
100D Radiation 18 Fission products including strontium-90; Haematite mining with exposure to radon (underground); Ionizing radiation (all types);
Neutron radiation; Phosphorus-32, as phosphate; Plutonium-239; Radioiodines, including iodine-131; Internalized radionuclides
that emit α-particles; Internalized radionuclides that emit β-particles; Radium-224 and its decay products; Radium-226 and
its decay products; Radium-228 and its decay products; Radon-222 and its decay products; Solar radiation; Thorium-232 (as
Thorotrast); UV radiation (bandwidth 100–400 nm, encompassing UVC, UVB, and UVA); UV-emitting tanning devices; X- and
γ-radiation
100E Personal habits and 12 Acetaldehyde associated with consumption of alcoholic beverages; Alcoholic beverages; Areca nut; Betel quid with tobacco;
indoor combustions Betel quid without tobacco; Coal, indoor emissions from household combustion of; Ethanol in alcoholic beverages;
N′-Nitrosonornicotine (NNN) and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone NNK); Salted fish, Chinese-style; Second-hand
tobacco smoke; Tobacco smoking; Tobacco, smokeless
100F Chemical agents 32 Acid mists, strong inorganic; Aflatoxins; Aluminium production; 4-Aminobiphenyl; Auramine production; Benzene; Benzidine;
and related Benzidine, dyes metabolized to; Benzo[a]pyrene; Bis(chloromethyl)ether; Chloromethyl methyl ether (technical grade);
occupations 1,3-Butadiene; Coal gasification; Coal-tar distillation; Coal-tar pitch; Coke production; Ethylene oxide; Formaldehyde; Iron
and steel founding, occupational exposure during; Isopropyl alcohol manufacture using strong acids; Magenta production;
4,4′-Methylenebis(2-chloroaniline) (MOCA); Mineral oils, untreated or mildly treated; 2-Naphthylamine; ortho-Toluidine; Painter,
occupational exposure as a; 3,3′,4,4′,5-Pentachlorobiphenyl (PCB 126)a; 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF); Rubber
manufacturing industry, occupational exposures in the; Shale oils; Soot (as found in occupational exposure of chimney sweeps);
Sulfur mustard; 2,3,7,8-Tetrachlorodibenzo-para-dioxin; Vinyl chloride
214
Volume Type of agent Number Agents
of
agents
109c Outdoor air pollution 2 Outdoor air pollution; Particulate matter in outdoor air pollution
UV, ultraviolet.
a Although 113 Group 1 agents have been identified up to and including Monographs Volume 109, the present analysis is based on 111 distinct agents remaining after considering PCBs
and dioxin-like PCBs within the broader category of PCBs, and including PCB 126 within the broader category of PCBs.
b Human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 were evaluated as carcinogenic to humans.
c During the concordance analyses, the Group 1 agents in these Volumes were included with “chemical agents and related occupations” in Volume 100F*.
Table 21.2. Anatomically based taxonomy of tumour sites/organ systems in animals and humans
Organ system Sites coded from Volume 100 (A, B, C, D, E, and F*)a
Mesothelium Mesothelium
CHAPTER 21
Lymphoid tissue
PART 3
Skin Skin and adnexae
Cutaneous melanocytes
(see Supplemental Table 1. Animal and human tumour sites for 111 Group 1 agents identified up to and including Volume 109 of the
IARC Monographs).
216
Table 21.3. Information on animal and human tumours and tumour sites for Group 1 agents in the IARC Monographs (adapted from Annex 1, by Grosse et al.)
Volume Agent Sites with sufficient Site with limited Agent tested in Species Histology Study/sex/strain/ Comments
Agent evidence in evidence in experimental Site exposure route
number humans humans animals
100C Arsenic and Lung, bladder, skin Kidney, liver, Dimethylarsinic Mouse Bronchiolo- DMA(V): Tokar et al.
35 inorganic arsenic prostate acid [DMA(V)], Lung alveolar (2012a), M, CD1, d.w.;
compounds Monomethylarsinous carcinoma Sodium arsenite:
acid [MMA(III)], Waalkes et al. (2003),
Sodium arsenite F, C3H/HeNCr, in utero;
Waalkes et al. (2006),
M, CD1, in utero; Tokar
et al. (2011), MF, CD1,
in utero + p.o.; Tokar
et al. (2012a), M, CD1,
in utero; MMA(III): Tokar
217
PART 3
CHAPTER 21
Table 21.3. Information on animal and human tumours and tumour sites for Group 1 agents in the IARC Monographs (adapted from Annex 1, by Grosse et al.)
218
(continued)
Volume Agent Sites with sufficient Site with limited Agent tested in Species Histology Study/sex/strain/ Comments
Agent evidence in evidence in experimental Site exposure route
number humans humans animals
100D Fission products Solid cancers, Strontium-90 Mouse Osteosarcoma Nilsson (1970, 1971), M,
45 including leukaemia Bone CBA, i.p.; Nilsson et al.
strontium-90 (1980), F, CBA, i.p.
100E Coal, indoor Lung Coal smoke Mouse Bronchiolo- Liang et al. (1988), MF,
68 emissions from Lung alveolar Kunming, inh.; Lin et al.
household carcinoma (1995), MF, Kunming,
combustion of inh.
100F Benzene Acute myeloid Acute lymphoblastic Benzene Mouse Lymphoma Snyder et al. (1980), M,
80 leukaemia, acute leukaemia, chronic Thymus C57BI/6J, inh.; Cronkite
non-lymphoblastic lymphocytic leu- et al. (1984), F, C57BI/6
leukaemia kaemia, multiple BNL, inh.
myeloma, non-
Hodgkin lymphoma
105 Engine exhaust, Lung Bladder Whole diesel engine Rat Bronchiolo- Ishinishi et al.
107 diesel exhaust Lung alveolar (1986),MF, F344, inh.:
carcinoma Mauderly et al. (1986,
1987), MF F344, inh.:
Iwai et al. (1986), F,
F344, inh.: Heinrich
et al. (1995), F, Wistar,
inh.: Nikula et al..
(1995), F, F344, inh.:
Iwai et al. (2000), F,
F344, inh.
106 Trichloroethylene Kidney Non-Hodgkin Trichloroethylene Rat Renal cell National Toxicology
108 lymphoma, liver Kidney carcinoma Program (1990), M,
F344/N, g.; National
Toxicology Program
(1988), M, Osborne-
Mendel, g.; National
Toxicology Program
(1988), F, ACI, g.
Table 21.3. Information on animal and human tumours and tumour sites for Group 1 agents in the IARC Monographs (adapted from Annex 1, by Grosse et al.)
(continued)
Volume Agent Sites with sufficient Site with limited Agent tested in Species Histology Study/sex/strain/ Comments
Agent evidence in evidence in experimental Site exposure route
number humans humans animals
107 Polychlorinated Skin (melanoma) Non-Hodgkin Aroclor 1260 Rat Hepatocellular Mayes et al. (1998),
109 biphenyls lymphoma, breast Liver carcinoma F, Sprague-Dawley,
p.o.; Norback and
Weltman (1985), F,
Sprague-Dawley, p.o.;
Kimbrough et al. (1975),
F, Sherman, p.o.
F, female; d.w., drinking-water; g., gavage; inh., inhalation; i.p., intraperitoneally; M, male; MF, male and female; NK, natural killer; p.o., orally; s.c., subcutaneously.
220
alcoholic beverages, because no ep- judged as providing inadequate evi- which was found difficult to interpret,
idemiological data were available for dence of carcinogenicity in animals. whereas in another study busulfan,
areca nut alone or for ethanol in alco- The available studies with wood dust when given to rats during gestation,
holic beverages alone (see Annex 1, originally considered in Volume 62 affected the incidence of uterine ad-
by Grosse et al.). (IARC, 1995) did not show signifi- enocarcinomas in the offspring upon
No animal tumour sites were cant carcinogenic or co-carcinogen- intrauterine treatment with N-ethyl-
identified for 38 of the 111 agents ic potential of beech wood dust, but N′-nitro-N-nitrosoguanidine (IARC,
considered here (Table 21.6). These these studies were subject to several 2012e). As a second example, sulfur
included 20 agents with inadequate limitations as well as inadequacies in mustard significantly increased the
evidence in animals: seven agents data reporting. Upon re-evaluation of incidence of lung tumours (not oth-
representing occupational expo- wood dust in Volume 100C (IARC, erwise specified) in mice after ex-
sures that would be difficult to rep- 2012a), it was concluded that most of posure by inhalation for 15 minutes,
licate in the laboratory; two pharma- the studies conducted with wood dust and of pulmonary tumours (not oth-
ceutical agents used in combination (nearly all with beech wood dust) had erwise specified) after intravenous
for which no animal data were avail- small numbers of animals or were of injection; a significant increase in the
able on the mixture; seven biologi- short duration, thus providing inade- incidence of mammary tumours was
cal agents (all viruses) for which the quate evidence of carcinogenicity in seen after subcutaneous injection
selection of an appropriate animal animals. These considerations sug- of sulfur mustard in rats, relative to
model was problematic; two agents, gest that neither etoposide nor wood an external control group, whereas
etoposide and wood dust, for which dust have been subject to adequate forestomach tumours were numer-
the available animal tests were con- animal testing, therefore precluding ically, but not significantly, elevated
sidered inadequate; and two agents, a determination of their carcinogenic in rats treated by oral gavage (IARC,
treosulfan and leather dust, for potential in animals. 2012c). The exposure by subcutane-
which no animal data were available. Ten agents, including six pharma- ous and intravascular injection was
Although the two agents that lack ceutical products (busulfan, chlor- considered to be of limited relevance
any animal test data – treosulfan and naphazine, cyclosporine; combined to the most common human routes of
leather dust – clearly do not permit estrogen–progestogen menopausal exposure. Although not meeting the
an evaluation of concordance be- therapy, 1-(2-chloroethyl)-3-(4-meth- stringent criterion for sufficient evi-
tween animals and humans, the two ylcyclohexyl)-1-nitrosourea [methyl- dence of carcinogenicity in animals,
agents for which inadequate animal CCNU], and analgesic mixtures con- the limited evidence provided by
CHAPTER 21
data were available – etoposide and taining phenacetin), three biological busulfan, as well as by the other six
PART 3
wood dust – warrant some further agents (infections with Clonorchis chemicals with only limited evidence
discussion to distinguish between sinensis, Opisthorchis viverrini, and of carcinogenicity in animals, does
the case in which well-conducted Schistosoma haematobium), and suggest that these agents have the
animal studies have failed to demon- one chemical agent (sulfur mus- potential to cause cancer in animals.
strate carcinogenicity and the case tard), provided limited, but not suf- No tumour sites were specified
in which the animal data are largely ficient, evidence of carcinogenicity for eight agents demonstrating suf-
uninformative because of inadequate in animals. As mentioned above, ficient evidence of carcinogenicity
testing: Volume 76 (IARC, 2000) tumour sites are not specified in the in animals, because reproducible
and Volume 100A (IARC, 2012e) of IARC Monographs for agents that results were unavailable in two or
the IARC Monographs noted that demonstrate only limited evidence in more studies of adequate design in
etoposide was tested in only one animals. the same species for any of these
experiment with wild-type and het- The reasons that these 10 agents agents. Although melphalan showed
erozygous neurofibromatosis type 1 were judged as providing only limited evidence of a statistically significant
(Nf1) knockout mice that were treat- evidence of carcinogenicity in ani- increase in the incidence of tumours
ed by gastric intubation for 6 weeks mals varied. For example, treatment of the forestomach, skin, and lung
with etoposide at 100 mg/kg body with busulfan resulted in a significant in mice, as well as lymphosarcoma,
weight/week (Mahgoub et al., 1999). increase in the incidence of thymic these results were not replicated in
This single short-duration study was and ovarian tumours in BALB/c mice, a second, independent study (IARC,
222
Agent Level of evidence Human tumour Basis for mechanistic upgrade
in humans/ site
animals
Aristolochic acid Limited/ Not specified Herbal remedies containing aristolochic acid provide sufficient evidence for
Sufficient upper urinary tract cancer in humans; genotoxic mechanistic data
Benzo[a]pyrene (B[a]P) [No epidemio- Not specified PAH mixtures containing B[a]P provide sufficient evidence for lung or skin
logical data]/ cancer in humans; extensive mechanistic data on B[a]P linking animal and
Sufficient human biology
Dyes metabolized to benzidine Inadequate/ Not specified Benzidine provides sufficient evidence of being a human bladder
Sufficient carcinogen
Ethylene oxide Limited/ Not specified Limited evidence for non-Hodgkin lymphoma, breast cancer in humans;
Sufficient genotoxic mechanistic data
Etoposide Limited/ Not specified Limited evidence of acute myeloid leukaemia in humans, with distinctive
Inadequate chromosomal translocations
4,4′-Methylenebis(2-chloroaniline) (MOCA) Inadequate/ Not specified Bladder cancer expected in humans, based on mechanistic data and
Sufficient human case report
Neutron radiation Inadequate/ Not specified Biophysics of radiation damage induction similar across different types of
Sufficient radiation
N′-Nitrosonornicotine (NNN) and Inadequate/ Not specified Target sites correspond to those of smokeless tobacco; mechanistic data
4-(Methylnitrosamino)-1-(3-pyridyl)- Sufficient on tobacco smoke
1-butanone (NNK)
2,3,4,7,8-Pentachlorodibenzofuran [No epidemio- Not specified Sufficient evidence in experimental animals combined with strong
(PeCDF) logical data]/ mechanistic support for receptor-mediated mechanism, with biological
Sufficient activity identical to that of 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD)
for every mechanistic step
dioxin-like PCBs have been subsumed within the broader category of PCBs for the purposes of the present analysis of 111 distinct Group 1 agents, and are therefore not included in this
table.
Table 21.5. Group 1 agents with no human tumour sites specified (15 agents)
Mechanistic upgrades
Mechanistic upgrade with no human tumour Volume 100A: Aristolochic acid; Etoposide. Volume 100D:
site specified (9 agents) Neutron radiation. Volume 100E: N′-Nitrosonornicotine (NNN) and
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Volume
100F: Benzo[a]pyrene (B[a]P); Dyes metabolized to benzidine;
Ethylene oxide; 4,4′-Methylenebis(2-chloroaniline) (MOCA);
2,3,4,7,8-Pentachlorodibenzofuran (PeCDF)
Generic evaluations
Generic evaluation, of all types of ionizing Volume 100D: Ionizing radiation (all types); Internalized radionuclides
radiation; internalized radionuclides that emit that emit α-particles; Internalized radionuclides that emit β-particles; UV
α-particles; internalized radionuclides that radiation (bandwidth 100–400 nm, encompassing UVC, UVB, and UVA)
emit β-particles; and the UV region (100–
400 nm) of the electromagnetic spectrum
(4 agents)
No epidemiological data available for agent Volume 100E: Areca nut; Ethanol in alcoholic beverages
alone (2 agents)
2012c). In rats, melphalan also pro- the PAHs detected in air samples evidence of carcinogenic activity of
duced mammary gland tumours and from such plants, and previous- PeCDF, based on increased inci-
peritoneal sarcoma, but these find- ly evaluated in Volume 92 (IARC, dences of hepatocellular adenoma
ings were again not replicated in in- 2010). Had the animal evidence for and cholangiocarcinoma of the liver
dependent studies. Phosphorous-32 the agents mentioned above been el- and gingival squamous cell carcino-
caused leukaemia in mice and os- igible for inclusion in the tumour site ma of the oral mucosa. The occur-
CHAPTER 21
teogenic sarcomas in rats in single concordance database, additional rence of cystic keratinizing epithe-
PART 3
studies. Similarly, acetaldehyde in concordant results would have been lioma of the lung, neoplasms of the
drinking-water induced pancreatic noted, including concordance be- pancreatic acinus, and carcinoma
adenomas, combined lymphomas tween lymphoid and haematopoietic of the uterus may have been related
and leukaemias, uterine and mam- tissues in mice and humans for both to administration of PeCDF. There
mary gland adenocarcinomas, and melphalan and phosphorous-32, and were also three rat studies of PeCDF
head osteosarcomas in rats, but concordance between tumours of in combination with N-methyl-N′-
without replication. Betel quid with to- the upper aerodigestive tract in ham- nitro-N-nitrosoguanidine (MNNG)
bacco produced malignant forestom- sters and humans for betel quid with and N-nitrosodiethylamine (NDEA),
ach and cheek pouch tumours in a tobacco. where increased tumour multiplicity
single study in hamsters. Sufficient Although PeCDF provided suffi- was observed in each case (IARC,
evidence of carcinogenicity in ani- cient evidence of carcinogenicity in 2012c). These observations led to
mals of aluminium refining was based animals, no animal site was iden- the conclusion that there is sufficient
on a single limited skin application tified. PeCDF was tested by the evidence for the carcinogenicity of
study in mice with PAH-containing United States National Toxicology PeCDF in animals, although there
particulates from aluminium pro- Program in a 2-year animal bioassay is no specific organ site that can be
duction plants, in conjunction with (female rats only) with exposure by designated as responsible for this
sufficient evidence of carcinogenicity oral gavage (National Toxicology sufficient evidence. Because of the
in experimental animals for many of Program, 2006). There was some absence of a specific tumour site in
224
Nature of evidence in animals Volume: Agent(s)
(number of agents)
Occupational exposures are complex Volume 100F: Acid mists, strong inorganic; Auramine production; Iron and steel founding, occupational exposure during; Isopropyl
and probably could not be reliably alcohol manufacture using strong acids; Magenta production; Painter, occupational exposure as a; Rubber manufacturing industry,
replicated in the laboratory (7 agents) occupational exposures in the.
Used in combination; no animal data Volume 100A: Etoposide in combination with cisplatin and bleomycin; MOPP.
available on mixture (2 agents)
Use of animal models problematic Volume 100B: Infection with Epstein–Barr virus; Hepatitis B virus; Hepatitis C virus; Human immunodeficiency virus type 1; Human
because of species specificity and papillomaviruses; Human T-cell lymphotropic virus type 1; Kaposi sarcoma-associated herpesvirus.
other limitations (7 agents)
Animal tests conducted but considered Volume 100A: Etoposide. Volume 100C: Wood dust.
inadequate (2 agents)
No animal data available (2 agents) Volume 100A: Treosulfan. Volume 100C: Leather dust.
Evidence of carcinogenicity in animals Volume 100A: Busulfan; Chlornaphazine; Ciclosporin; Estrogen–progestogen menopausal therapy (combined); 1-(2-Chloroethyl)-
judged as limited for various reasons 3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU); Phenacetin, analgesic mixtures containing. Volume 100B: Clonorchis
(10 agents) sinensis (infection with); Opisthorchis viverrini (infection with); Schistosoma haematobium (infection with). Volume 100F: Sulfur
mustard.
Sufficient evidence in animals, but no Volume 100A: Melphalan. Volume 100D: Phosphorus-32, as phosphate. Volume 100E: Acetaldehyde associated
tumour sites specifieda (8 agents) with the consumption of alcoholic beverages; Betel quid with tobacco. Volume 100F: Aluminium production;
2,3,4,7,8-pentachlorodibenzofuran (PeCDF); Volume 109: Outdoor air pollution; Particulate matter in outdoor air pollution.
aSufficient evidence in experimental animals, but no organ sites identified due to the absence of at least two studies of adequate design and quality showing tumours at the same organ
site with a similar histological origin in the same species.
animals, PeCDF is not included in or limited evidence (nine agents) of pharmaceuticals account for half (9
the concordance analyses. carcinogenicity in animals. This ob- of 18) of the agents that cause tu-
A component of four Group 1 servation provides support for the mours in haematopoietic tissues.
agents, but not the agents them- use of animal data in human cancer The number of agents that induce
selves, demonstrated sufficient risk assessment. tumours in one or more animal spe-
evidence of carcinogenicity in an- To further explore the correspon- cies at each of the 39 tumour sites is
imals. These are: fission products dence between sites where tumours shown in Fig. 21.2 by type of agent.
including strontium-90, where stron- are seen in animals and humans As in humans, lung tumours are the
tium-90 demonstrated sufficient ev- among the 111 distinct Group 1 most common tumour in animals,
idence of carcinogenicity in animals agents considered here, descriptive with 29 of the 111 known human car-
(IARC, 2012f); haematite mining with statistics are presented on tumour cinogens inducing lesions at this site,
exposure to radon (underground), site profiles by species, followed by mostly from the categories of chem-
where radon demonstrated sufficient an evaluation of concordance be- ical agents and related occupations
evidence of carcinogenicity in ani- tween tumour sites seen in animals (10 agents), arsenic, metals, fibres,
mals (IARC, 2012f); acetaldehyde and humans. Results are presented and dusts (7 agents), and radiation
associated with consumption of al- first for the 39 tumour sites included (7 agents). After the lung, the ani-
coholic beverages, where acetal- in the anatomically based tumour mal sites associated with the largest
dehyde demonstrated sufficient ev- nomenclature system seen in either number of carcinogenic agents are
idence of carcinogenicity in animals animals or humans, followed by the the liver parenchyma and bile ducts
(IARC, 2012d); and occupational data for the 14 organ and tissue (19 agents), the skin and adnexae (18
exposures during aluminium produc- systems. agents), lymphoid tissue (14 agents),
tion, where airborne particulate poly- the breast (12 agents), and soft con-
Tumour site profiles by
nuclear organic matter from alumin- nective tissue (11 agents). Separate
species
ium production plants demonstrated tumour profiles are shown for
sufficient evidence of carcinogenicity The number of agents that induce tu- agents that cause tumours in mice
in animals (IARC, 2012c). Although mours in humans at each of the 39 (48 agents) and rats (49 agents) in
this animal evidence is consistent tumour sites is shown in Fig. 21.1 by Fig. 21.3 and Fig. 21.4, respectively.
with the sufficient evidence for the type of agent (pharmaceuticals; bio- In rodents (mice and rats combined),
carcinogenicity of these four agents logical agents; arsenic, metals, fibres, the lung is the site associated with
in humans, the animal evidence rep- and dusts; radiation; personal habits the largest number of carcinogens.
CHAPTER 21
resents only a component of these and indoor combustions; and chemi-
Organ and tissue system
PART 3
agents. cal agents and related occupations).
profiles by species
Excluding the 20 agents in Lung tumours are the most common
Table 21.5 that lack appropriate an- tumour seen in humans, with 28 of The number of agents that induce
imal data, i.e. seven occupational the 111 known human carcinogens tumours in humans in each of the 14
exposures not reproducible in the inducing lesions at this site; of these, aggregate organ and tissue systems
laboratory, two agents used in com- 13 are associated with exposure to is shown in Fig. 21.5 by type of agent.
bination with no animal data avail- chemical agents and related occupa- Tumours of the respiratory system
able on the mixture, seven agents tions and seven are in the category are caused by 31 of the 111 human
where the use of animal models of arsenic, metals, fibres, and dusts. carcinogens, mostly from the cate-
is problematic because of species Tumours of the haematopoietic tis- gories of chemical agents and relat-
specificity or other limitations, and sues are associated with exposure to ed occupations (14 agents), arsenic,
four agents for which animal tests 18 agents, urothelial tumours with 18 metals, fibres, and dusts (7 agents),
were inadequate (two agents) or un- agents, skin tumours with 12 agents, and personal habits and indoor com-
available (two agents), all 91 distinct and liver and bile duct tumours with bustions (5 agents). After the res-
Group 1 agents identified by IARC 11 agents. The category chemical piratory system, the organ and tissue
up to and including Volume 109 of agents and related occupations ac- systems associated with the largest
the IARC Monographs provided ei- counts for half (9 of 18) of the agents number of agents are lymphoid and
ther sufficient evidence (82 agents) that cause urothelial tumours, and haematopoietic tissues (26 agents),
the urothelium (18 agents), and the the digestive organs are caused by chemical agents and related occupa-
upper aerodigestive tract (16 agents). 19 agents, mostly from the catego- tions (5 agents).
Pharmaceuticals are the largest ries of chemical agents and related
Qualitative assessment of
group of agents associated with tu- occupations (12 agents) and radi-
concordance
mours of the lymphoid and haemato- ation (4 agents). Skin tumours are
poietic tissues (11 of 26 agents), and caused by 18 agents, mostly from Of the 111 distinct Group 1 agents
chemical agents and related occupa- the category of chemical agents identified up to and including Volume
tions are most often associated with and related occupations (12 agents). 109 (see Table 21.1), for 60 agents
tumours of the urothelium (9 of 18 Connective tissue tumours are as- both a human tumour site and an ani-
agents). Personal habits and indoor sociated with 17 agents, mostly from mal tumour site have been identified,
combustions are most commonly as- the categories of radiation (8 agents) 15 agents had no human tumour site
specified (Table 21.5), and 38 agents
sociated with tumours of the upper and chemical agents and related oc-
had no animal tumour site identified
aerodigestive tract (7 of 16 agents). cupations (5 agents).
(Table 21.6). Because two agents –
The number of agents that induce In mice (Fig. 21.7), tumours of
etoposide and PeCDF – have neither
tumours in one or more animal spe- the skin and connective tissues are
a human nor an animal tumour site
cies at each of the 14 organ and tis- caused by 29 agents, consisting
specified, there are 111 − 15 − 38 +
sue systems is given in Fig. 21.6 by mostly of tumours caused by chem-
2 = 60 agents with at least one tu-
type of agent. Tumours of the res- ical agents and related occupa- mour site identified in both humans
piratory system are caused by 29 of tions (14) and radiation (10). In rats and animals. These 60 agents have
the 111 agents, mostly from the cate- (Fig. 21.8), tumours of the respirato- been used to evaluate concordance
gories of chemical agents and relat- ry system are caused by 19 agents, between tumour sites seen in ani-
ed occupations (10 agents), arsenic, including those in the categories of mals and humans, because at least
metals, fibres, and dusts (7 agents), arsenic, metals, fibres, and dusts one tumour site has been identified
and radiation (7 agents). Tumours of (6 agents), radiation (6 agents), and in both.
226
Fig. 21.2. Number of agents that induce tumours in animals in each of 39 tumour sites, by type of agent.
Fig. 21.3. Number of agents that induce tumours in mice in each of 39 tumour sites, by type of agent.
CHAPTER 21
PART 3
The overlap between human Nine agents cause tumours of the humans or animals, as in the phar-
and animal tumour sites targeted by upper aerodigestive tract in humans, ynx, tongue, and salivary gland.
these 60 agents is summarized in and nine agents cause tumours in The lung is the most common site
Table 21.7 by organ and tissue system this organ and tissue system in ani- at which tumours are observed, with
and tumour site. The category “other mals; four agents cause tumours in 62% overlap among the 26 agents
groupings” of tumours – which com- this system in both humans and ani- that cause lung tumours in humans
prises “all cancers combined”, “all mals. There are 9 + 9 − 4 = 14 distinct or animals. Among the 10 agents
solid cancers”, and “exocrine glands agents that cause tumours in this that cause tumours in the urotheli-
not otherwise specified” – was creat- system in either humans or animals, um (renal pelvis, ureter, or bladder),
ed to accommodate tumour sites re- for an overlap of 4 of 14, or 29%. there is 70% overlap between agents
ported in the IARC Monographs that Within the upper aerodigestive tract, that cause tumours in humans or
did not fall into any of the other cate- there are three agents that cause tu- animals.
gories in Table 21.2. The only human mours in the nasal cavity and para- Because results for individual tu-
site identified for 2,3,7,8-tetrachlo- nasal sinuses in humans and three mour sites are often based on small
rodibenzo-para-dioxin (TCDD) is “all agents that cause tumours at this numbers, emphasis is placed on in-
cancers combined”; fission products site in animals, with no overlap. Of terpretation of results at the organ
including strontium-90 are associat- the three agents that induce tumours and tissue system level, where the
ed with “all solid cancers” in humans, in the nasopharynx, one agent sample size is generally larger than
but also with tumours in haemato- causes tumours in both humans and for individual tumour sites within
poietic tissue. Because this category animals, for an overlap of 33%. In the organ and tissue systems. Overlap
lacks biological cohesiveness, “other oral cavity, overlap is 25%. Overlap varies among the organ and tissue
groupings” of tumours were not con- is not calculated when there are no systems, ranging from 20% (based
sidered in the concordance analysis. agents that cause tumours in either on 10 agents) in the digestive tract
228
Fig. 21.5. Number of agents that induce tumours in humans in each of 14 organ and tissue systems, by type of
agent.
CHAPTER 21
PART 3
to 100% in the mesothelium. Overall, clusion in the concordance analysis in this system in animals (and not in
high overlap is seen for some or- caused tumours at this site. humans), and four agents cause tu-
gan and tissue systems but not for The results in Table 21.7 are de- mours in this system in both humans
others. Some caution is needed in picted in graphical form in Fig. 21.9. and animals, for an overlap of 29%.
interpreting concordance at sites As noted above, of the 14 Group 1 Of the 27 agents that cause tumours
where the sample size is particularly agents that cause tumours of the of the respiratory system in either
small: although 100% concordance upper aerodigestive tract in either humans or animals, 21 agents cause
was noted for agents that cause humans or animals, nine agents respiratory tumours in humans, 22
tumours of the mesothelium, only cause tumours in the upper aerodi- agents cause respiratory tumours
two Group 1 agents – asbestos and gestive tract in humans (and not in in animals, and 16 agents cause
erionite – meeting the criteria for in- animals), nine agents cause tumours respiratory tumours in both humans
and animals, for an overlap of 59%. between tumour sites seen in hu- ysis, 40, 38, 8, 7, and 3 agents cause
Although they present the same data mans and all animal species test- tumours in mice, rats, hamsters,
as shown in Table 21.7, the graphical ed, reflecting the interest in evalu- dogs, and monkeys, respectively.
representations of these results in ating the extent to which tumours Therefore, including only mice and
Fig. 21.9 for all organ and tissue sys- caused by Group 1 agents occur in rats in the analysis yielded results
tems also illustrate the large varia- similar organ and tissue systems in similar to those in Table 21.7 (see
tion in sample size among the organ humans and in animals. The animal details in Supplemental Material
and tissue systems; the area of the data included in this analysis are II [online only; available from:
circles is proportional to sample size. dominated by results obtained in http://publications.iarc.fr/578], where
The results presented in Ta- studies with rats and mice: of the 60 Supplemental Table 6 presents re-
ble 21.7 are based on concordance Group 1 agents included in the anal- sults for all animal species tested
230
Fig. 21.7. Number of agents that induce tumours in mice in each of 14 organ and tissue systems, by type of agent.
CHAPTER 21
PART 3
and Supplemental Table 7 presents As detailed in Supplemental Material tumours in that system in either
results for mice and rats only). II (online only; available from: http:// humans or animals, providing an
Fig. 21.10 shows the percentage publications.iarc.fr/578), it is impor- overall measure of overlap between
of Group 1 agents that cause tu- tant to note that the measures of animal and human carcinogens in
mours in specific organ and tissue concordance presented in Fig. 21.10 a specific organ and tissue system.
systems in humans that are also differ from those in Table 21.7. The The percentage overlap in panel A of
associated with tumours in animals percentage overlap in Table 21.7 Fig. 21.10 provides a measure of the
(panel A), as well as the percent- (and Fig. 21.9) reflects the number overlap between agents that cause
age of agents that cause tumours in of agents that cause tumours in a tumours in a specific organ and
specific organ and tissue systems specific organ and tissue system in tissue system in animals with agents
in animals that are also associated both humans and animals, relative that cause tumours in that system in
with tumours in humans (panel B). to the number of agents that cause humans. Conversely, the percentage
overlap in panel B of Fig. 21.10 pro- panel A, where human carcinogens mours in those organ and tissue sys-
vides a measure of the overlap be- constitute the reference set against tems in animals. Overlap of at least
tween agents that cause tumours in which animal carcinogens are com- 50% is observed for all other organ
a specific organ and tissue system pared, will differ from those in panel and tissue systems, with the excep-
in humans with agents that cause B, where animal carcinogens consti- tion of the upper aerodigestive tract
tumours in that system in animals. tute the reference set for comparison (44%) and the digestive tract (33%).
Note that unless the numbers of with human carcinogens. Conversely, there is less overlap
agents that cause tumours in hu- As indicated in panel A of between agents that cause tumours
mans and animals in a specific organ Fig. 21.10, all agents (100%) that in specific organ and tissue systems
and tissue system are the same (as cause tumours of the mesothelium, in animals with results in humans
is the case for tumours of the upper endocrine system, and connective (Fig. 21.10, panel B), possibly re-
aerodigestive tract), the results in tissues in humans also cause tu- flecting the larger number of studies
232
Table 21.7. Concordance between tumours seen in humans and animals for 60 Group 1 agents by organ and tissue
system and tumour site
Nasopharynx 3 1 1 33
Oral cavity 4 6 2 25
Pharynx 2 0 0 N/A
Tongue 0 1 0 N/A
Respiratory system 21 22 16 59
Larynx 3 1 1 33
Lung 20 22 16 62
Mesothelium 2 2 2 100
Mesothelium 2 2 2 100
Digestive tract 6 6 2 20
Oesophagus 5 0 0 N/A
Stomach 3 5 1 14
Digestive organs 8 14 4 22
CHAPTER 21
PART 3
Pancreas NOS 2 0 0 N/A
Eye 1 0 0 N/A
Endocrine system 2 3 2 67
Kidney 3 5 2 33
Urothelium 10 7 7 70
Haematopoietic tissues 10 2 2 20
Lymphoid tissue 2 10 1 9
Skin 11 16 7 35
Connective tissues 6 14 6 43
Breast 4 8 2 20
Ovary 3 1 0 0
Uterine cervix 3 2 1 25
Uterus 2 2 1 33
Vulva/vagina 1 0 0 N/A
Other groupings 2 4 0 0
CNS, central nervous system; N/A, not applicable: assigned to sites/systems when overlap is not possible (positive data are available
in either humans or animals, but not in both); NOS, not otherwise specified.
a Systems/sites in the anatomically based tumour nomenclature system (see Table 21.2) that lack sufficient evidence in both humans
and animals not shown. For example, there were insufficient data on tumours of the male reproductive tract in both humans and
animals.
b Percentage overlap calculated as [N /(N + N − N )] × 100%, where N , N , and N denote the number of agents with sufficient
b h a b h a b
evidence of carcinogenicity in humans, animals, or both humans and animals, respectively.
234
Fig. 21.9. Concordance between tumour sites seen in humans and animals for 60 Group 1 agents by organ and
tissue system.
2 4 2 4
5 4 5 5 16 6
4 4 10 2 2 1 2 3
Digestive organs (18 agents) Nervous system and eye (2 agents) Endocrine system (3 agents) Kidney (6 agents)
7 3 5 7 3 4 7 9 6 8
Legend
4 4 5
2 4
Humans only Animals only Both
CHAPTER 21
conducted in animals compared with tissue system level only, because in at least one tumour site in both hu-
PART 3
humans, the broader spectrum of tis- results for individual tumour sites mans and animals, 52 (87%) cause
sues (potential tumour sites) exam- are too sparse to support meaningful tumours within at least one of the
ined in animal studies than in human comparisons. The human data are same organ and tissue systems in
studies, or the limitations associated presented in the column on the left, Table 21.8.
with the conduct of human studies at the animal data in the column on the To permit a more complete com-
environmental exposure levels. As is right, and the overlap in the middle parison between animal and human
the case with the concordance re- column. With this display, potential tumour sites, tumour sites with only
sults focusing on overall overlap, as relationships among agents that limited evidence in humans are in-
presented in Table 21.7, caution is cause tumours within the same or- cluded in Table 21.8 (in italics). For
needed in interpreting results where gan and tissue system can be exam- agents such as diethylstilbestrol (a
there are few agents for comparison ined. Overlap between human and synthetic non-steroidal estrogen
in Fig. 21.10 (both panels A and B). animal carcinogens acting within the that was widely prescribed in the
The 60 agents included in the same organ and tissue system can USA between the 1940s and the
present concordance analysis are also be examined both for individu- 1970s but is rarely used now), there
listed in Table 21.8. This table pre- al agents and for groups of agents. is difficulty in generating newer data
sents the tumour site data for hu- Of the 60 agents for which there is on human exposure. Because men
mans and animals at the organ and sufficient evidence of carcinogenicity exposed to diethylstilbestrol in utero
236
systems. (A) Overlap between animals and humans; the number of Group 1 agents that cause tumours in specific organ and tissue systems in humans is shown.
(B) Overlap between humans and animals; the number of Group 1 agents that cause tumours in specific organ and tissue systems in animals is shown.
B
Table 21.8. Comparison of 60 Group 1 agents with sufficient or limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in
animals in specific organ and tissue systemsa
238
animals in specific organ and tissue systemsa (continued)
Arsenic and inorganic arsenic compounds (100C) Arsenic and inorganic arsenic compounds (100C) Cyclophosphamide (100A)
Asbestos (all forms, including actinolite, amosite, Asbestos (all forms, including actinolite, amosite, Arsenic and inorganic arsenic compounds (100C)
anthophyllite, chrysotile, crocidolite, and tremolite) anthophyllite, chrysotile, crocidolite, and tremolite) Asbestos (all forms, including actinolite, amosite,
(100C) (100C) anthophyllite, chrysotile, crocidolite, and tremolite) (100C)
Beryllium and beryllium compounds (100C) Beryllium and beryllium compounds (100C) Beryllium and beryllium compounds (100C)
Cadmium and cadmium compounds (100C) Cadmium and cadmium compounds (100C) Cadmium and cadmium compounds (100C)
Chromium(VI) compounds (100C) Chromium(VI) compounds (100C) Chromium(VI) compounds (100C)
Nickel compounds (100C) Nickel compounds (100C) Nickel compounds (100C)
Silica dust, crystalline, in the form of quartz or Silica dust, crystalline, in the form of quartz or Silica dust, crystalline, in the form of quartz or cristobalite
cristobalite (100C) cristobalite (100C) (100C)
Haematite mining with exposure to radon Haematite mining with exposure to radon Haematite mining with exposure to radon (underground)
(underground) (100D) (underground) (100D) (100D)
Plutonium-239 (100D) Plutonium-239 (100D) Plutonium-239 (100D)
Radon-222 and its decay products (100D) Radon-222 and its decay products (100D) Radon-222 and its decay products (100D)
X- and γ-radiation (100D) X- and γ-radiation (100D) X- and γ-radiation (100D)
Alcoholic beverages (100E) Coal, indoor emissions from household combustion Coal, indoor emissions from household combustion of (100E)
Coal, indoor emissions from household combustion of of (100E) Second-hand tobacco smoke (100E)
(100E) Second-hand tobacco smoke (100E) Tobacco smoking (100E)
Second-hand tobacco smoke (100E) Tobacco smoking (100E) Benzene (100F)
Tobacco smoking (100E) Coke production (100F) 1,3-Butadiene (100F)
Bis(chloromethyl)ether; Chloromethyl methyl ether Engine exhaust, diesel (100F) Coke production (100F)
(technical grade) (100F) 2,3,7,8-Tetrachlorodibenzo-para-dioxin (100F) Vinyl chloride (100F)
Coal gasification (100F) Engine exhaust, diesel (100F*)
Coal-tar pitch (100F) 2,3,7,8-Tetrachlorodibenzo-para-dioxin (100F*)
Coke production (100F) Trichloroethylene (100F*)
Soot (as found in occupational exposure of chimney
sweeps) (100F)
2,3,7,8-Tetrachlorodibenzo-para-dioxin (100F)
Engine exhaust, diesel (100F)
Table 21.8. Comparison of 60 Group 1 agents with sufficient or limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in
animals in specific organ and tissue systemsa (continued)
Asbestos (all forms, including actinolite, amosite, Asbestos (all forms, including actinolite, amosite, Asbestos (all forms, including actinolite, amosite,
anthophyllite, chrysotile, crocidolite, and tremolite) anthophyllite, chrysotile, crocidolite, and tremolite) anthophyllite, chrysotile, crocidolite, and tremolite) (100C)
(100C) (100C) Erionite (100C)
Erionite (100C) Erionite (100C)
Helicobacter pylori (infection with) (100B) Helicobacter pylori (infection with) (100B) Aristolochic acid, plants containing (100A)
X- and γ-radiation (100D) Betel quid without tobacco (100E) Helicobacter pylori (infection with) (100B)
Radioiodines, including iodine-131 (100D) Chromium(VI) compounds (100C)
Alcoholic beverages (100E) Betel quid without tobacco (100E)
Betel quid without tobacco (100E) Benzene (100F)
Salted fish, Chinese-style (100E) 1,3-Butadiene (100F)
Tobacco smoking (100E)
Tobacco, smokeless (100E)
Estrogen–progestogen oral contraceptives (combined) Arsenic and inorganic arsenic compounds (100C) Tamoxifen (100A)
(100A) Plutonium-239 (100D) Arsenic and inorganic arsenic compounds (100C)
Arsenic and inorganic arsenic compounds (100C) Thorium-232 (as Thorotrast) (100D) Thorium-232 (as Thorotrast) (100D)
Cadmium and cadmium compounds (100C) X- and γ-radiation (100D) Plutonium-239 (100D)
Thorium-232 (as Thorotrast) (100D) Aflatoxins (100F) X- and γ-radiation (100D)
Plutonium-239 (100D) Vinyl chloride (100F) Aflatoxins (100F)
X- and γ-radiation (100D) Trichloroethylene (100F*) 4-Aminobiphenyl (100F)
Alcoholic beverages (100E) Benzidine (100F)
Betel quid without tobacco (100E) 1,3-Butadiene (100F)
Tobacco smoking (100E) 2-Naphthylamine (100F)
Tobacco, smokeless (100E) 2,3,7,8-Tetrachlorodibenzo-para-dioxin (100F)
Aflatoxins (100F) Vinyl chloride (100F)
Vinyl chloride (100F) Trichloroethylene (100F*)
239
PART 3
CHAPTER 21
Table 21.8. Comparison of 60 Group 1 agents with sufficient or limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in
240
animals in specific organ and tissue systemsa (continued)
Radioiodines, including iodine-131 (100D) Radioiodines, including iodine-131 (100D) Nickel compounds (100C)
X- and γ-radiation (100D) X- and γ-radiation (100D) Radioiodines, including iodine-131 (100D)
X- and γ-radiation (100D)
Arsenic and inorganic arsenic (100C) X- and γ-radiation (100D) Diethylstilbestrol (100A)
Cadmium and cadmium compounds (100C) Trichloroethylene (100F*) Estrogen-only menopausal therapy (100A)
X- and γ-radiation (100D) Phenacetin (100A)
Tobacco smoking (100E) X- and γ-radiation (100D)
Trichloroethylene (100F*) Trichloroethylene (100F*)
Aristolochic acid, plants containing (100A) Aristolochic acid, plants containing (100A) Aristolochic acid, plants containing (100A)
Cyclophosphamide (100A) Cyclophosphamide (100A) Cyclophosphamide (100A)
Phenacetin (100A) Phenacetin (100A) Phenacetin (100A)
Arsenic and inorganic arsenic compounds (100C) Arsenic and inorganic arsenic compounds (100C) Arsenic and inorganic arsenic compounds (100C)
X- and γ-radiation (100D) 4-Aminobiphenyl (100F) 2-Naphthylamine (100F)
Tobacco smoking (100E) 2-Naphthylamine (100F) 4-Aminobiphenyl (100F)
Coal-tar pitch (100F) ortho-Toluidine (100F) ortho-Toluidine (100F)
Soot (as found in occupational exposure of chimney
sweeps) (100F)
4-Aminobiphenyl (100F)
Benzidine (100F)
2-Naphthylamine (100F)
ortho-Toluidine (100F)
Engine exhaust, diesel (100F*)
Table 21.8. Comparison of 60 Group 1 agents with sufficient or limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in
animals in specific organ and tissue systemsa (continued)
242
animals in specific organ and tissue systemsa (continued)
Azathioprine (100A) Methoxsalen in combination with UVA (100A) Methoxsalen in combination with UVA (100A)
Methoxsalen in combination with UVA (100A) Solar radiation (100D) Solar radiation (100D)
Arsenic and inorganic arsenic compounds (100C) UV-emitting tanning devices (100D) UV-emitting tanning devices (100D)
Solar radiation (100D) Coal-tar distillation (100F) Coal, indoor emissions from household combustion of (100E)
UV-emitting tanning devices (100D) Mineral oils, untreated or mildly treated (100F) Tobacco smoking (100E)
X- and γ-radiation (100D) Shale oils (100F) Benzene (100F)
Coal-tar distillation (100F) Soot (as found in occupational exposure of chimney Bis(chloromethyl)ether; Chloromethyl methyl ether
Mineral oils, untreated or mildly treated (100F) sweeps) (100F) (technical grade) (100F)
Shale oils (100F) Coal gasification (100F)
Soot (as found in occupational exposure of chimney Coal-tar distillation (100F)
sweeps) (100F) Coal-tar pitch (100F)
Polychlorinated biphenyls (100F*) Coke production (100F)
Mineral oils, untreated or mildly treated (100F)
Shale oils (100F)
Soot (as found in occupational exposure of chimney sweeps)
(100F)
2,3,7,8-Tetrachlorodibenzo-para-dioxin (100F)
ortho-Toluidine (100F)
Table 21.8. Comparison of 60 Group 1 agents with sufficient or limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in
animals in specific organ and tissue systemsa (continued)
Female breast, female reproductive organs, and female reproductive tract (31% overlap)
244
animals in specific organ and tissue systemsa (continued)
Diethylstilbestrol (100A)
Arsenic and inorganic arsenic compounds (100C)
Cadmium and cadmium compounds (100C)
Thorium-232 (as Thorotrast) (100D)
X- and γ-radiation (100D)
N/A, not applicable: denotes organ and tissue systems when overlap is not possible (positive data are available in either humans or animals, but not in both); UV, ultraviolet.
a Organ and tissue systems in the anatomically based tumour nomenclature system (see Supplemental Table 1. Animal and human tumour sites for 111 Group 1 agents identified up
to and including Volume 109 of the IARC Monographs). Data inputs for human and animal data with sufficient evidence of carcinogenicity are from Supplemental Table 2. Database of
animal and human tumour sites for 111 distinct Group 1 agents up to and including Volume 109 of the IARC Monographs. Agents that lack sufficient evidence in both humans and animals
are not shown, with the exception of limited additional data inputs for limited evidence of human sites from Volumes 100A–F, Volume 107, and Volume 109 (in italics) and included data
for ethylene oxide, estrogen–progestogen oral contraceptives, and diethylstilbestrol. Data for male reproductive organs are also included, although they are not part of the concordance
analyses. 2,3,7,8-Tetrachlorodibenzo-para-dioxin is included, but its designation of “all cancers combined” for human data precludes specific site analyses between species.
b Agents with sufficient evidence in humans, animals, and both humans and animals.
c Part A, B, C, D, E, or F in Volume 100 of the IARC Monographs in which the agent is included. Volume 100F* denotes chemical agents and related occupations identified as Group 1
CHAPTER 21
that human exposure to TCE was and mammary adenocarcinomas in production). Lymphohaematopoietic
PART 3
associated with a possibly increased female mice. Osteosarcomas and cancers are a consistent end-point
risk of liver cancer (Hansen et al., Leydig cell tumours were induced for antineoplastic alkylating agents
2013). Inclusion of the limited data for in rasH2 [transgenic] and Xpa/p53 that induce these cancers after their
TCE-induced liver cancer in humans [knockout] male mice, respectively. use in chemotherapy to eradicate
allows for the observation of overlap Subcutaneous implantation of die- other neoplasms (IARC, 2012e), for
between animals and humans for thylstilbestrol induced mammary tu- radioactive materials (IARC, 2012f),
this end-point. mours in female Wistar rats. Perinatal and for several chemical agents and
This example illustrates that exposure to diethylstilbestrol induces related compounds that are metabo-
the inclusion of agents with limited lymphoma, uterine sarcomas, ade- lized to or are in themselves agents
evidence of carcinogenicity in nocarcinomas, and pituitary, vaginal, that are reactive with DNA (IARC,
humans enhances the ability to and ovarian tumours in female mice. 2012c).
identify concordant relationships. Uterine adenocarcinomas and mam- Table 21.8 also illustrates some of
Comparison between Table 21.7, mary and vaginal tumours were also the potential relationships between
which mentions only sites with suf- induced in female rats. In hamsters, agents that may act in a similar
ficient evidence in humans, and diethylstilbestrol perinatal exposure fashion in humans. Tobacco smoke
Table 21.8, which also lists sites with induced kidney tumours.” and its related agents (smokeless
limited evidence in humans, illus- Although agents affecting male tobacco and second-hand tobacco
trates increased coherence, when reproductive organs are included in smoke) affect several similar organ
246
However, an immediate challenge er respiratory tract are considered model. Animal studies may also
in making comparisons for tumour together as the respiratory system. show tumours that are species- and/
site concordance between species Aggregation also allows more data or sex-specific.
was how to compare tumours in to be considered for analysis, which As part of the determination of
animals and in humans. A detailed increases the robustness of the en- weight of evidence, agents that in-
historical discussion of approaches suing conclusions. For the concor- duce tumours at multiple sites and
to the coding of human tumours was dance analyses, data at both the across multiple species are consid-
provided by Muir and Percy (1991), individual tumour site level and the ered to present a more robust can-
considering the topographical, mor- organ and tissue system level were cer hazard to humans. However,
phological, and histological char- the experimental animal database
examined.
acteristics of the lesion to be clas- used for the analysis consists pri-
Although the present analysis
sified. In the absence of a common marily of rodent data. It is notable
demonstrates generally good agree-
coding system for animal and human that of the 111 Group 1 agents ex-
ment between tumour sites in ani-
tumours, an anatomically based tu- amined here, three agents caused
mals and in humans after exposure
mour taxonomy system was devel- tumours in humans and in four ani-
to Group 1 carcinogens, concor-
oped during the course of the work mal species (mice, rats, hamsters,
dance was not demonstrated with
presented here.
every agent and tumour site. There and non-human primates): asbestos,
Although this system worked which causes lung tumours in all five
well for the purposes of the present are several factors and important
species; plutonium-239, which caus-
concordance analysis, there are limitations that may result in lack of
es skin tumours in these species;
some animal sites that do not have tumour concordance based on these
and 2-naphthylamine, which causes
a human counterpart, including the data. For many of the 111 agents,
urinary tract/uroendothelial tumours
Harderian gland and the Zymbal relevant and reliable data to support
in these species. These agents are
gland. Tumours at these unique sites a complete analysis of concordance
examples of carcinogens that cause
occurred rarely and were included are unavailable for either animals or
the same type of tumour in multiple
within the category of “other group- humans. For some agents, notably
species, thereby demonstrating a
ings” in the anatomically based tu- the human tumour viruses, relevant
high degree of interspecies tumour
mour nomenclature system used animal models are lacking, thereby
site concordance.
here. Other sites that are unique to precluding the possibility of obtaining
The present analyses exclude
animals but are, however, closely results on concordance. There may
the human tumour viruses evaluated
also be little motivation for conduct-
CHAPTER 21
related to a similar human site were in Volume 100B, because, with the
PART 3
aligned with the corresponding hu- ing animal tests for other agents,
possible exception of human T-cell
man tumour site; for example, the such as leather dust in occupational
lymphotropic virus type 1 (HTLV-
forestomach was considered as part environments or acetaldehyde asso- 1), the use of animals to assess the
of the stomach in the anatomically ciated with consumption of alcoholic potential cancer risks of human tu-
based taxonomy system. beverages. Mixtures such as those mour viruses is problematic (IARC,
This tool, developed for tumour in combined estrogen–progestogen 2012b). The best animal models to
comparisons across and within spe- menopausal therapy may also not study human viruses are non-hu-
cies, included 39 individual tumour have been evaluated in animals, man primates, which are difficult to
sites for which agents showed suf- particularly if the components of the use experimentally both because
ficient evidence of carcinogenicity in mixture had been previously evaluat- of the time and expense involved in
humans and/or animals, which were ed separately. Relevant animal tests conducting studies with long-lived
further aggregated into 14 organ and may still provide only limited or inad- species and because the incidence
tissue systems. This aggregation al- equate evidence of carcinogenicity of cancer is low in non-human pri-
lows comparisons to be made at a through limitations in study design mates. Although transgenic mouse
higher level of organization, reflect- or conduct, or if the mechanism of models have been developed for
ing anatomical and physiological action of the agent of interest was evaluating human cancer viruses,
similarities among certain tumour specific to humans and not easily such models are considered more
sites; for example, the lung and low- replicated in an experimental animal informative for understanding cancer
248
stress, (6) induces chronic inflam- ty to determine concordance may The concordance analyses reported
mation, (7) is immunosuppressive, change as additional Group 1 agents here are based either on 39 tumour
(8) modulates receptor-mediated are identified, or as additional ani- sites or on the broader classification
effects, (9) causes immortalization, mal or human evidence on current of 14 organ and tissue systems.
and/or (10) alters cell proliferation, Group 1 agents becomes available.
Effects of sex, strain, and
cell death, or nutrient supply. These New mechanistic data could affect
route of exposure
considerations will be relevant in IARC evaluations of agents currently
planned future analyses of coher- classified in Group 2A (probably car- Risks of cancer can differ between
ence between tumours in animals cinogenic to humans) and Group 2B male and female animals, among
and humans, taking into account (possibly carcinogenic to humans), different strains of the same animal
key characteristics of carcinogens. and hence affect the concordance species, and by route of exposure.
However, mechanistic upgrades limit estimates reported here. Birkett et al. Because of incomplete information
the ability to identify tumour site con- (2019) noted that additional informa- on these three factors in the data-
cordance when human tumour sites tion on the 10 mechanistic key char- base used in the present analysis,
are not identified. acteristics of human carcinogens it was not possible to evaluate how
Exposure assessment is one described by Smith et al. (2016) is concordance might vary by sex,
of the most difficult aspects of ep- available in the general scientific lit- strain, or exposure route.
idemiological investigations (Nieu erature, beyond what is summarized
Effects of dose
wenhuijsen, 2003). In some cases, in the IARC Monographs.
such as ecological studies that com- In addition to the restrictions used Because the primary objective of the
pare two population groups subject by Grosse et al. (Annex 1) for inclu- IARC Monographs Programme is to
to notably different exposure circum- sion of certain experimental animal identify agents with the potential to
stances, exposure may not be mea- data, other limitations of the data- cause cancer in humans in qualita-
sured at all. In other cases, however, base affect the ability to determine tive terms, rather than to quantify the
exposures may be very well deter- tumour site concordance, including level of risk at a given dose, informa-
mined, as with the use of personal incomplete information on tumour tion on dose dependence in cancer
dosimeters to measure exposures to histology, limited information on the risk is not systematically collected in
agents such as ambient air pollution effects of sex, strain, and route of the Monographs, although this is cur-
or ionizing radiation, or in the dose exposure, and limited information on rently under review by IARC (IARC
regimens of pharmaceutical drugs or dose-dependent effects. These and Advisory Group to Recommend on
medical radiation. In the future, en- other limitations are discussed brief- Quantitative Risk Characterization,
CHAPTER 21
hanced exposure assessment meth- ly below.
PART 3
2013). Therefore, analyses of con-
odologies may serve to strengthen cordance considering dose–re-
Incomplete information on
the ability of epidemiological studies tumour histology sponse relationships seen in animals
to identify Group 1 agents (Cohen- and humans were not attempted at
Hubal et al., 2010; National Research Because of incomplete information
this time.
Council, 2012). Biomarkers of expo- on the histology of lesions in both an-
sure are expected to play an impor- imal and human studies, it was not Multisite/multiorgan
tant part in the future of exposure sci- possible to conduct concordance an- carcinogenicity
ence (Gurusankar et al., 2017). alyses for specific histological sub-
The data set assembled and eval- types of cancers at a given site (such Several agents, notably radiation
uated by Grosse et al. (Annex 1) was as adenocarcinoma or squamous and tobacco smoke, induce malig-
retrieved from the IARC Monographs. cell carcinoma of the lung). The con- nant lesions at multiple sites or in
Thus, these agents do not represent cordance analyses reported here multiple organ and tissue systems.
a “random sample” of all potential are necessarily restricted to tumours Volume 100F (IARC, 2012c) sum-
human carcinogens, and the data occurring in a given organ or tissue marizes the evidence that 1,3-buta-
set is populated by the available an- (such as lung cancer) or in a more diene induces haemangiosarcomas
imal and human evidence that was broadly defined organ and tissue sys- of the heart, malignant lymphomas,
the focus of the Monographs from tem (such as the upper aerodigestive bronchiolo-alveolar neoplasms,
which they were drawn. The abili- tract and the respiratory system). and squamous cell neoplasms of
250
leading scientific experts world- the previous 99 Volumes of the IARC Monographs Programme (Wilbourn
wide, who apply the guidance pro- Monographs, providing a veritable et al., 1986) and commented upon by
vided in the Preamble to the IARC “encyclopaedia of carcinogens”. other authors (Tomatis et al., 1989;
Monographs (IARC, 2006) to eval- This information, supplemented with Huff, 1994; Maronpot et al., 2004).
uate the weight of evidence that an data on Group 1 agents identified in However, it is important to note that
agent may present a cancer risk to Volumes 101 to 109, formed the ba- the present database cannot be
humans. Up to and including Volume sis for the analyses included in this used to estimate the predictive value
109, more than 2000 scientists have chapter. After both PCB 126 and of animal cancer tests for humans,
contributed to the development of the dioxin-like PCBs were subsumed because it comprised by design only
IARC Monographs; nearly 200 sci- within the broader category of PCBs, Group 1 agents; the PPV and the
entists were involved in Volume 100 113 – 2 = 111 district Group 1 agents NPV of the animal data for humans
alone. Since its beginning in 1971– were included in the concordance would be 100% and 0%, respectively
1972 (Saracci and Wild, 2015), the analyses presented in this chap- (an artefact of a database that com-
IARC Monographs Programme has ter. The importance of human data prises human carcinogens only).
evaluated more than 1000 agents in the IARC carcinogen evaluation Despite the challenges in eval-
for their potential to cause cancer process is highlighted by the obser- uating concordance between tu-
in humans, with 120 of these agents vation that 102 of the 111 distinct mour sites in animals and humans,
assigned to Group 1, indicating that Group 1 agents identified at the time the IARC concordance database
the weight of evidence supports the this analysis was done demonstrated is a useful source of information for
conclusion that the agent is carcino- sufficient evidence of carcinogenicity comparing animal and human data
genic to humans. in humans. with respect to the tumours caused
A noteworthy aspect of the pro- Analysis of concordance between in different species by the 111 dis-
cess used by IARC to identify the tumour sites in animals and humans tinct Group 1 agents identified by
causes of cancer in humans is the was restricted to 60 Group 1 agents IARC up to and including Volume
reliance on leading experts in the demonstrating sufficient evidence for 109 of the IARC Monographs.
Working Groups that conduct the at least one tumour site in animals Future Monographs may benefit
evaluations documented in the and in humans. Substantial overlap from a more systematic summary
Monographs to interpret the data between animal and human tumours of the animal and human data on
according to the weight-of-evidence was seen in some organ and tissue agents evaluated within the IARC
guidelines provided in the Preamble systems but not in others. This anal- Monographs Programme, including
CHAPTER 21
to the IARC Monographs (IARC, ysis focused on tumours seen in the data on the types of tumours seen in
PART 3
2006). With the trend towards great- 14 organ and tissue systems in the animal and human studies, possibly
er reliance on systematic review anatomically based tumour classi- using the anatomically based tumour
(National Research Council, 2014) fication system rather than 39 indi- nomenclature system introduced
and structured weight-of-evidence vidual tumour sites, because of the in this chapter to facilitate compari-
approaches to the evaluation of sparseness of data at the individual sons between animals and humans.
toxic substances (Rhomberg et al., tumour site level. Data on route of exposure, sex, and
2013), the continued involvement The principle that agents that are animal strain would also support
of international experts in the IARC carcinogenic in experimental animals comparisons of animal and human
Monographs to interpret the often should be regarded as presenting a tumours at a finer level of biological
extensive human, animal, and mech- carcinogenic risk to humans was fur- resolution. Data on the exposure or
anistic data is a major strength of the ther confirmed in the course of this dose levels at which tumours are
IARC Monographs Programme. investigation. Excluding agents for seen in animals and humans would
Collectively, the IARC Mono- which animal data are lacking or oth- further support evaluation of the rel-
graphs provide a rich source of erwise uninformative, all agents that ative carcinogenic potency of agents
information on the causes of can- cause cancer in humans also cause evaluated in animals and humans.
cer in humans. In particular, Volume cancer in one more animal species, Information on tumour sites affected
100 presents a review and update a finding consistent with an earlier by agents evaluated within the IARC
of 107 Group 1 agents identified in evaluation of results from the IARC Monographs Programme should be
252
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PMID:16712894
CHAPTER 21
PART 3
chapter 22.
CHAPTER 22
PART 3
Introduction evaluate and integrate the evidence limited evidence of carcinogenicity,
provided by human epidemiological inadequate evidence of carcinogen-
Since its establishment in the ear- studies, animal cancer bioassays, icity, or evidence suggesting lack of
ly 1970s, the IARC Monographs and information on possible biolog- carcinogenicity. The information on
Programme has evaluated more ical mechanisms of action, to clas- biological mechanisms of action may
than 1000 agents with evidence of sify agents into one of the following be evaluated as strong, moderate, or
human exposure and for which some categories: carcinogenic to humans weak, and is taken into consideration
suspicion exists of an increased (Group 1), probably carcinogenic to in the overall evaluation.
cancer risk to humans. The IARC humans (Group 2A), possibly carci- The role of mechanistic informa-
Monographs Programme has devel- nogenic to humans (Group 2B), not tion in evaluating carcinogenicity
oped detailed criteria against which classifiable as to its carcinogenicity to has increased substantially during
to evaluate the available scientific humans (Group 3), and probably not the history of the IARC Monographs
evidence on the carcinogenic poten- carcinogenic to humans (Group 4). Programme. In 1991, IARC convened
tial of such agents. These criteria, These evaluations involve classifying a Working Group on the Use of Data
which are described in the Preamble the data from both the human and on Mechanisms of Carcinogenesis
to the IARC Monographs (Cogliano the animal studies as providing suf- in Risk Identification, to explore how
et al., 2004; IARC, 2006), are used to ficient evidence of carcinogenicity, mechanistic data could be used to
258
Table 22.1. Number of Group 1 agents in Volumes 100–118 of the IARC Monographs, by type of agenta
100 105 106 107 109 110 111 113 114 117 118
Pharmaceuticals 23 – – – – – – – – – – 23
Biological agents 11 – – – – – – – – – – 11
Arsenic, metals, 10 – – – – – 2b – – – – 12
fibres, and dusts
Radiation 18 – – – – – – – – – 1c 19
carbide fibres.
c Ultraviolet radiation from welding.
d Processed meat.
f Trichloroethylene.
i 1,2-Dichloropropane.
j Lindane.
k Pentachlorophenol (PCP).
l Welding fumes.
CHAPTER 22
can be inherited through cell divi- reactive oxygen and detoxification of leading to the recruitment and acti-
PART 3
sion. Epigenetic phenomena include the radical species within cells and vation of inflammatory cells. Strong
genomic imprinting, X-chromosome tissues. Reactive oxygen species links exist between inflammation
inactivation, global reconfiguration induce a cascade of events that can and the induction of oxidative stress
of the DNA methylome, changes in include DNA mutation and oxidative and genomic instability; this makes
chromatin compaction states and DNA damage. Both are key events in it difficult to separate out the rel-
histone modification patterns, and carcinogenesis (Klaunig et al., 2011). ative importance of each of these
altered expression of microRNAs mechanisms. These linkages might
Characteristic 6: Induces
(miRNAs). These phenomena occur be the basis of the relationship be-
chronic inflammation
during organ development and con- tween chronic inflammation and can-
tribute to the lineage-specific epi- Chronic inflammation can arise from cer (Multhoff and Radons, 2012).
genome that is maintained over the persistent infection (e.g. with human
Characteristic 7: Is
lifetime of an organism. papillomavirus or with Helicobacter
immunosuppressive
pylori) as well as from exogenous ir-
Characteristic 5: Induces
ritants (e.g. silica or asbestos fibres). Immunosuppression is an induced
oxidative stress
Persistent infection and chronic in- reduction in the capacity of the
Oxidative stress results from an flammation disrupt local tissue ho- immune system to respond effec-
imbalance between formation of meostasis and alter cell signalling, tively to foreign antigens, including
Alters DNA repair or causes genomic instability DNA repair alteration, leading to genomic instability
Induces epigenetic alterations Epigenetic alterations (DNA methylation, histone modification, and altered
expression of microRNAs)
antigens on tumour cells. In contrast receptors, thereby inducing or mod- Characteristic 9: Causes
to other key characteristics, immuno- ifying a plethora of signal transduc- immortalization
suppression does not play a direct tion pathways that, among other re-
Immortalization refers to a cell evad-
part in transforming normal cells into sponses, stimulate cell proliferation. ing normal cellular senescence and
tumour cells, but enables them to es- Receptor-mediated effects can in- proliferating indefinitely. In culture,
cape immune surveillance. Among
duce hormonal effects whereby ex- normal cells have a fixed number of
other roles, the immune system also
ternal agents can interfere with the replication cycles before they enter
plays a major part in the inflammato-
synthesis, secretion, transport, bind- cellular senescence and stop repli-
ry response to injury. cating. Evasion of senescence is fre-
ing, action, or elimination of natural
Characteristic 8: Modulates quently associated with activation of
hormones in the body. These exter-
receptor-mediated effects telomerase (Willeit et al., 2010) and
nal factors can also demonstrate re-
plays a critical part in carcinogenesis
activity similar to endogenously pro-
Modulation of receptor-mediated ef- (Reddel, 2000). Carcinogenesis may
fects can occur when agents mimic duced hormones, which can lead to involve activation of a telomerase
the structure of endogenous ligands them mediating changes in homeo- that prevents loss of telomere length,
that bind to cells and activate cell stasis, reproduction, development, leading to immortalization of cells
surface receptors or intracellular or behaviour. (Willeit et al., 2010).
260
Characteristic 10: Alters cell (evaluated in Volume 106; Guha for 109 Group 1 agents identified in
proliferation, cell death, or et al., 2012; IARC, 2014). Had these the IARC Monographs up to and in-
nutrient supply two agents been evaluated within cluding Volume 106. The 86 Group 1
Volume 100, they would have been agents for which separate mech-
Cell proliferation is affected by alter-
included in Volume 100F; they have anistic summaries are provided in
ations in the rates of cell growth with-
therefore been listed with other the IARC Monographs up to and
in a tissue. It may be a direct effect or
chemical agents and related occupa- including Volume 106 are listed in
a secondary regenerative effect after
tions in Volume 100F*. Table 22.3, along with their relation-
induction of cell death by cytotoxic
Although additional Group 1 ship to the 111 distinct agents identi-
agents. Two associated toxicological
agents have since been identified fied up to and including Volume 109
end-points are (i) cell-cycle effects,
(Table 22.1), the present analysis is used by Krewski et al. (Chapter 21)
i.e. alterations in the functioning restricted to Group 1 agents identi- in a parallel analysis of overlap be-
of the complex series of factors fied in the IARC Monographs up to tween tumours and tumour sites in
that control the cell cycle and cell and including Volume 106, the most animals and humans.
division, which have been associat- recent volume for which mechanis-
ed with carcinogenesis (Diaz-Moralli tic information was available at the Database of mechanistic
et al., 2013), and (ii) alterations in cell time of the present analysis. Group 1
characteristics
signalling pathways, which relate to agents not included in the present A database of toxicological end-
the ability of the agent to interfere analysis are (i) polychlorinated bi- points was assembled for the 86
with cell signalling pathways, leading phenyls (PCBs) and dioxin-like PCBs
Group 1 agents identified up to and
to expression of a carcinogenic trait (reviewed in Volume 107; Lauby-
including Volume 106 of the IARC
or phenotype in the cell. Secretan et al., 2013; IARC, 2016b),
For cell death, necrosis triggers Monographs. The database in-
(ii) outdoor air pollution and (iii) par-
the invasion of cells such as mac- cludes information from in vivo and
ticulate matter in outdoor air pollu-
rophages into the affected area, in vitro studies in humans and ani-
tion (both evaluated in Volume 109;
and enhances the proliferation and mals. Information on the 24 toxico-
Loomis et al., 2013; IARC, 2016a),
spread of cancer cells. Defects in logical end-points was retrieved from
(iv) 1,2-dichloropropane (reviewed in
programmed cell death can cause Section 4 (“Other relevant data”) of
Volume 110; Benbrahim-Tallaa et al.,
cancer; evasion of apoptosis is a re- the IARC Monographs (Al-Zoughool
2014; IARC, 2017a), (v) fluoro-eden-
quirement for both neoplastic trans- et al., 2019).
ite fibrous amphibole and (vi) occu-
formation and sustained growth of Recognizing that, among other
pational exposures associated with
CHAPTER 22
cancer cells. limitations, new data may have be-
the Acheson process used in the
PART 3
Adequate cell nutrition is essen- come available since 2009, when
manufacture of silicon carbide fi-
tial to proliferating cancer cells, and the various parts of Volume 100 were
bres (both evaluated in Volume 111;
agents that promote or inhibit the Grosse et al., 2014; IARC, 2017b); compiled, PubMed searches were
growth of blood vessels (angiogene- (vii) lindane (Volume 113; Loomis conducted to identify evidence on
sis) will affect tumour growth. et al., 2015), and (viii) processed any of the 24 toxicological end-points
meat (Volume 114; Bouvard et al., linked to these agents that was not
Group 1 agents included in recorded in the IARC Monographs
2015).
the analysis (Birkett et al., 2019). The mechanistic
In some cases, the discussion of
Volume 100 of the IARC Monographs mechanisms of action in Section 4 database distinguishes information
provided a review and update of the (“Other relevant data”) of the IARC derived from the Monographs from
107 Group 1 agents identified as Monographs is based on groups of that found in the PubMed search,
of 2009. Since the publication of agents that act via the same mech- thereby permitting an assessment
Volume 100, mechanistic informa- anism. For example, internalized of the extent to which Section 4
tion has become available on two radionuclides that emit α-particles (“Other relevant data”) of the IARC
additional Group 1 agents: diesel are discussed in the Monographs as Monographs captured all relevant
engine exhaust (reviewed in Volume a group with the same mechanism information on these end-points.
105; Benbrahim-Tallaa et al., 2012; of action. Birkett et al. (2019) re- The analyses in the present chapter
IARC, 2013) and trichloroethylene viewed the mechanistic information are restricted to information taken
Volumea Agent 86 agents used in the analysis of key 111 agents used in the analysis of
number characteristics concordance between tumours and tumour
sites in humans and animals
100B 21 Opisthorchis viverrini and Clonorchis sinensis Clonorchis sinensis (infection with)
Opisthorchis viverrini (infection with)
262
Table 22.3. Relationship between 86 agents used in the analysis of key characteristics of human carcinogens
and 111 agents used in the analysis of concordance between tumours and tumour sites in humans and animals
(continued)
Volumea Agent 86 agents used in the analysis of key 111 agents used in the analysis of
number characteristics concordance between tumours and tumour
sites in humans and animals
100B 28 Human T-cell lymphotropic virus type 1 Human T-cell lymphotropic virus type 1
100C 31 Arsenic and inorganic arsenic compounds Arsenic and inorganic arsenic compounds
100C 32 Asbestos (all forms, including actinolite, amosite, Asbestos (all forms, including actinolite, amosite,
anthophyllite, chrysotile, crocidolite, and anthophyllite, chrysotile, crocidolite, and
tremolite) tremolite)
100C 39 Silica dust, crystalline, in the form of quartz or Silica dust, crystalline, in the form of quartz or
cristobalite cristobalite
CHAPTER 22
PART 3
100D 42 X- and γ-radiation X- and γ-radiation
Ionizing radiation (all types)
100D 45 Internalized radionuclides that emit β-particles Fission products including Sr-90
Radioiodines, including iodine-131
Phosphorus-32, as phosphate
Internalized radionuclides that emit β-particles
Volumea Agent 86 agents used in the analysis of key 111 agents used in the analysis of
number characteristics concordance between tumours and tumour
sites in humans and animals
100E 48 Coal, indoor emissions from household Coal, indoor emissions from household
combustion of combustion of
100F 71 Iron and steel founding, occupational exposure Iron and steel founding, occupational exposure
during during
264
Table 22.3. Relationship between 86 agents used in the analysis of key characteristics of human carcinogens
and 111 agents used in the analysis of concordance between tumours and tumour sites in humans and animals
(continued)
Volumea Agent 86 agents used in the analysis of key 111 agents used in the analysis of
number characteristics concordance between tumours and tumour
sites in humans and animals
100F 72 Isopropyl alcohol manufacture using strong acids Isopropyl alcohol manufacture using strong acids
100F 75 Mineral oils, untreated or mildly treated Mineral oils, untreated or mildly treated
100F 82 Soot (as found in occupational exposure of Soot (as found in occupational exposure of
chimney sweeps) chimney sweeps)
CHAPTER 22
107 Polychlorinated biphenylsb
PART 3
109 Outdoor air pollutionb
UV, ultraviolet.
a IARC Monographs Volumes 100A (IARC, 2012e), 100B (IARC, 2012b), 100C (IARC, 2012a), 100D (IARC, 2012f), 100E (IARC,
2012d), 100F (IARC, 2012c), 105 (IARC, 2013), 106 (IARC, 2014), 107 (IARC, 2016b), and 109 (IARC, 2016a).
b Because the mechanistic sections for Monographs Volumes 107–109 were not available for review at the time that the present
analysis was conducted, Group 1 agents in these volumes were not included in the present analysis.
directly from the IARC Monographs: animal in vivo and animal in vitro sources of information noted above.
Birkett et al. (2019) present the re- sources, it is possible to aggregate To evaluate the extent to which the
sults of a sensitivity analysis incorpo- this information according to human Group 1 agents demonstrated more
rating the additional information ob- and animal sources (by combining than one key characteristic, the num-
tained through the PubMed search. across in vivo and in vitro sources) ber of agents demonstrating multiple
After the collection of informa- or according to in vivo and in vitro characteristics was also tabulated.
tion on the toxicological end-points sources (by combining across hu- A heat map showing the number
identified by the Workshop partici- man and animal sources). Of primary
(0, 1, 2, 3, or 4) of sources of infor-
pants during the April 2012 meeting, interest here is aggregation across
mation (human in vivo, human in vi-
the database of key characteristics all four sources combined, to obtain
tro, animal in vivo, and animal in vitro
was then created by mapping the an overall indicator of whether any of
studies) supporting a given charac-
24 toxicological end-points to the the key characteristics is associated
teristic for a specified agent was pre-
10 characteristics as indicated in with each of the 86 Group 1 agents
pared, to evaluate the consistency
Table 22.2. As noted by Al-Zoughool of interest.
of information provided by different
et al. (2019), two of the toxicological
Statistical analysis sources. A heat map showing the
end-points – susceptibility and
changes in gene expression – did Descriptive statistical methods were overlap between human and animal
not link to any of the key character- used to explore the key characteris- sources of information (after combin-
istics, and thus were not included in tics associated with the 86 Group 1 ing in vivo and in vitro sources in both
the development of the database of agents, beginning with a tabulation cases) on the key characteristics was
key characteristics. Because the da- of the number of agents demonstrat- also prepared, to evaluate the extent
tabase includes information derived ing any of the 10 characteristics, to which there was overlap between
from human in vivo, human in vitro, both overall and stratified by the four these two sources.
266
Fig. 22.2. Sources of information on key characteristics of 86 Group 1 agents (sources are human in vivo, human in vitro, animal in vivo, and animal in vitro
studies).
Human In Vivo
Human In Vitro
Animal In Vivo
Animal In Vitro
268
Fig. 22.3. Number of Group 1 agents demonstrating one or more key characteristics.
of human carcinogens is shown in icity. Ten agents – diethylstilbestrol, oxidative stress”), but Fig. 22.5 clar-
the heat map in Fig. 22.5. This heat Kaposi sarcoma-associated herpes- ifies that there are both human and
CHAPTER 22
map, prepared by combining the in virus, arsenic and inorganic arsenic animal data for only five of these.
PART 3
vivo and in vitro sources of informa- compounds, cadmium and cadmium For chlornaphazine, Fig. 22.4 shows
tion on the key characteristics for compounds, asbestos, crystalline two sources of information, for “is
humans and for animals, indicates silica, solar and ultraviolet radiation, electrophilic or can be metabolical-
whether information on the key char- sulfur mustard, diesel and gaso- ly activated to electrophiles” and “is
acteristics for a given agent is de- line engine exhausts, and trichloro- genotoxic”, whereas the correspond-
rived from both human and animal ethylene – demonstrate overlap be- ing data in Fig. 22.5 show overlap
sources (reflecting concordance tween human and animal sources of between human and animal sources
between humans and animals), from information for at least five of the key only for “is electrophilic or can be
human sources alone, from animal characteristics. metabolically activated to electro-
sources alone, or from neither of Comparisons between the results philes”, with human but not animal
these. These results indicate overlap in Fig. 22.4 and Fig. 22.5 can pro- data on “is genotoxic”.
between human and animal sourc- vide additional insights into the key Fig. 22.6 shows the key character-
es of information for several agents. characteristics of the Group 1 agents istics of the six categories of Group 1
The concordance is particularly considered here. For example, in the agents considered in Volume 100:
strong for genotoxicity: information case of diethylstilbestrol, Fig. 22.4 pharmaceuticals; biological agents;
from both human and animal sourc- indicates that there is information arsenic, metals, fibres, and dusts;
es is available for 63 of the 85 agents from 1, 2, or 3 sources on nine key radiation; personal habits and in-
demonstrating evidence of genotox- characteristics (all except “induces door combustions; and chemical
270
Fig. 22.5. Heat map showing the degree of concordance between human and animal sources of information on key
characteristics of 86 Group 1 agents (after combining in vivo and in vitro sources of information for humans and for
animals).
CHAPTER 22
PART 3
272
Fig. 22.6. Key characteristics of 86 Group 1 agents by type of agent (expressed as a percentage of the number of
agents of each type demonstrating each of the 10 mechanistic characteristics): (a) pharmaceuticals; (b) biological
agents; (c) arsenic, metals, fibres, and dusts; (d) radiation; (e) personal habits and indoor combustions; and
(f) chemical agents and related occupations (continued).
CHAPTER 22
PART 3
274
agents and related occupations. al., 2019 and Birkett et al., 2019). Information drawn from the IARC
Genotoxicity was the most preva- The profiles of key characteristics Monographs showed that the over-
lent key characteristic demonstrat- of these agents show several inter- whelming majority of the agents ex-
ed by agents in the categories of esting patterns. First, all but seven amined here induce one or more of
pharmaceuticals; arsenic, metals, agents exhibited multiple character- these end-points. Even biological
fibres, and dusts; personal habits istics, an observation consistent with agents such as viruses that act pri-
and indoor combustions; and chem- previous findings on the complexity marily through non-genotoxic mech-
ical agents and related occupations, and heterogeneity of carcinogenic anisms induce cytogenetic effects
and genotoxicity was exhibited by pathways (Hanahan and Weinberg, and gene mutations as secondary
all agents in the category of radia- 2011; Floor et al., 2012; Baker, 2014; events through chronic inflammation
tion. Immortalization, genotoxicity, Pickup et al., 2014; Roessler et al., and oxidative stress.
and altered cell proliferation, cell 2014). Agents in the categories of Another important observation
death, or nutrient supply are promi- biological agents; arsenic, metals, fi- is that information on the key char-
nent characteristics of the biological bres, and dusts; personal habits and acteristics of the 86 Group 1 agents
agents. None of the biological agents indoor combustions; and radiation considered here is often derived from
demonstrated modulation of recep- demonstrated a wide spectrum of bi- multiple sources (human in vivo, hu-
tor-mediated effects, and none of the ological activity. Radiation has been man in vitro, animal in vivo, and ani-
agents in the category of personal linked to many hallmarks of cancer mal in vitro studies); for many agents,
habits and indoor combustions ap- (Boss et al., 2014): this mechanistic evidence is available from more than
peared to act through modulation of profile, with multiple pathways in- one of these sources. Concordance
receptor-mediated effects, through volved for most radiation agents, is between animal and human sources
immunosuppression or through im- consistent with the broad spectrum of information was seen for sever-
mortalisation. There are five agents of tumours associated with exposure al agents, particularly with respect
in the category of radiation, all of to ionizing radiation (Chapter 21, by to genotoxicity, an observation that
which demonstrate the following Krewski et al.). Viral oncogenesis lends additional support to the rele-
key characteristics: is genotoxic; al- is also multifaceted, and the multi- vance of animal data for human can-
ters DNA repair or causes genomic step nature of viral oncogenesis is cer risk assessment.
instability; induces oxidative stress; thought to be influenced by host ge- Some caution must be used in
causes immortalization; and alters netic variability (Mesri et al., 2014). interpreting the distribution of key
cell proliferation, cell death, or nu- Genotoxicity was the most prev- characteristics across the Group 1
CHAPTER 22
trient supply. The profiles of key alent mechanistic characteristic, agents considered here. It is possi-
PART 3
characteristics for pharmaceutical demonstrated by 85 of the 86 agents ble that the near universality of ge-
agents and for chemical agents and considered, possibly reflecting the notoxicity as a carcinogenic mech-
related occupations are remarkably fact that the process of carcino- anism may be related to the way in
similar, possibly reflecting the fact genesis necessarily involves geno- which the IARC Monographs were
that despite their different expo- mic changes. This finding is consis- compiled, with emphasis on the re-
sure circumstances, some of these tent with an earlier evaluation of 180 porting of genotoxicity data. This
chemical entities may act via similar Group 1, Group 2A, and Group 2B would have been partially mitigat-
mechanisms. agents conducted by Bartsch and ed by the inclusion of mechanistic
Malaveille (1989), who reported that information from outside the IARC
Discussion 80–90% of the agents in these three Monographs in the preparation of
categories demonstrated genotoxic the mechanistic database evaluated
The present analysis of key charac- characteristics. In the present ana- separately by Birkett et al. (2019). It
teristics of 86 agents classified as lyses, genotoxicity was considered should also be noted that the IARC
carcinogenic to humans (Group 1) by to include the following end-points: Monographs have been published
the IARC Monographs Programme DNA damage, cytogenetic effects over a long time span, extending
was based on mechanistic infor- (including chromosomal aberra- from the early 1970s to the present
mation retrieved from the IARC tions, micronucleus formation, and (Saracci and Wild, 2015). Studies of
Monographs (see Al-Zoughool et aneuploidy), and gene mutations. agents in earlier Monographs would
276
However, to conduct a series of com- The 10 key characteristics are and reproducible manner. The EPA
prehensive systematic reviews of the features of carcinogens rather than is also currently supporting the de-
key characteristics of all 86 agents mechanisms. The analysis presented velopment of software tools specifi-
considered in the present analysis here does not address the sequence cally designed for systematic review
would require a considerable ef- of events involved in carcinogenesis. of toxicological and epidemiological
fort, and was not attempted as part For example, if the carcinogenic data (ICF, 2017).
of the present project. The expert mechanism of action is being in- The strong evidence linking geno-
opinion of future IARC Working vestigated for a genotoxic agent toxicity to carcinogenesis is consis-
Groups charged with evaluating the that requires metabolic activation, tent with epidemiological data and
mechanistic data on new agents the mechanism needs to consider experimental research. Genotoxic
selected for evaluation by the IARC the entire metabolic pathway. If the effects include the formation of DNA
Monographs would be of consider- agent is not metabolized to produce adducts or induction of single- and
able value in this regard, but would an electrophile, DNA damage will double-strand DNA breaks. Several
ideally be supported by a concomi- not occur. In such a case, biological lines of evidence from epidemio-
tant systematic review of the relevant effects that occur after induction of logical studies and in experimental
scientific literature on the key char- DNA damage also would not be ob-
animals and model systems have
acteristics to ensure that the analysis served. This sequential relationship
shown that DNA adducts are strongly
would be as complete as possible. is also apparent for characteristics
associated with cancer (Kriek et al.,
Another issue that arises when such as chronic inflammation, which
1998; Phillips et al., 2015). Some
discussing key characteristics of hu- acts through the production of oxida-
genotoxic effects can lead to gene
man carcinogens is whether indirect tive stress, release of cytokines, and
mutation, an important event in the
effects should be considered. Many stimulation of cell proliferation, which
pathway towards carcinogenesis,
agents have a direct carcinogenic ultimately produces DNA damage.
especially if it involves oncogenes or
effect, but in other cases the carci- The results of the present analysis
tumour suppressor genes. Chromo-
nogenic characteristic is the result of can provide a basis for future efforts
somal aberrations are another type
a secondary event along the mecha- to categorize mechanistic data for
of genetic alteration that occurs fre-
nistic pathway. For example, cell pro- carcinogens through a systemat-
quently in many tumours, especial-
liferation can arise either as a result of ic review process. A full systematic
review of all agents and all potential ly solid tumours. Most tumour cells
a direct action of the agent on the cell
carcinogenic mechanisms is an in- display aneuploidy, and for some tu-
or indirectly, as a result of cytotoxici-
timidating prospect. However, such mours, characteristic chromosomal
ty that stimulates cell proliferation to
CHAPTER 22
a review would provide a more com- abnormalities have been identified
replace cells, through alterations in
PART 3
prehensive examination of mech- (e.g. the Philadelphia chromosome
cell signalling without cytotoxicity, or
via inhibition of cell proliferation that anisms, because it would include in chronic myeloid leukaemia).
then results in selection of an altered studies that failed to find effects. It The complexity of the pathways
clone of cells with a high prolifera- might also support a process that involved in carcinogenesis and the
tion rate. Although the downstream involves a sequence of mechanistic fact that the cellular response to car-
effect is the same (increased cell steps and mechanistic characteris- cinogen exposure is modulated by
proliferation), the pathway leading to tics relevant to the development of host cell physiology, genetics, and
that result can be different. A similar cancer in humans. other variables have prompted the
issue arises with genotoxicity: many The importance of systematic re- development and application of sen-
agents are not directly genotoxic but view in assembling all relevant evi- sitive assays that measure toxicity
cause DNA damage by stimulating dence on a particular issue has been pathways and perturbations in the
a chain of molecular changes (e.g. emphasized in the recent review of molecular functioning of the cell. The
chronic inflammation). The current the EPA’s Integrated Risk Information newly proposed toxicological test-
database does not contain the in- System (IRIS) (National Research ing paradigm (Krewski et al., 2014)
formation needed to address these Council, 2014) and is currently being focuses on high-throughput screen-
issues and cannot be used to draw implemented within the IRIS pro- ing to detect changes in the molec-
conclusions about the detailed gramme as a way of summarizing ular pathways of the cell in response
mechanism of action of an agent. all relevant data in a comprehensive to chemical exposure. This new
278
Smith (Chapter 10) and Smith et al. There could be value in revisiting relevant mechanistic information.
(2016), mechanistic evaluations of the present retrospective analysis Although this approach could expe-
new agents undertaken within the of the 86 Group 1 agents identified dite identification of relevant articles,
IARC Monographs Programme in the IARC Monographs up to and expert opinion and application of
are beginning to make use of these including Volume 106, with respect weight-of-evidence criteria would still
characteristics, including the use of to the conduct of a series of compre- have value in reducing the errors in
formal methods of systematic review hensive systematic reviews on the 10 the assignment of key characteristics
to identify relevant mechanistic infor- key characteristics of these agents, to specific agents.
mation. This has been successfully followed by an in-depth evaluation
attempted in recent evaluations of of the findings of the systematic re- Conclusions
some organochlorine insecticides views by experts in relevant disci-
and some chlorophenoxy herbicides plines. The development of criteria In considering the results present-
(Loomis et al., 2015; Volume 113) for evaluating the weight of evidence ed in this chapter, it is important to
and of red meat and processed meat for the key characteristics, similar to emphasize that these mechanistic
(Bouvard et al., 2015; Volume 114). that included in the Preamble to the analyses are a first step in under-
It is expected that the search IARC Monographs for human and standing the biological mechanisms
strategies used in future mechanistic animal data (IARC, 2006), might be by which cancer may occur in hu-
evaluations will be refined as expe- mans. Although considerable effort
contemplated at that time. Group 1
rience with the key characteristics was expended in developing the
agents identified beyond Volume 106
accumulates. In an earlier evaluation database of key characteristics and
for which mechanistic information
of evidence of epigenetic alterations their analyses in this chapter, these
had become available could also be
for 28 Group 1 agents, Chappell results should be viewed as prelim-
included in such an analysis.
et al. (2016) searched for evidence of inary, to be refined through more
Baker et al. (2016) have recently
DNA methylation, histone modifica- exhaustive systematic reviews of
applied supervised machine learn-
tion, and expression of non-coding the relevant scientific literature and/
ing techniques to classify PubMed
miRNAs, as was done in the pres- or through discussion with a broad
literature according to the hallmarks
ent analysis, but with the addition of
of cancer (Hanahan and Weinberg, panel of experts on the mechanisms
several more detailed search terms,
2000, 2011). In a case study of basal of carcinogenesis. The 10 key char-
specifically long non-coding RNA
cell carcinoma and melanoma, only acteristics were endorsed by the
(lncRNA), small RNA, chromatin,
46,727 of 121,488 abstracts from participants in the IARC Workshop
and promotor methylation. Chappell
CHAPTER 22
their original systematic literature on Tumour Site Concordance and
et al. (2016) noted that the great ma-
PART 3
search were classified as relevant, Mechanisms of Carcinogenesis,
jority (89%) of the studies on lncR-
reflecting the potential time savings which provided oversight for this
NAs included in their review report-
that may be achieved through auto- project; additional experience with
ed alterations in miRNAs, leading
matic classification. An approach to the exploration of these characteris-
to results largely consistent with the
extracting information on the 10 key tics in cancer research will serve to
search terms used here: 43% (12 of
28) of the agents evaluated by these characteristics of human carcinogens define their utility more fully. Equally
authors demonstrated evidence of would be to apply these machine important is to consider the nature
epigenetic alterations, similar to the learning techniques and biomedical of the evidence needed to establish
38% (33 of 86) of agents included in text mining methods to identify, in an that specific mechanistic charac-
the present analysis. Continued ex- automated fashion, articles associ- teristics are associated with human
perience with the evaluation of the ating these key characteristics with carcinogens. The current database
10 key characteristics of human car- specific Group 1 agents. Because has relied on the demonstration of
cinogens can be expected to further of the sheer size of a full systemat- certain toxicological end-points as
refine the criteria used for their iden- ic review of mechanistic information evidence of these mechanistic char-
tification, including both the toxico- on all Group 1 agents, the use of acteristics; further consideration of
logical events associated with these automated search algorithms of this these and other possible markers
key characteristics and the assays type could offer considerable effi- of the key characteristics of human
used as evidence of these events. ciency gains in identifying potentially carcinogens is warranted.
280
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annex 1.
evaluations of agents that may in- (IARC, 2006). The reviews and eval- nience, Volume 100 was organized
crease the risk of cancer in humans. uations are published as the IARC in six parts (100A–100F), covering
The reviews of the relevant literature Monographs on the Evaluation of pharmaceuticals (IARC, 2012e);
and the ensuing evaluations are Carcinogenic Risks to Humans. biological agents (IARC, 2012b);
Annex 1. Development of a data set on tumours and tumour sites in humans and in experimental
animals for Group 1 agents identified up to and including Volume 109 of the IARC Monographs
283
arsenic, metals, fibres, and dusts what level of concordance may exist become less reliable or impossible.
(IARC, 2012a); radiation (IARC, between humans and experimen- Therefore, although the data set
2012f); personal habits and indoor tal animals with respect to tumours described in this Annex (Table A1;
combustions (IARC, 2012d); and and tumour sites. To this end, the online only; available from: http://
chemical agents and related occu- pertinent information in Volume 100 publications.iarc.fr/578) provides in-
pations (IARC, 2012c).The reviews was captured in a comprehensive ta- formation on all the Group 1 agents,
and analyses were discussed dur- ble (Table A1; online only; available the actual database of human carcin-
ing a two-part Workshop on Tumour from: http://publications.iarc.fr/578) ogens eligible for the concordance
Site Concordance and Mechanisms that could then serve as a basis to analysis is appreciably smaller (see
of Carcinogenesis, which was con- develop a database on tumour sites Chapter 21, by Krewski et al.).
vened by IARC on 16–18 April 2012 in animals and humans. The creation
and 28–30 November 2012 in Lyon. of such a database – designed to be Methods
The data set described in this amenable to biostatistical analysis
In making an evaluation of the evi-
Annex also includes information on (see Chapter 21, by Krewski et al.)
dence of carcinogenicity to humans,
five additional human carcinogens – was motivated by the interest in a
an IARC Monographs Working
that were added to Group 1 after statistical assessment of the degree
Group is generally asked to identi-
completion of Volume 100, i.e. diesel of concordance between animal and
fy organ sites in humans for which
engine exhaust (Volume 105; IARC, human tumour sites. This important
there is sufficient evidence of carci-
2013), trichloroethylene (Volume scientific question bears upon the
nogenicity of the agent under study.
106; IARC, 2014), polychlorinated bi- extent to which the animal cancer
However, the Working Group is not
phenyls (Volume 107; IARC, 2016b), data collected here may be extrap-
required to identify organ sites for
and outdoor air pollution and partic- olated to humans. It is anticipated
carcinogenicity in experimental ani
ulate matter in outdoor air pollution that the database will also find other
mals at the time of the evaluation,
(Volume 109; IARC, 2016a). For applications, including in the devel-
but is required more simply to as-
ease of reference, these five agents opment of human tumour profiles to
sess the overall weight of the ev-
are included in an expanded group assist in the identification of addition- idence in experimental animals.
of chemical agents and related oc- al Group 1 agents. Consequently, for the purpose of this
cupations denoted by Volume 100F*. It should be noted that for agents IARC Scientific Publication, the spe-
Although additional Group 1 agents classified in Group 2A (probably car- cies-specific tumour sites in experi-
have been identified in subsequent cinogenic to humans) or Group 2B mental animals needed to be identi-
volumes of the Monographs, the (possibly carcinogenic to humans) fied for each Group 1 agent before
current data set extends only up to the information on cancer in humans proceeding to explore concordance
and including Volume 109, the last may often be lacking or may not be between animal and human cancers.
Monograph for which final results strong enough for a proper interspe- During the six meetings for
were available at the time this Annex cies comparison to be made. For this Volumes 100A–F, the respective
was completed. reason, the concordance analysis Working Groups identified studies in
The reviews and updates in (see Chapter 21, by Krewski et al.) is experimental animals that provided
Volumes 100A–F specifically fo- focused on agents in Group 1. In ad- results on species-specific tumour
cused on identification of tumours, dition, it was decided that sufficient sites. This was based on criteria
both in humans and in experimental evidence of carcinogenicity in hu- adapted from the Preamble to the
animals, resulting from exposure to mans and sufficient evidence of car- IARC Monographs. It was consid-
each of the Group 1 agents. In ad- cinogenicity in experimental animals ered that there is sufficient evidence
dition, the organs where the tumours were required for an agent to be in- for identifying a species-specific tu-
were reported to arise were docu- cluded in the statistical concordance mour site in experimental animals
mented where possible. The avail- analysis; with less than sufficient under any one of the following three
ability of this information on the more evidence of carcinogenicity, in hu- conditions:
than 100 human carcinogens in mans or in animals, the definition of • An increased incidence of mali-
Group 1 prompted an investigation of a tumour site in either species would gnant neoplasms or an appropriate
284
combination of benign and mali- Workshop participants to confirm the data set (see Table A1; online only;
gnant neoplasms originating from entries. Ultimately, more than 2000 available from: http://publications.
the same organ (or tissue) is iden- studies were reviewed, and more iarc.fr/578) but is not included in the
tified in two or more independent than 1000 of these contributed to the statistical analysis of concordance
studies in one species carried out at identification of species-specific tu- (see Chapter 21, by Krewski et al.).
different times or in different labora- mour sites in experimental animals. All the information on tumours
tories or under different protocols. Studies were not considered if any and tumour sites in humans and in
• An increased incidence of malig- one of the following exclusion de- experimental animals from IARC
nant neoplasms or an appropriate scriptors was applicable: Monographs Volumes 100–109 is
combination of benign and malig- • initiation–promotion studies; given in Table A1 (online only; avail-
nant neoplasms originating from • co-carcinogenicity studies; able from: http://publications.iarc.
the same organ (or tissue) is iden- • studies in genetically modified fr/578).
tified in both sexes of one species animals;
in one well-conducted study, ideally • studies with precancerous lesions Observations
performed under good laboratory as the outcome;
practice (GLP). For some Group 1 agents, there
• studies on the carcinogenicity of
• A single study in one species and were only a few studies that contrib-
metabolites and derivatives;
sex might be considered to provide uted to the identification of a tumour
• studies with non-laboratory animals
sufficient evidence for a specific site in experimental animals, and fre-
(livestock; companion animals);
organ site when malignant neo- quently the studies did not enable the
• studies with analogous agents
plasms occur to an unusual degree definition of an organ site, as a result
(similar chemical structure or simi-
with regard to incidence, type of tu- of inadequate reporting. There were
lar virus type).
mour, or age at onset. many instances where the reported
Confirmation of the tumours and tumour incidences were uninforma-
Results
tumour sites identified in Volume 100 tive, possibly as a result of the small
was performed by one member each Table A2 illustrates the format of number of animals tested. In other
from the IARC secretariat and from the data set on tumours and tumour cases, studies reported an increased
the project team at the University of sites, with one agent from each of incidence of tumours but without
Ottawa, Canada, who systematically Volumes 100A–F. From epidemio- mention of malignancy or proper de-
consulted the original publications logical studies, human tumour sites scription of histopathological details.
describing the studies cited in the with sufficient evidence and those Also, some reports did not specify
Volume 100 reviews. It was decided with limited evidence are mentioned. the purity of the administered agent.
by the Workshop participants that ex- For experimental animals, tumour In these cases the experts in the
traction of the following information sites are recorded only for agents that Monographs Working Groups and
was required for each study: spe- demonstrate sufficient evidence of the two team members (one mem-
cies, strain, sex, route of exposure, carcinogenicity, as indicated above. ber each from the IARC secretari-
and tumour site including histology. Strain, sex, and route of exposure at and from the project team at the
Further information would be record- reported for each animal study are University of Ottawa, Canada) had to
ed as “study details”, for example also captured. Comments are pro- consider the possibility of confound-
dose, number of test animals, num- vided as appropriate. For example, ing, because the existence of other
ber of control animals, age at start no human tumour site is specified for agents in the administered sample
of exposure, duration of exposure, aristolochic acid, because this agent could have contributed to the out-
duration of follow-up, and statistical was placed in Group 1 on the basis of come. In some studies, animals were
analyses. The two team members the classification of plants containing followed up for only short periods of
independently captured the informa- aristolochic acid as a Group 1 agent, time after treatment, especially in
ANNEX 1
tion, and any disagreements were re- supported by mechanistic data on studies investigating acute adverse
solved in a group discussion. Tables genotoxicity (IARC, 2012e). Together effects, which precluded observation
summarizing this information were with other “mechanistic upgrades”, of carcinogenic outcomes that may
created to enable peer review by the this agent is listed in the complete take longer to develop.
Annex 1. Development of a data set on tumours and tumour sites in humans and in experimental 285
animals for Group 1 agents identified up to and including Volume 109 of the IARC Monographs
Table A2. Template for presentation of data on tumours and tumour sites in humans and in experimental animals from the IARC Monographs
286
Volume Agent Sites with Sites Agent Species Histology Study, sex, strain, Comments
100 part sufficient evidence with tested in Site exposure route
Agent in humans limited experimental
number evidence animals
in
humans
A Aristolochic Aristolochic Rat Squamous cell Mengs et al. (1982) (Volume The experts consider
1 acid acid Forestomach carcinoma 82; Volume 100A), MF, concordance when an
Wistar, g.; Mengs (1983) agent in humans such
(Volume 82; Volume 100A), as Plants containing
M, Wistar, g.; Schmeiser aristolochic acid is tested
et al. (1990) (Volume 100A), in animals by one of its
M, Wistar, d.w.; Hwang et al. main components such
(2006) (Volume 100A), M, as Aristolochic acid.
Sprague-Dawley, g.
A Aristolochic Aristolochic Rat Transitional Mengs et al. (1982) (Volume The experts consider
1 acid acid Renal pelvis cell carcinoma 82; Volume 100A), M, concordance when an
Wistar, g. agent in humans such
as Plants containing
aristolochic acid is tested
in animals by one of its
main components such
as Aristolochic acid.
Volume Agent Sites with Sites Agent Species Histology Study, sex, strain, Comments
100 part sufficient evidence with tested in Site exposure route
Agent in humans limited experimental
number evidence animals
in
humans
C Arsenic and Lung, urinary Kidney, Dimethylarsinic Mouse Bronchiolo- DMA(V): Tokar
35 inorganic bladder, skin liver, acid [DMA(V)], Lung alveolar et al. (2012a), M, CD1, d.w.;
arsenic prostate Monomethyl- carcinoma Sodium arsenite: Waalkes
compounds arsonous acid et al. (2003), F, C3H/HeNCr,
[MMA(III)], in utero; Waalkes et al.
Sodium (2006a, b), M, CD1, in utero;
arsenite Tokar et al. (2011), MF,
CD1, in utero + p.o.; Tokar
et al. (2012a), M, CD1, in
utero; MMA(III): Tokar et al.
(2012b), M, CD1, in utero
C Arsenic and Lung, urinary Kidney, Sodium Mouse Hepatocellular Sodium arsenite: Waalkes
35 inorganic bladder, skin liver, arsenite, Liver carcinoma et al. (2003), M, C3H/HeNCr,
arsenic prostate Monomethyl- in utero; Waalkes et al.
compounds arsonous acid (2004a), M, C3H/HeNCr, in
[MMA(III)] utero; Waalkes et al. (2006a,
b), M, CD1, in utero; Tokar
et al. (2011), MF, CD1, in
utero + p.o.; Tokar et al.
(2012a), M, CD1, in utero;
MMAIII: Tokar et al. (2012b),
M, CD1, in utero
C Arsenic and Lung, urinary Kidney, Dimethylarsinic Rat Transitional Wei et al. (1999, 2002), M,
35 inorganic bladder, skin liver, acid [DMA(V)] Urinary cell carcinoma F344/DuCrj, p.o.; Arnold
arsenic prostate bladder et al. (2006), F, F344, p.o.
compounds
animals for Group 1 agents identified up to and including Volume 109 of the IARC Monographs
Annex 1. Development of a data set on tumours and tumour sites in humans and in experimental
Sr-90
287
ANNEX 1
Table A2. Template for presentation of data on tumours and tumour sites in humans and in experimental animals from the IARC Monographs (continued)
288
Volume Agent Sites with Sites Agent Species Histology Study, sex, strain, Comments
100 part sufficient evidence with tested in Site exposure route
Agent in humans limited experimental
number evidence animals
in
humans
D Fission Solid cancers, Sr-90 Dog Osteosarcoma Gillett et al. (1992), MF,
45 products leukaemia Bone beagle, i.v.; White et al.
including (1993), MF, beagle, p.o.;
Sr-90 Gillett et al. (1987), MF,
beagle, inh.
b.pouch, buccal pouch; d.w., drinking water; F, positive female; g., gavage; i.col., intracolonic; i.f., intrafetal; i.m., intramuscular; i.mam., intramammary; inh., inhalation; i.p., intraperitoneal;
i.pulmo., intrapulmonary; i.t., intratracheal; i.v., intravenous; M, positive male; MF, positive male and female; NR, not reported; per., perinatal; p.o., feeding; s.c., subcutaneous; skin, skin
application.
Conclusions addressing the important scientific of Yann Grosse at IARC during the
question, i.e. to which extent these summers of 2011 and 2012. Mélissa
The data set developed here to de- animal cancer data are comparable Billard also contributed to the devel-
fine tumour sites for carcinogeni- with human cancer data. The value opment of the data set while working
city in humans and in experimental of this data set is demonstrated by as a Visiting Scientist at IARC during
animals summarizes all available the initial concordance analyses that the summers of 2013 and 2014 un-
data on Group 1 agents identified have been conducted with the data- der the direction of Robert Baan and
in Volumes 100–109 of the IARC base derived from it (see Chapter 21, Yann Grosse. Daniel Krewski is the
Monographs. At the time of com- by Krewski et al.). Natural Sciences and Engineering
pletion of Volume 109, a total of 111 Research Council of Canada Chair
Group 1 agents had been identified, Acknowledgements in Risk Science at the University of
and these are included in the list Ottawa.
presented in Table A1 (online only; Pascale Lajoie assembled the data
available from: http://publications. set on tumours and tumour sites
iarc.fr/578). This comprehensive set presented here while working as a
of data constitutes a unique basis for Visiting Scientist under the direction
ANNEX 1
Annex 1. Development of a data set on tumours and tumour sites in humans and in experimental 289
animals for Group 1 agents identified up to and including Volume 109 of the IARC Monographs
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Disclosures of interests
Each participant was asked to Mélissa Billard’s travel expenses Association regarding the listing of
disclose pertinent research, employ- to attend the Workshop were paid by glass wool fibres in the 12th Report
ment, and financial interests. Current the R. Samuel McLaughlin Centre for on Carcinogens.
financial interests and research and Population Health Risk Assessment,
employment interests during the past where she was a master’s student. Agnes B. Kane received re-
4 years or anticipated in the future are search support from the Gulf of
identified here. Minor pertinent inter- Michael Bird is retired from Exxon Mexico Research Initiative (funded
ests are not listed and include stock Mobil Biomedical Sciences Inc. and by BP) to investigate remediation
valued at no more than US$ 1000 receives a pension and holds sig- of deep water oil spills, and from
overall, grants that provide no more nificant stock from the company. He Unilever to Brown University to de-
than 5% of the research budget of has an affiliate appointment with the velop predictive toxicity testing for
the participant’s organization and R. Samuel McLaughlin Centre for engineered nanomaterials.
that do not support the participant’s Population Health Risk Assessment,
research or position, and consulting which also paid for his travel expens- Robert J. Kavlock’s research
or speaking on matters not before es to attend the Workshop. unit receives research support
a court or government agency that from L’Oréal for the United States
does not exceed 2% of total pro- Bernard D. Goldstein is a Environmental Protection Agency’s
fessional time or compensation. All member of the Dow Chemical Toxicity Forecaster (ToxCast).
grants that support the participant’s Sustainability External Advisory
research or position and all consult- Committee. Daniel Krewski holds a Natural
ing or speaking on behalf of an inter- Sciences and Engineering Research
ested party on matters before a court Charles William Jameson Council (NSERC) of Canada
or government agency are listed as serves as a consultant for the North Industrial Research Chair in Risk
significant pertinent interests. American Insulation Manufacturers Science at the University of Ottawa.
292
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ISBN 978-92-832-2215-6